Posts Tagged ‘cancer immunotherapeutics’

Advent of genomics have revolutionized how we diagnose and treat lung cancer
We are currently needing to understand the driver mutations and variants where we can personalize therapy
PD-L1 and other checkpoint therapy have not really been used in pediatric cancers even though CAR-T have been successful
The incidence rates and mortality rates of pediatric cancers are rising
Large scale study of over 700 pediatric cancers show cancers driven by epigenetic drivers or fusion proteins. Need for transcriptomics. Also study demonstrated that we have underestimated germ line mutations and hereditary factors.
They put together a database to nominate patients on their IGM Cancer protocol. Involves genetic counseling and obtaining germ line samples to determine hereditary factors. RNA and protein are evaluated as well as exome sequencing. RNASeq and Archer Dx test to identify driver fusions
PECAN curated database from St. Jude used to determine driver mutations. They use multiple databases and overlap within these databases and knowledge base to determine or weed out false positives
They have used these studies to understand the immune infiltrate into recurrent cancers (CytoCure)
They found 40 germline cancer predisposition genes, 47 driver somatic fusion proteins, 81 potential actionable targets, 106 CNV, 196 meaningful somatic driver mutations

Tuesday, June 23

12:00 PM – 12:30 PM EDT

Awards and Lectures

NCI Director’s Address

Norman E Sharpless, Elaine R Mardis

DETAILS

Introduction: Elaine Mardis

NCI Director Address: Norman E Sharpless

They are functioning well at NCI with respect to grant reviews, research, and general functions in spite of the COVID pandemic and the massive demonstrations on also focusing on the disparities which occur in cancer research field and cancer care
There are ongoing efforts at NCI to make a positive difference in racial injustice, diversity in the cancer workforce, and for patients as well
Need a diverse workforce across the cancer research and care spectrum
Data show that areas where the clinicians are successful in putting African Americans on clinical trials are areas (geographic and site specific) where health disparities are narrowing
Grants through NCI new SeroNet for COVID-19 serologic testing funded by two RFAs through NIAD (RFA-CA-30-038 and RFA-CA-20-039) and will close on July 22, 2020

Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Immunology, Tumor Biology, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Tumor Immunology and Immunotherapy for Nonimmunologists: Innovation and Discovery in Immune-Oncology

This educational session will update cancer researchers and clinicians about the latest developments in the detailed understanding of the types and roles of immune cells in tumors. It will summarize current knowledge about the types of T cells, natural killer cells, B cells, and myeloid cells in tumors and discuss current knowledge about the roles these cells play in the antitumor immune response. The session will feature some of the most promising up-and-coming cancer immunologists who will inform about their latest strategies to harness the immune system to promote more effective therapies.

Judith A Varner, Yuliya Pylayeva-Gupta

Introduction

Judith A Varner

New techniques reveal critical roles of myeloid cells in tumor development and progression

Different type of cells are becoming targets for immune checkpoint like myeloid cells
In T cell excluded or desert tumors T cells are held at periphery so myeloid cells can infiltrate though so macrophages might be effective in these immune t cell naïve tumors, macrophages are most abundant types of immune cells in tumors
CXCLs are potential targets
PI3K delta inhibitors,
Reduce the infiltrate of myeloid tumor suppressor cells like macrophages
When should we give myeloid or T cell therapy is the issue

Judith A Varner

Novel strategies to harness T-cell biology for cancer therapy

Positive and negative roles of B cells in cancer

Yuliya Pylayeva-Gupta

New approaches in cancer immunotherapy: Programming bacteria to induce systemic antitumor immunity

Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Cancer Chemistry

Chemistry to the Clinic: Part 2: Irreversible Inhibitors as Potential Anticancer Agents

There are numerous examples of highly successful covalent drugs such as aspirin and penicillin that have been in use for a long period of time. Despite historical success, there was a period of reluctance among many to purse covalent drugs based on concerns about toxicity. With advances in understanding features of a well-designed covalent drug, new techniques to discover and characterize covalent inhibitors, and clinical success of new covalent cancer drugs in recent years, there is renewed interest in covalent compounds. This session will provide a broad look at covalent probe compounds and drug development, including a historical perspective, examination of warheads and electrophilic amino acids, the role of chemoproteomics, and case studies.

Benjamin F Cravatt, Richard A. Ward, Sara J Buhrlage

Discovering and optimizing covalent small-molecule ligands by chemical proteomics

Benjamin F Cravatt

Multiple approaches are being investigated to find new covalent inhibitors such as: 1) cysteine reactivity mapping, 2) mapping cysteine ligandability, 3) and functional screening in phenotypic assays for electrophilic compounds
Using fluorescent activity probes in proteomic screens; have broad useability in the proteome but can be specific
They screened quiescent versus stimulated T cells to determine reactive cysteines in a phenotypic screen and analyzed by MS proteomics (cysteine reactivity profiling); can quantitate 15000 to 20,000 reactive cysteines
Isocitrate dehydrogenase 1 and adapter protein LCP-1 are two examples of changes in reactive cysteines they have seen using this method
They use scout molecules to target ligands or proteins with reactive cysteines
For phenotypic screens they first use a cytotoxic assay to screen out toxic compounds which just kill cells without causing T cell activation (like IL10 secretion)
INTERESTINGLY coupling these MS reactive cysteine screens with phenotypic screens you can find NONCANONICAL mechanisms of many of these target proteins (many of the compounds found targets which were not predicted or known)

Electrophilic warheads and nucleophilic amino acids: A chemical and computational perspective on covalent modifier

The covalent targeting of cysteine residues in drug discovery and its application to the discovery of Osimertinib

Richard A. Ward

Cysteine activation: thiolate form of cysteine is a strong nucleophile
Thiolate form preferred in polar environment
Activation can be assisted by neighboring residues; pKA will have an effect on deprotonation
pKas of cysteine vary in EGFR
cysteine that are too reactive give toxicity while not reactive enough are ineffective

Accelerating drug discovery with lysine-targeted covalent probes

Tuesday, June 23

12:45 PM – 2:15 PM EDT

Virtual Educational Session

Molecular and Cellular Biology/Genetics

Virtual Educational Session

Tumor Biology, Immunology

Metabolism and Tumor Microenvironment

This Educational Session aims to guide discussion on the heterogeneous cells and metabolism in the tumor microenvironment. It is now clear that the diversity of cells in tumors each require distinct metabolic programs to survive and proliferate. Tumors, however, are genetically programmed for high rates of metabolism and can present a metabolically hostile environment in which nutrient competition and hypoxia can limit antitumor immunity.

Jeffrey C Rathmell, Lydia Lynch, Mara H Sherman, Greg M Delgoffe

T-cell metabolism and metabolic reprogramming antitumor immunity

Jeffrey C Rathmell

Introduction

Jeffrey C Rathmell

Metabolic functions of cancer-associated fibroblasts

Mara H Sherman

Tumor microenvironment metabolism and its effects on antitumor immunity and immunotherapeutic response

Greg M Delgoffe

Multiple metabolites, reactive oxygen species within the tumor microenvironment; is there heterogeneity within the TME metabolome which can predict their ability to be immunosensitive
Took melanoma cells and looked at metabolism using Seahorse (glycolysis): and there was vast heterogeneity in melanoma tumor cells; some just do oxphos and no glycolytic metabolism (inverse Warburg)
As they profiled whole tumors they could separate out the metabolism of each cell type within the tumor and could look at T cells versus stromal CAFs or tumor cells and characterized cells as indolent or metabolic
T cells from hyerglycolytic tumors were fine but from high glycolysis the T cells were more indolent
When knock down glucose transporter the cells become more glycolytic
If patient had high oxidative metabolism had low PDL1 sensitivity
Showed this result in head and neck cancer as well
Metformin a complex 1 inhibitor which is not as toxic as most mito oxphos inhibitors the T cells have less hypoxia and can remodel the TME and stimulate the immune response
Metformin now in clinical trials
T cells though seem metabolically restricted; T cells that infiltrate tumors are low mitochondrial phosph cells
T cells from tumors have defective mitochondria or little respiratory capacity
They have some preliminary findings that metabolic inhibitors may help with CAR-T therapy

Obesity, lipids and suppression of anti-tumor immunity

Lydia Lynch

Hypothesis: obesity causes issues with anti tumor immunity
Less NK cells in obese people; also produce less IFN gamma
RNASeq on NOD mice; granzymes and perforins at top of list of obese downregulated
Upregulated genes that were upregulated involved in lipid metabolism
All were PPAR target genes
NK cells from obese patients takes up palmitate and this reduces their glycolysis but OXPHOS also reduced; they think increased FFA basically overloads mitochondria
PPAR alpha gamma activation mimics obesity

Tuesday, June 23

12:45 PM – 2:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials

The Evolving Role of the Pathologist in Cancer Research

Long recognized for their role in cancer diagnosis and prognostication, pathologists are beginning to leverage a variety of digital imaging technologies and computational tools to improve both clinical practice and cancer research. Remarkably, the emergence of artificial intelligence (AI) and machine learning algorithms for analyzing pathology specimens is poised to not only augment the resolution and accuracy of clinical diagnosis, but also fundamentally transform the role of the pathologist in cancer science and precision oncology. This session will discuss what pathologists are currently able to achieve with these new technologies, present their challenges and barriers, and overview their future possibilities in cancer diagnosis and research. The session will also include discussions of what is practical and doable in the clinic for diagnostic and clinical oncology in comparison to technologies and approaches primarily utilized to accelerate cancer research.

Jorge S Reis-Filho, Thomas J Fuchs, David L Rimm, Jayanta Debnath

DETAILS

Tuesday, June 23

12:45 PM – 2:45 PM EDT

High-dimensional imaging technologies in cancer research

David L Rimm

Using old methods and new methods; so cell counting you use to find the cells then phenotype; with quantification like with Aqua use densitometry of positive signal to determine a threshold to determine presence of a cell for counting
Hiplex versus multiplex imaging where you have ten channels to measure by cycling of flour on antibody (can get up to 20plex)
Hiplex can be coupled with Mass spectrometry (Imaging Mass spectrometry, based on heavy metal tags on mAbs)
However it will still take a trained pathologist to define regions of interest or field of desired view

Introduction

Jayanta Debnath

Challenges and barriers of implementing AI tools for cancer diagnostics

Jorge S Reis-Filho

Implementing robust digital pathology workflows into clinical practice and cancer research

Jayanta Debnath

Invited Speaker

Thomas J Fuchs

Founder of spinout of Memorial Sloan Kettering
Separates AI from computational algothimic
Dealing with not just machines but integrating human intelligence
Making decision for the patients must involve human decision making as well
How do we get experts to do these decisions faster
AI in pathology: what is difficult? =è sandbox scenarios where machines are great,; curated datasets; human decision support systems or maps; or try to predict nature
1) learn rules made by humans; human to human scenario 2)constrained nature 3)unconstrained nature like images and or behavior 4) predict nature response to nature response to itself
In sandbox scenario the rules are set in stone and machines are great like chess playing
In second scenario can train computer to predict what a human would predict
So third scenario is like driving cars
System on constrained nature or constrained dataset will take a long time for commuter to get to decision
Fourth category is long term data collection project
He is finding it is still finding it is still is difficult to predict nature so going from clinical finding to prognosis still does not have good predictability with AI alone; need for human involvement
End to end partnering (EPL) is a new way where humans can get more involved with the algorithm and assist with the problem of constrained data
An example of a workflow for pathology would be as follows from Campanella et al 2019 Nature Medicine: obtain digital images (they digitized a million slides), train a massive data set with highthroughput computing (needed a lot of time and big software developing effort), and then train it using input be the best expert pathologists (nature to human and unconstrained because no data curation done)
Led to first clinically grade machine learning system (Camelyon16 was the challenge for detecting metastatic cells in lymph tissue; tested on 12,000 patients from 45 countries)
The first big hurdle was moving from manually annotated slides (which was a big bottleneck) to automatically extracted data from path reports).
Now problem is in prediction: How can we bridge the gap from predicting humans to predicting nature?
With an AI system pathologist drastically improved the ability to detect very small lesions

Virtual Educational Session

Epidemiology

Cancer Increases in Younger Populations: Where Are They Coming from?

Incidence rates of several cancers (e.g., colorectal, pancreatic, and breast cancers) are rising in younger populations, which contrasts with either declining or more slowly rising incidence in older populations. Early-onset cancers are also more aggressive and have different tumor characteristics than those in older populations. Evidence on risk factors and contributors to early-onset cancers is emerging. In this Educational Session, the trends and burden, potential causes, risk factors, and tumor characteristics of early-onset cancers will be covered. Presenters will focus on colorectal and breast cancer, which are among the most common causes of cancer deaths in younger people. Potential mechanisms of early-onset cancers and racial/ethnic differences will also be discussed.

Stacey A. Fedewa, Xavier Llor, Pepper Jo Schedin, Yin Cao

Cancers that are and are not increasing in younger populations

Stacey A. Fedewa

Early onset cancers, pediatric cancers and colon cancers are increasing in younger adults
Younger people are more likely to be uninsured and these are there most productive years so it is a horrible life event for a young adult to be diagnosed with cancer. They will have more financial hardship and most (70%) of the young adults with cancer have had financial difficulties. It is very hard for women as they are on their childbearing years so additional stress
Types of early onset cancer varies by age as well as geographic locations. For example in 20s thyroid cancer is more common but in 30s it is breast cancer. Colorectal and testicular most common in US.
SCC is decreasing by adenocarcinoma of the cervix is increasing in women’s 40s, potentially due to changing sexual behaviors
Breast cancer is increasing in younger women: maybe etiologic distinct like triple negative and larger racial disparities in younger African American women
Increased obesity among younger people is becoming a factor in this increasing incidence of early onset cancers

Press Coverage

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Drugging Undrugged Cancer Targets 1:30 pm – 5:00 pm

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, Immunotherapy, Modulating Macrophages in Cancer Immunotherapy, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, tumor microenvironment, tagged #endcancer, AACR, American Association for Cancer Research, cancer conference, cancer immunotherapeutics, coupled with MTOR, immune checkpoint, MEK inhibition, mTOR, real time conference coverage, Resistance to MEK inhibitors on April 27, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Drugging Undrugged Cancer Targets 1:30 pm – 5:00 pm

SESSION VMS.ET01.01 – Drugging Undrugged Cancer Targets

April 27, 2020, 1:30 PM – 3:30 PM
Virtual Meeting: All Session Times Are U.S. EDT

Session Type
Virtual Minisymposium
Track(s)
Experimental and Molecular Therapeutics,Drug Development
18 Presentations
1:30 PM – 1:30 PM
– ChairpersonPeter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA

1:30 PM – 1:30 PM
– ChairpersonJohn S. Lazo. University of Virginia, Charlottesville, VA

1:30 PM – 1:35 PM
– IntroductionPeter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA

1:35 PM – 1:45 PM
3398 – PTPN22 is a systemic target for augmenting antitumor immunityWon Jin Ho, Jianping Lin, Ludmila Danilova, Zaw Phyo, Soren Charmsaz, Aditya Mohan, Todd Armstrong, Ben H. Park, Elana J. Fertig, Zhong-Yin Zhang, Elizabeth M. Jaffee. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD, Purdue University, Baltimore, MD, Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD, Vanderbilt University Medical Center, Baltimore, MD

Abstract: Remarkable progress in cancer immunology has revolutionized cancer therapy. The majority of patients, however, do not respond to immunotherapeutic options, warranting the ongoing search for better strategies. Leveraging the established role of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in autoimmune diseases, we hypothesized that PTPN22 is a novel target for cancer immunotherapy. PTPN22 is a physiologic regulator of T cell receptor (TCR) signaling acting by dephosphorylating activating tyrosine residues in Lck and Zap70. We first confirmed the relevance of PTPN22 expression by exploring its expression in multiple human cancer types using The Cancer Genome Atlas (TCGA). PTPN22 expression positively correlated with T cell and M1 macrophage gene signatures and immune regulatory genes, especially inflamed tumor types. Next, we directly investigated the role of PTPN22 in antitumor immunity by comparing in vivo tumor characteristics in wild-type (WT) and PTPN22 knockout (KO) mice. Consistent with our hypothesis, PTPN22 KO mice resisted MC38 and EG7 tumors significantly compared with WT. Mass cytometry (CyTOF) profiling of the immune tumor microenvironment demonstrated that MC38 tumors in PTPN22 KO mice were infiltrated with greater numbers of T cells, particularly CD8+ T cells expressing granzyme B and PD1. To further delineate the effects of PTPN22 KO on TCR signaling, we established an optimized CyTOF panel of 9 phosphorylation sites involved in the TCR signaling pathway, including two enzymatic substrates of PTPN22 (Lck Y394 and Zap70 Y493) and 15 immune subtyping markers. CyTOF phospho-profiling of CD8 T cells from tumor-bearing mouse spleens and the peripheral blood of immunotherapy-naïve cancer patients showed that the phosphorylated state of Zap70 Y493 correlated strongly with granzyme B expression. Furthermore, phospho-profiling of tumor-infiltrating CD8+ T cells (a measure of T cell activation) revealed the highest TCR-pathway phosphorylation levels in memory CD8+ T cells that express PD1. The difference in phosphorylation levels between WT and PTPN22 KO was most pronounced for Lck Y394. Based on these findings, we then hypothesized that PD1 inhibition will further enhance the antitumor immune responses promoted by the lack of PTPN22. Indeed, PTPN22 KO mice bearing MC38 and EG7 tumors responded more significantly to anti-PD1 therapy when compared with tumor-bearing WT mice. Finally, we treated WT tumor bearing mice with two different small molecule inhibitors of PTPN22, one previously published compound, LTV1, and one novel compound, L1 (discovered through structure based synthesis). While both inhibitors phenocopied the PTPN22 KO mice in resisting MC38 tumor growth, L1 treatment gave an immune profile that resembled what was observed in tumor-bearing PTPN22 KO mice. Taken together, our results demonstrate that PTPN22 is a novel systemic target for augmenting antitumor immunity.

can they leverage autoimmune data to look at new targets for checkpoint inhibition; we have a long way to go in immunooncology as only less than 30-40% of cancer types respond
using Cancer Genome Atlas PTPN22 is associated with autoimmune disorders
PTPN22 KO increases many immune cells; macrophages t-cells and when KO in tumors get more t cell infiltrate
PTP KO enhances t cell response, and may be driving t cells to exhaustion
made a inhibitor or PTPN22; antitumor phenotype when given inhibitor was like KO mice; a PDL1 inhibitor worked in KO mice
PTPN22 only in select hematopoetic cells

1:45 PM – 1:50 PM
– Discussion

1:50 PM – 2:00 PM
3399 – Preclinical evaluation of eFT226, a potent and selective eIF4A inhibitor with anti-tumor activity in FGFR1,2 and HER2 driven cancers. Peggy A. Thompson, Nathan P. Young, Adina Gerson-Gurwitz, Boreth Eam, Vikas Goel, Craig R. Stumpf, Joan Chen, Gregory S. Parker, Sarah Fish, Maria Barrera, Eric Sung, Jocelyn Staunton, Gary G. Chiang, Kevin R. Webster. eFFECTOR Therapeutics, San Diego, CA @RuggeroDavide

Abstract: Mutations or amplifications affecting receptor tyrosine kinases (RTKs) activate the RAS/MAPK and PI3K/AKT signaling pathways thereby promoting cancer cell proliferation and survival. Oncoprotein expression is tightly controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex consisting of eIF4A, eIF4E, and eIF4G. eIF4A functions to catalyze the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA facilitating ribosome scanning and translation initiation. The activation of oncogenic signaling pathways, including RAS and PI3K, facilitate formation of eIF4F and enhance eIF4A activity promoting the translation of oncogenes with highly structured 5’-UTRs that are required for tumor cell proliferation, survival and metastasis. eFT226 is a selective eIF4A inhibitor that converts eIF4A into a sequence specific translational repressor by increasing the affinity between eIF4A and 5’-UTR polypurine motifs leading to selective downregulation of mRNA translation. The polypurine element is highly enriched in the 5’-UTR of eFT226 target genes, many of which are known oncogenic drivers, including FGFR1,2 and HER2, enabling eFT226 to selectively inhibit dysregulated oncogene expression. Formation of a ternary complex [eIF4A-eFT226-mRNA] blocks ribosome scanning along the 5’-UTR leading to dose dependent inhibition of RTK protein expression. The 5’-UTR sequence dependency of eFT226 translational inhibition was evaluated in cell-based reporter assays demonstrating 10-45-fold greater sensitivity for reporter constructs containing an RTK 5’-UTR compared to a control. In solid tumor cell lines driven by alterations in FGFR1, FGFR2 or HER2, downregulation of RTK expression by eFT226 resulted in decreased MAPK and AKT signaling, potent inhibition of cell proliferation and an induction of apoptosis suggesting that eFT226 could be effective in treating tumor types dependent on these oncogenic drivers. Solid tumor xenograft models harboring FGFR1,2 or HER2 amplifications treated with eFT226 resulted in significant in vivo tumor growth inhibition and regression at well tolerated doses in breast, non-small cell lung and colorectal cancer models. Treatment with eFT226 also decreased RTK protein levels supporting the potential to use these eFT226 target genes as pharmacodynamic markers of target engagement. Further evaluation of predictive markers of sensitivity or resistance showed that RTK tumor models with mTOR mediated activation of eIF4A are most sensitive to eFT226. The association of eFT226 activity in RTK tumor models with mTOR pathway activation provides a means to further enrich for sensitive patient subsets during clinical development. Clinical trials with eFT226 in patients with solid tumor malignancies have initiated.

ternary complex formed blocks transcription selectively downregulating RTKs
drug binds in 5′ UTR and inhibits translation
RTKs activate eIF4 and are also transcribed through them so inhibition destroys this loop; also with KRAS too
main antitumor activity are by an apoptotic mechanisms; refractory tumors are not sensitive to drug induced apoptosis
drug inhibits FGFR2 in colorectal cancer
drug also effective in HER2+ tumors
mTOR mediated eIF4 inhibited by drug
they get prolonged antitumor activity after washout of drug because forms this tight terniary complex

2:00 PM – 2:05 PM
– Discussion

2:05 PM – 2:15 PM
3400 – Adenosine receptor antagonists exhibit potent and selective off-target killing of FOXA1-high cancers: Steven M. Corsello, Ryan D. Spangler, Ranad Humeidi, Caitlin N. Harrington, Rohith T. Nagari, Ritu Singh, Vickie Wang, Mustafa Kocak, Jordan Rossen, Amael Madec, Nancy Dumont, Todd R. Golub. Dana-Farber Cancer Institute, Boston, MA, Broad Institute of MIT and Harvard, Cambridge, MA @corsellos

Abstract: Drugs targeting adenosine receptors were originally developed for the treatment of Parkinson’s disease and are now being tested in immuno-oncology clinical trials in combination with checkpoint inhibitors. We recently reported the killing activity of 4,518 drugs against 578 diverse cancer cell lines determined using the PRISM molecular barcoding approach. Surprisingly, three established adenosine receptor antagonists (CGS-15943, MRS-1220, and SCH-58261) showed potent and selective killing of FOXA1-high cancer cell lines without the need for immune cells. FOXA1 is a lineage-restricted transcription factor in luminal breast cancer, hepatocellular carcinoma, and prostate cancer without known small molecule inhibitors. We find that cytotoxic activity is limited to adenosine antagonists with a three-member aromatic core bound to a furan group, thus indicating a potential off-target mechanism of action. To identify genomic modulators of drug response, we performed genome-wide CRISPR/Cas9 knockout modifier screens. Killing by CGS-15943 and MRS-1220 was rescued by knockout of the aryl hydrocarbon receptor (AHR) and its nuclear partner ARNT. In confirmatory studies, knockout of AHR completely rescued killing by CGS-15943 in multiple cell types. Co-treatment with an AHR small molecule antagonist also rescued cell viability. Knockout of adenosine receptors did not alter drug response. Given that AHR is a known transcriptional regulator, we performed global mRNA sequencing to assess transcriptional changes induced by CGS-15943. The top two genes induced were the p450 enzymes CYP1A1 and CYP1B1. To determine sufficiency, we overexpressed CYP1A1 in a resistant cell line. Ectopic CYP1A1 expression sensitized to CGS-15943-mediated killing. Mass spectrometry revealed covalent trapping of a reactive metabolite by glutathione and potassium cyanide following in vitro incubation with liver microsomes. In addition, treatment of breast cancer cells with CGS-15943 for 24 hours resulted in increased γ-H2AX phosphorylation by western blot, indicative of DNA double stranded breaks. In summary, we identified off-target anti-cancer activity of multiple established adenosine receptor antagonists mediated by activation of AHR. Future studies will evaluate the functional contribution of FOXA1 and activity in vivo. Starting from a phenotypic screening hit, we leverage functional genomics to unlock the underlying mechanism of action. This project will pave the way for developing more effective therapies for biomarker-selected cancers, with potential to improve the care of patients with liver, breast, and prostate cancer.

developed a chemical library of over 6000 compounds (QC’d) to determine drugs that have antitumor effects
used a PRISM barcoded library to make cell lines to screen genotype-phenotype screens
for nononcology drugs fourteen drugs had activity in the PRISM assay
FOXA1 transcription factor high cancer cells seemed to be inhibited best with adenosine receptor inhibitor found in PRISM assay

2:15 PM – 2:20 PM
– Discussion

2:20 PM – 2:30 PM
3401 – Targeting lysosomal homeostasis in ovarian cancer through drug repurposing: Stefano Marastoni, Aleksandra Pesic, Sree Narayanan Nair, Zhu Juan Li, Ali Madani, Benjamin Haibe-Kains, Bradly G. Wouters, Anthony Joshua. University Health Network, Toronto, ON, Canada, Janssen Inc, Toronto, ON, Canada, The Kinghorn Cancer Centre, Sydney, Australia

Background: Drug repurposing has become increasingly attractive as it avoids the long processes and costs associated with drug discovery. Itraconazole (Itra) is a broad-spectrum anti-fungal agent which has an established broad spectrum of activity in human cell lines including cholesterol antagonism and inhibition of Hedgehog and mTOR pathways. Many in vitro, in vivo and clinical studies have suggested anti-proliferative activity both alone and in combination with other chemotherapeutic agents, in particular in ovarian cancer. This study is aimed at supporting the therapeutic potential of Itra and discovering and repurposing new drugs that can increase Itra anticancer activity as well as identifying new targets in the treatment of ovarian cancer.
Methods: We tested a panel of 32 ovarian cancer cell lines with different doses of Itra and identified a subset of cells which showed significant sensitivity to the drug. To identify genetic vulnerabilities and find new therapeutic targets to combine with Itra, we performed a whole genome sensitivity CRISPR screen in 2 cell lines (TOV1946 and OVCAR5) treated with non-toxic (IC10) concentrations of Itra.
Results: Pathway analysis on the top hits from both the screens showed a significant involvement of lysosomal compartments, and in particular dynamics between trans Golgi network and late endosomes/lysosomes, pathways that are affected by the autophagy inhibitor Chloroquine (CQ). We subsequently demonstrated that the combination of Itra and CQ had a synergistic effect in many ovarian cancer cell lines, even in those resistant to Itra. Further, genetic and pharmacological manipulation of autophagy indicated that upstream inhibition of autophagy is not a key mediator of the Itra/CQ mechanism of action. However, combination of Itra with other lysosomotropic agents (Concanamycin A, Bafilomycin A and Tamoxifen) displayed overlapping activity with Itra/CQ, supporting the lysosomal involvement in sensitizing cells to Itra resulted from the CRISPR screens. Analysis of lysosomal pattern and function showed a combined effect of Itra and CQ in targeting lysosomes and neutralizing their activity.
Conclusion: We identified two FDA approved drugs – CQ and Tamoxifen – that can be used in combination with Itra and exert a potent anti-tumor effect in ovarian cancer by affecting lyosomal function and suggesting a likely dependency of these cells on lysosomal biology. Further studies are in progress.

repurposing itraconozole in ovarian cancer potential mechanism of action is pleitropic
increasing doses of chloroquine caused OVCA cell death by accumulating in Golgi

2:30 PM – 2:35 PM
– Discussion

2:35 PM – 2:45 PM
3402 – BCAT1 as a druggable target in immuno-oncologyAdonia E. Papathanassiu, Francesca Lodi, Hagar Elkafrawy, Michelangelo Certo, Hong Vu, Jeong Hun Ko, Jacques Behmoaras, Claudio Mauro, Diether Lambrechts. Ergon Pharmaceuticals, Washington, DC, VIB Cancer Centre-KULeuven, Leuven, Belgium, Alexandria University, Alexandria, Egypt, University of Birmingham, Birmingham, United Kingdom, Ergon Pharmaceuticals, Washington, DC, Imperial College London, London, United Kingdom

2:45 PM – 2:50 PM
– Discussion

2:50 PM – 3:00 PM
3403 – Drugging the undruggable: Lessons learned from protein phosphatase 2A: Derek Taylor, Goutham Narla. Case Western Reserve University, Cleveland, OH, University of Michigan, Ann Arbor, MI @gouthamnarla

Abstract: Protein phosphatase 2A (PP2A) is a key tumor suppressor responsible for the dephosphorylation of many oncogenic signaling pathways. The PP2A holoenzyme is comprised of a scaffolding subunit (A), which serves as the structural platform for the catalytic subunit (C) and for an array of regulatory subunits (B) to assemble. Impairment of PP2A is essential for the pathogenesis of many diseases including cancer. In cancer, PP2A is inactivated through a variety of mechanisms including somatic mutation of the Aαsubunit. Our studies show that the most recurrent Aαmutation, P179R, results in an altered protein conformation which prevents the catalytic subunit from binding. Additionally, correcting this mutation, by expressing wild type PP2A Aαin cell lines harboring the P179R mutation, causes a reduction in tumor growth and metastasis. Given its central role in human disease pathogenesis, many strategies have been developed to therapeutically target PP2A.Our lab developed a series of small molecules activators of protein phosphatase 2A. One of our more advanced analogs in this series, DT-061, drives dephosphorylation and degradation of select pathogenic substrates of PP2A such as c-MYC in cellular and in vivo systems. Additionally, we have demonstrated the phosphomimetics of MYC that prevent PP2A mediated dephosphorylation and degradation markedly reduce the anti-tumorigenic activity of this series of PP2A activators further validating the target-substrate specificity of this approach. Specific mutations in the site of drug interaction or overexpression of the DNA tumor virus small T antigen which has been shown to specifically bind to and inactivate PP2A abrogate the in vivo activity of this small molecule series further validating the PP2A specificity of this approach. Importantly, treatment with DT-061 results in tumor growth inhibition in an array of in vivocancer models and marked regressions in combination with MEKi and PARPi.To further define the mechanism of action of this small molecule series, we have used cryo-electron microscopy (cryo-EM) to visualize directly theinteraction between DT-061 and a PP2A heterotrimeric complex. We have identified molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme through the marked prolongation of the kOFF of the native complex. Furthermore, we demonstrate that DT-061 specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate oncogenic targets such as c-MYC in both cellular and in vivo systems. This 3.6 Å structure identifies dynamic molecular interactions between the three distinct PP2A subunits and highlight the inherent mechanisms of PP2A complex assembly and disassembly in both cell free and cellular systems. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for the therapeutic targeting of previously undruggable proteins, and aid in the development of phosphatase-based therapeutics tailored against disease specific phosphor-protein targets. The marriage of multidisciplinary scientific practices has allowed us to present here a previously unrecognized therapeutic strategy of complex stabilization for the activation of endogenous disease combating enzymes.

Reactivating PP2A; dephosphorylation of proteins (serine/threonine phosphatases); regulates multiple processes in the cell
SV40T has an antigen that inactivates PP2A; recurrent mutations in high grade endometrial cancers
P179R mutation promotes uterine tumor formation (also in a distal tubule ligation model)
project started in a phenotypic screen that tricyclic antidepressants could have an off target which was phosphatase activators (uncoupling GPCR from anticancer activity)
small T antigen block the activity of these small molecule activators;
acts as a molecular glue to bring the activators with a heterotrimer of phosphatases
so their small molecule activators effective in triple negative breast cancers; one of targets of PP2A is MYC
question: have not yet seen resistance to these compounds but are currently looking at this

3:00 PM – 3:05 PM
– Discussion

3:05 PM – 3:15 PM
3404 – Inhibition of BCL10-MALT1 interaction to treat diffuse large B-cell lymphomaH: eejae Kang, Dong Hu, Marcelo Murai, Ahmed Mady, Bill Chen, Zaneta Nikolovska-Coleska, Linda M. McAllister-Lucas, Peter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA, Merck, Kenilworth, NJ, University of Michigan School of Medicine, Ann Arbor, MI, University of Pittsburgh School of Medicine, Pittsburgh, PA, University of Michigan School of Medicine, Ann Arbor, MI, UPMC Children’s Hospital, Pittsburgh, PA

Abstract: The CARMA1/BCL10/MALT1 (CBM) signaling complex mediates antigen receptor-induced activation of NF-kB in lymphocytes to support normal adaptive immunity. As the effector protein of the complex, MALT1 exhibits two activities: protease and scaffolding activities. Gain-of-function mutations in the CARMA1 moiety or its upstream regulators trigger antigen-independent assembly of oligomeric CBM complexes, leading to constitutive activation of MALT1, unregulated NF-kB activity, and development of Activated B-Cell subtype of Diffuse Large B-Cell Lymphoma (ABC-DLBCL). Existing MALT1 inhibitors block only MALT1 protease activity, causing incomplete and unbalanced inhibition of MALT1, and have the potential for inducing autoimmune side effects. Since MALT1 is recruited to the CBM complex via its interaction with BCL10, we sought to identify inhibitors of BCL10-MALT1 interaction in order to target both the protease and scaffolding activities of MALT1 to treat ABC-DLBCL.
Our previous work suggested that an antibody-epitope-like interface governs the interaction between BCL10 and MALT1, so that a therapeutic opportunity exists for developing a small molecule inhibitor of the interaction to terminate inappropriate CBM activity. Using co-immunoprecipitation studies, a mammalian two-hybrid system, and surface plasmon resonance (SPR), we confirmed that BCL10 residues 107-119 and the tandem Ig-like domains of MALT1 are critical for this interaction. We then performed a structure-guided in silico screen of 3 million compounds, based on a computational model of the BCL10-MALT1 interaction interface, to identify compounds with potential for disrupting the interaction.
Compound 1 from the initial screening hits showed dose-responsive inhibition of BCL10-MALT1 interaction in both SPR and ELISA-based assays. Functionally, Compound 1 inhibits both MALT1 protease and scaffolding activities in Jurkat T cells, as demonstrated by its inhibition of CD3/CD28-induced RelB and N4BP1 cleavage, and inhibition of IKK phosphorylation, respectively. Compound 1 also blocks IL-2 transcription and IL-2 secretion by PMA/ionomycin-treated Jurkat T cells, as well as constitutive CBM-dependent secretion of IL-6 and IL-10 by ABC-DLBCL cells. Accordingly, Compound 1 selectively suppresses the growth of ABC-DLBCL cell lines, but does not affect the growth of MALT1-independent GCB-DLBCL cell lines.
In conclusion, we have identified an early-stage small molecule compound that inhibits the BCL10-MALT1 interaction, MALT1 protease and scaffolding activities, downstream CBM-dependent signaling, and ABC-DLBCL cell growth. Structure-guided modification of this lead compound is underway to further develop a new class of protein-protein interaction inhibitors that could provide more efficacious blockade of MALT1, while offering protection from undesirable autoimmune side effects in the treatment of this aggressive form of lymphoma.

3:15 PM – 3:20 PM
– Discussion

3:20 PM – 3:30 PM
– Closing RemarksJohn S. Lazo. University of Virginia, Charlottesville, VA

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New Type of Killer T-cell

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, CAR-T, Cell Biology, tagged cancer immunotherapeutics, Cancer research, cancer therapeutics, HLA-like molecule, MR-1 restricted T-cells on January 28, 2020| Leave a Comment »

New Type of Killer T-Cell

Reporter: Irina Robu, PhD

Scientists at Cardiff University have revealed a new type of killer T-cell which offers hope of a “one-size-fits-all” cancer therapy. Cancer-targeting via MR1-restricted T-cells is a thrilling new frontier, it increases the prospect of a ‘one-size-fits-all’ cancer treatment; a single type of T-cell that could be proficient of destroying numerous different types of cancers across the population.

T-cell therapies for cancer anywhere immune cells are removed, modified and returned to the patient’s blood to seek and destroy cancer cells – are the latest paradigm in cancer treatments. The most extensively-used therapy, known as CAR-T (Chimeric Antigen Receptor T-cell therapy) encompasses genetic modification of patient’s autologous T-cells to express a CAR specific for a tumor antigen, subsequent by ex vivo cell expansion and re-infusion back to the patient. The therapy is personalized to each patient, but targets only a few types of cancers.

Currently, Cardiff academics discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognizes and kills most human cancer types, while ignoring healthy cells. This new TCR distinguishes when a molecule is present on the surface of a wide range of cancer cells and is able to distinguish between cancerous and healthy cells. Normal T-cells scans the surface of other cells to find anomalies and eliminate cancerous cells, yet ignores cells that contain only normal proteins.

The researchers at Cardiff was published in Nature Immunology, labels a unique TCR that can identify various types of cancer via a single HLA-like molecule called MR1 which varies in the human population. HLA differs extensively between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people. To investigate the therapeutic potential of these cells in vivo, the investigators injected T-cells able to identify MR1 into mice bearing human cancer and with a human immune system.

The Cardiff group were able to demonstrate that T-cells of melanoma patients modified to express this new TCR could destroy not only the patient’s own cancer cells, but also other patients’ cancer cells in the laboratory, irrespective of the patient’s HLA type. Experiments are under way to regulate the exact molecular mechanism by which the new TCR differentiates between healthy cells and cancer.

Source

https://www.eurekalert.org/pub_releases/2020-01/cu-don012020.php

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Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Immuno-Oncology & Genomics, Immunotherapy, RNA Biology, Cancer and Therapeutics, tagged and Moderna Therapeutics, breast cancer, cancer immunotherapeutics, cancer vaccine, Galena, Merck & Co., mRNA, mRNA vaccines on August 11, 2016| Leave a Comment »

Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?

Curator & Reporter: Stephen J. Williams, Ph.D.

UPDATED: 3/11/2023

Source: https://www.fiercebiotech.com/biotech/chasing-moderna-merck-pays-50m-join-race-develop-cancer-preventing-vaccine

Chasing Moderna, Merck pays $50M to join race to develop cancer-preventing vaccine

By Nick Paul TaylorMar 8, 2023 10:15am

Merck & Co.vaccine development Opko Health biobucks

Merck & Co. has joined the emerging race to develop an Epstein-Barr virus (EBV) vaccine, paying ModeX Therapeutics $50 million upfront and dangling $872.5 million in biobucks for global rights to a preclinical challenger to shots in clinical development at Moderna and the National Institutes of Health (NIH).

EBV infects most people at some point in their lives. Many people have no symptoms, but the virus can cause infectious mononucleosis, a condition associated with fatigue and fever as well as linked to a range of other diseases. Carried as an asymptomatic infection, the virus is associated with 200,000 cancer cases a year, and a paper published last year showed it greatly increases the risk of multiple sclerosis.

Merck, which pioneered the idea of vaccinating to prevent cancer with HPV shot Gardasil, sees the evidence as an opportunity—and has identified ModeX as the company to help it realize that opportunity. The deal with ModeX gives Merck an exclusive worldwide license to the preclinical vaccine candidate MDX-2201.

ModeX developed MDX-2201 using a modular nanoparticle vaccine platform. The approach has resulted in a vaccine that presents antigens from four viral proteins—gH, gL, gp42 and gp350—involved in viral entry into host cells. By targeting four proteins, the vaccine could inhibit the infection of both B cells and epithelial cells.

Atara’s stock plummets 55% following inconclusive phase 2 MS analysis

The vaccine is differentiated from other candidates. Moderna’s mRNA-1189 uses lipid nanoparticles to get mRNA encoding for four viral proteins—gp42, gp220, gH and gL—into human cells. Other candidates, including the NIH’s clinical-phase prospect, target gp350, the most abundant glycoprotein on the EBV envelope, although this approach has so far failed to yield an effective vaccine.

Merck sees potential in ModeX’s broader approach and will work with the biotech to get the prospect ready for the clinic. Tarit Mukhopadhyay, Ph.D., vice president of infectious diseases and vaccine discovery at Merck Research Laboratories, highlighted the company’s experience with Gardasil in a statement to disclose the deal.

“We have a proud legacy of developing vaccines including several that have the potential to help protect against certain types of cancer. We look forward to working with the ModeX Therapeutics team to apply our experience and expertise to evaluate the potential of MDX-2201 to help protect against EBV infection and other, potentially related, conditions,” Mukhopadhyay said.

The deal is a win for Opko Health, which bought ModeX for $300 million in stock last year. In addition to MDX-2201, the takeover gave Opko control of a tetra-specific antibody for treating solid tumors that is on course to enter the clinic next year.

Take aways:

RNA based vaccines are a cost-effective method of developing and manufacturing a personalized cancer vaccine strategy; traditional vaccine methodology has not been met with much success as a cancer therapeutic
Most of the older RNA vaccine technology depended on isolated dendritic cells or T cell populations and ex-vivo treatment with RNA vaccine, HOWEVER, Moderna has developed a technology that circumvents the need for ex-vivo vaccination
There are multiple companies involved in this new RNA strategy (Moderna, Caperna {now Moderna}, CureVac, Biontech)

From BusinessWire at http://www.businesswire.com/news/home/20160629005446/en/Merck-Moderna-Announce-Strategic-Collaboration-Advance-mRNA-Based

Merck and Moderna Announce Strategic Collaboration to Advance Novel mRNA-Based Personalized Cancer Vaccines with KEYTRUDA^®(pembrolizumab) for the Treatment of Multiple Types of Cancer

Collaboration Combines Merck’s Leadership in Immuno-Oncology with Moderna’s Pioneering mRNA Vaccine Technology and Rapid Cycle Time, Small-Batch GMP Manufacturing Capabilities

KENILWORTH, N.J. & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, and Moderna Therapeutics today announced a strategic collaboration and license agreement to develop and commercialize novel messenger RNA (mRNA)-based personalized cancer vaccines. The collaboration will combine Merck’s established leadership in immuno-oncology with Moderna’s pioneering mRNA vaccine technology and GMP manufacturing capabilities to advance individually tailored cancer vaccines for patients across a spectrum of cancers.

“Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients”

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Moderna and Merck will develop personalized cancer vaccines that utilize Moderna’s mRNA vaccine technology to encode a patient’s specific neoantigens, unique mutations present in that specific patient’s tumor. When injected into a patient, the vaccine will be designed to elicit a specific immune response that will recognize and destroy cancer cells. The companies believe that the mRNA-based personalized cancer vaccines’ ability to specifically activate an individual patient’s immune system has the potential to be synergistic with checkpoint inhibitor therapies, including Merck’s anti-PD-1 therapy, KEYTRUDA^® (pembrolizumab). In addition, Moderna has developed a rapid cycle time, small-batch manufacturing technique that will uniquely allow the company to supply vaccines tailored to individual patients within weeks.

Under the terms of the agreement, Merck will make an upfront cash payment to Moderna of $200 million, which Moderna will use to lead all research and development efforts through proof of concept. The development program will entail multiple studies in several types of cancer and include the evaluation of mRNA-based personalized cancer vaccines in combination with Merck’s KEYTRUDA® (pembrolizumab). Moderna will also utilize the upfront payment to fund a portion of the build-out of a GMP manufacturing facility in suburban Boston for the purpose of personalized cancer vaccine manufacturing.

Following human proof of concept studies, Merck has the right to elect to make an additional undisclosed payment to Moderna. If exercised, the two companies will then equally share cost and profits under a worldwide collaboration for the development of personalized cancer vaccines. Moderna will have the right to elect to co-promote the personalized cancer vaccines in the U.S. The agreement entails exclusivity around combinations with KEYTRUDA. Moderna and Merck will each have the ability to combine mRNA-based personalized cancer vaccines with other (non-PD-1) agents.

“Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients,” said Dr. Roger Perlmutter, President, Merck Research Laboratories. “While the area of personalized cancer vaccine research has faced challenges in the past, there have been many recent advances, and we believe that working with Moderna to combine an immuno-oncology approach, using KEYTRUDA, with mRNA-based personalized cancer vaccines may have the potential to transform the treatment of cancer.”

“Our team has made significant progress since beginning our work in personalized cancer vaccines just last year. Through this collaboration with Merck, we are now well-positioned to accelerate research and development with a goal of entering the clinic in 2017, as well as to apply our unique GMP manufacturing capabilities to support the rapid production of these highly individualized vaccines,” said Stéphane Bancel, chief executive officer of Moderna. “We value our continued collaboration with Merck, and we look forward to working together to harness the potential of personalized cancer vaccines and immuno-oncology to bring a new treatment paradigm to patients.”

Merck and Moderna have an existing collaboration and license agreement focused on the discovery and development of mRNA-based infectious disease vaccines and passive immunity treatments. Moderna is also advancing its own pipeline of infectious disease vaccine candidates and currently has two phase 1 studies underway in Europe and the U.S.

About Moderna Therapeutics

Moderna is a clinical stage pioneer of messenger RNA Therapeutics™, an entirely new in vivo drug technology that produces human proteins, antibodies and entirely novel protein constructs inside patient cells, which are in turn secreted or active intracellularly. This breakthrough platform addresses currently undruggable targets and offers a potentially superior alternative to existing drug modalities for a wide range of diseases and conditions. Moderna is developing and plans to commercialize its innovative mRNA drugs through its own ventures and its strategic relationships with established pharmaceutical and biotech companies. Its current ventures are:

Onkaido, focused on oncology,
Valera, focused on infectious diseases,
Elpidera, focused on rare diseases, and
Caperna, focused on personalized cancer vaccines.

Cambridge-based Moderna is privately held and currently has strategic agreements with AstraZeneca, Alexion Pharmaceuticals and Merck. To learn more, visit www.modernatx.com.

From the Moderna Therapeutics Website

Our mRNA Platform

At Moderna, we are pioneering the development of a new class of drugs made of messenger RNA (mRNA). This novel drug platform builds on the discovery that modified mRNA can direct the body’s cellular machinery to produce nearly any protein of interest, from native proteins to antibodies and other entirely novel protein constructs that can have therapeutic activity inside and outside of cells.

Our efforts are helping Moderna and the industry to flatten the mRNA learning curve across the full breadth of competencies needed to drive the platform forward, including chemistry, mRNA biology, formulation, process development, automation and high-throughput production, quality, and Good Manufacturing Practice (GMP) manufacturing.

Drug Modalities

Building from our mRNA core expression platform, we have created a new scale of drug discovery and development that enables a series of new drug modalities. Each modality represents a distinct approach to using the mRNA platform to encode proteins that achieve a therapeutic benefit, enabling us to develop numerous drug candidates across a wide array of therapeutic areas.

Vaccines

Vaccines are substances that teach the immune system to rapidly recognize and destroy invading pathogens such as bacteria or viruses, preparing the body’s adaptive immunity for future exposure to the pathogen. Historically, vaccines have introduced immune-activating markers from pathogens into the body. Conversely, Moderna is developing mRNA-based vaccines that enable the body to produce and present immunogenic proteins to the immune system.

Moderna is also developing mRNA-based personalized cancer vaccines to prime the immune system to recognize cancer cells and mount a strong, tailored response to each individual patient’s cancer. Moderna’s technology allows for a rapid turn-around time in production of these unique mRNA vaccines.

Intracellular/Transmembrane

Many diseases are caused by defects in proteins that function inside cells. Existing methods of protein-based therapy do not allow for proteins to reach the intracellular space, and as such are unable to replace the defective, disease-causing proteins within cells. Moderna’s platform allows for the development of mRNA therapies that can stimulate production of intracellular proteins as well as transmembrane proteins. This could potentially lead to a novel approach to treating a vast array of rare genetic and other diseases caused by intracellular protein defects.

Intratumoral

Many targets for the treatment of cancer have been identified but their therapeutic potential has been limited by either the inability to access these targets, or by systemic toxicities. Moderna’s platform allows for localized expression of therapeutic proteins within the tumor microenvironment.

Secreted antibodies

Antibodies are secreted proteins that bind to and inhibit specific targets. Moderna’s platform has the potential to stimulate the body’s own cells to produce specific antibodies that can bind to cellular targets.

Secreted proteins

Proteins are large, complex molecules that have many critical functions both inside and outside of cells. Moderna’s platform stimulates cells to produce and secrete proteins that can have a therapeutic benefit through systemic exposure.

Moderna is comprised of four smaller companies, the following three are involved in their personalized immunotherapy and cancer vaccine strategy

Caperna LLC

Caperna LLC is the fourth Moderna venture company — formed, funded and wholly-owned by Moderna — and focused exclusively on the advancement of personalized cancer vaccines.

Caperna will apply Moderna’s mRNA vaccine technology to the field of cancer vaccines, building on advances in recent years in cancer immunotherapy. Utilizing Moderna’s demonstrated engineering and process capability to synthesize over 1,000 unique novel mRNA’s per month in Moderna’s, automated, in-house productions systems. This provides the basis for a vision of rapid turnaround times that will allow Caperna’s personalized cancer vaccine, customized after tumor biopsy and sequencing to code for specific neoantigens in patients’ tumors, to be used to treat patients with aggressive tumors and high unmet need (rather than those with less aggressive tumors which can’t wait for prolonged turnaround times). Caperna will develop its personalized cancer vaccines in combination with checkpoint inhibitors that unleash the immune system and other cancer immunotherapies.

Corporate Facts

President: Tal Zaks, M.D., Ph.D.
Head of Research: Nicholas Valiante, Ph.D.
Head of Operations: Ted Ashburn, M.D., Ph.D.
Headquarters: 500 Technology Square, Cambridge, Mass.
Phone: 617-714-6500
Website: Caperna.com

Onkaido

Onkaido Therapeutics is the first Moderna venture company – formed, funded and wholly-owned by Moderna. Onkaido is focused exclusively on developing mRNA-based oncology treatments for currently undruggable targets or as a superior alternative to existing drug modalities. Onkaido is leveraging all of the tools and modalities developed at Moderna, with plans to rapidly turn mRNA science into truly novel cancer therapies that can make a real difference for patients.

Onkaido is currently focused on three therapeutic areas of oncology drug discovery and development: immuno-oncology, hepatocellular carcinoma (liver cancer) and myeloid malignancies – with programs investigating multiple targets and therapies simultaneously. Onkaido scientists are also exploring the power of mRNA technology in precision cancer pharmacology – researching areas such as tumor biology, targeting and gene silencing, driving the science toward the delivery of truly personalized cancer treatment.

Corporate Facts

President: Stephen Kelsey, M.D.
Headquarters: 500 Technology Square, Cambridge, Mass.
Phone: 617-714-6500
Website: Onkaido.com

Valera

Valera LLC is the second Moderna venture company — formed, funded and wholly-owned by Moderna — and focused exclusively on the advancement of vaccines and therapeutics for the prevention and treatment of viral, bacterial and parasitic infectious diseases.

The vaccines work of Valera builds on a body of preclinical research at Moderna showing the ability of modified mRNA to express viral antigens in vivo and to induce robust immune responses. Valera’s therapeutic passive immunity programs will expand on Moderna’s research using mRNA to express antibodies that bind to viral and other targets. The robust data from these programs across a range of preclinical infectious disease models, together with the inherent, rapid turn-around time in creating novel mRNA constructs, provide Valera with a potentially powerful and versatile new platform for the creation of a broad array of vaccines and passive immunity therapies.

Corporate Facts

President: Michael Watson, MB ChB, MRCP, AFPM
Chief Scientific Officer: Giuseppe Ciaramella, Ph.D.
Interim Chief Medical Officer: Tal Zaks, M.D., Ph.D.
Headquarters: 500 Technology Square, Cambridge, Mass.
Phone: 617-714-6500
Website: Valeratx.com

And from http://endpts.com/neoantigens-beckon-merck-into-a-200m-cancer-collaboration-with-moderna/

Neoantigens beckon Merck into a $200M cancer collaboration with Moderna

by john carroll
June 29, 2016

Now that Galena has added fresh evidence that first-gen cancer vaccines make for a poor R&D program, Merck is betting $200 million upfront that the next-gen neoantigen approach to personalized cancer vaccines can succeed where all else has failed.

Merck is tying up with the mRNA specialists at Cambridge, MA-based Moderna, which has inked a long lineup of marquee partnerships. The big idea here is that each person’s cancer cells present unique “neoantigens” that can be used to tailor a cancer vaccine for each patient.

That’s a radical idea that has gained considerable steam in recent months, with Gritstone and Neon Therapeutics — paired now with Bristol-Myers on Opdivo — rounding up significant venture cash. Biotech billionaire Patrick Soon-Shiong has also jumped into the game, including it in its growing slate of cancer R&D work in a group of startups.

Moderna says it has already set up a manufacturing system that can be used to create these personalized vaccines in a matter of weeks. And Merck will use the partnership to advance new combination therapies that include its checkpoint inhibitor Keytruda.

The way the deal works, Moderna notes in its statement, is that Merck can step up after it sees some evidence in humans that the tech is working as planned. After human proof-of-concept, if Merck wants to opt in they can pay a significant milestone and then both companies can share the cost on Phase III and commercializations, profiting equally.Moderna CEO Stéphane Bancel says they can jump into the clinic next year.

The deal marks another rare pact by Merck R&D chief Roger Perlmutter, who’s been carefully focused on making Keytruda a foundation franchise that can sustain the company for years to come. While Merck has been a couple of steps behind Bristol-Myers in gaining market share, Perlmutter’s not settling for a second place finish.

“Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients,” said Perlmutter, president, Merck Research Laboratories. “While the area of personalized cancer vaccine research has faced challenges in the past, there have been many recent advances, and we believe that working with Moderna to combine an immuno-oncology approach, using KEYTRUDA, with mRNA-based personalized cancer vaccines may have the potential to transform the treatment of cancer.”

From FierceBiotech on failure of Galena’s breast cancer vaccine trial

Galena plummets into microcap territory on Phase III breast cancer vaccine trial halt

Galena Biopharma fell more than 80% in premarket trading on news that an Independent Data Monitoring Committee (IDMC) stopped a Phase III trial of its NeuVax in early stage breast cancer for futility.

The company is waiting to evaluate the data from the study, known as PRESENT, to determine its next steps. It will hold a conference call next week to review the data and to update its immunotherapy and hematology pipeline plans.

“We are extremely disappointed with the outcome of the PRESENT futility analysis,” said Galena President and CEO Mark Schwartz in a statement. “To date, the trial has not been un-blinded other than by the IDMC, and we need to evaluate the data.”

NeuVax is the company’s lead candidate; it has it in an additional 4 clinical trials in various indications. It also has a pair of Phase II candidates: immunotherapy GALE-301 in ovarian and endometrial cancer and GALE-401 (Anagrelide CR) in MPN-related thrombocytosis.

The trial halt came at a planned safety and futility interim analysis that was triggered after 70 qualifying disease free survival (DFS) events.

“At this time the DMC recommends that the study be stopped for futility unless it is determined that there has been a systematic reversal in the study drug treatments in the two arms, in which case the IDMC should reevaluate the clinical evidence,” the committee said in a letter disclosed by Galena.

NeuVax (nelipepimut-S) is a cancer immunotherapy targeting human epidermal growth factor receptor (HER2) expressing cancers. It’s an immunodominant nonapeptide derived from the extracellular domain of the HER2 protein. It is combined with GM-CSF for injection under the skin.

The PRESENT trial enrolled 758 patients with a primary endpoint of disease free survival (DFS) upon reaching 141 events with three years minimum of follow-up. The trial is in breast cancer patients who are node positive, HER2 IHC 1+/2+, and HLA A2+ and/or A3+. The study is double blind, randomized 1:1, and is stratified by stage, type of surgery, hormone receptor status, and menopausal status.

Galena had $34.7 million in cash at the end of the first quarter, with an operating loss for that period of $13.1 million. So, at that point it already had less than roughly three quarters of runway.

BIONTECH Is Also developing a personalized mRNA Based Vaccine Strategy

from LABBIOTECH.EU at http://labiotech.eu/first-all-cancer-mrna-vaccine-that-works-is-published-in-nature/

BioNTech and its academic partners have published in well-know publication Nature. The work describes the first clinically applicable and systemic mRNA cancer immunotherapy vaccine.

The biggest private Biotech in Europe, BioNTech is one of major players in the mRNA field – along with money-magnet Moderna (US) and CureVac (Germany), which has already raised €300M.

BioNTech is now disclosing a major achievement: the first clinically relevant and systemic mRNA cancer vaccine in the world. Results show that the therapy has a body-wide effect and elicits a strong immune response.

The work was published in renowned scientific journal Nature, and also has the contributions of several academic and clinical partners – TRON, Research Center for Immunotherapy (FZI), the University Medical Center at the Johannes Gutenberg University Mainz and the Heidelberg University Hospital.

With this research, the group has pioneered a novel approach to target a nanoparticle mRNA vaccine (RNA-LPX) to dendritic cells (that collect antigens to present to cells of the immune system) in different parts of the body – spleen, lymph nodes and bone marrow.

Once the mRNA interacts with the dendritic cells, it rapidly sparks off a potent response that mimics a natural antiviral immune response.

It works with a dual mechanism, involving both the adaptive (T-cell-mediated) and innate (type-I interferon (IFN)-mediated) immune system. This innate response is particularly important for the full anti-tumor effects of the vaccines.

Besides a promising mode of action and efficacy data from preclinical tumor models, the work also presents early data from a Phase I trial in patients with melanoma.

CUREVAC from Germany Also A Major Player in RNA based Vaccine Technology

In the human body, RNA carries out diverse tasks. One of its key functions is the translation of genetic information into proteins. Messenger RNA (mRNA) acts as the carrier of specific building blocks for this process. Scientists have long sought to utilize this ingenious, natural concept for medical purposes, but up until just a few years ago, the molecule itself was considered uncontrollable, especially under clinical conditions. RNA was viewed as being too unstable, not particularly effective and was dwarfed by its sister DNA, the other and more prominent naturally occurring nucleic acid.

We have always held true to utilizing RNA, as we believe the first biomolecule of emerging life that nature designed could never be a faulty design. CureVac has generated its technologies to make RNA manageable and more stable, thus optimizing its properties.

CureVac’s RNA Technology – Inspired by Nature

CureVac’s active ingredients do not negatively manipulate the body, but rather work based on the very same functional principles found in nature. Our format is simple: the body receives specific information coded in RNA and uses this information to produce its own, custom-tailored protein as medicine.

After CureVac’s founding in 2000, we developed several technologies with which we specifically formulate and use RNA as the basic molecule in different ways.

Versatile RNA Technologies

RNActive® – Developed based on optimized, antigen-encoding and complexed mRNA molecules – stimulates the immune system, thereby providing potent vaccines for the prevention of infectious diseases or supplying potent novel immunotherapies against cancer.

RNArt® – Our novel mRNA-based approach in molecular therapy designed to trigger the body’s own production of desired proteins for therapeutic purposes.

RNAntibody® – Enables the prolonged expression of functional antibodies and antibody-like proteins from unmodified mRNA. This transient, reusable and safe passive immunization platform can be used in prophylactic and therapeutic settings for a range of indications.

RNAdjuvant® – Developed based on long-chain, non-coding RNA molecules – improves the quantity and quality of the immune response, thereby amplifying the effects of immunotherapeutic treatments against cancer or of conventional vaccines used to prevent infectious diseases.

In-House, GMP Production Facility

In addition to generating our own technology platform, CureVac maintains its own in-house GMP (Good Manufacturing Practice)-compliant pharmaceutical production facility. Here, we are able to manufacture all of our optimized RNA-based active ingredients.

PureMessenger® – A process developed by CureVac in which RNA is produced with a specifically desired composition and amount in an extremely pure form.

Strong Partnerships as Key to Success

CureVac is the leading mRNA company with unique expertise and know-how for the production and therapeutic application of mRNA. We are exploring the full therapeutic range for this innovative new class of medicine with our diverse platforms RNActive®, RNArt® and RNAdjuvant®. By partnering with strong pharmaceutical companies and organizations, we are in a position to fully unleash the huge potential of mRNA to the benefit of those that need new therapeutic options most.

We are the RNA people and want to share our vision to explore the transformative potential of this new technology with those who truly believe in innovation.

We are looking for partners who share with us our desire to revolutionize medicine and want to collaborate with like-minded organizations that want to make a real change.

We are motivated by challenges and see technical hurdles as opportunities to grow – as individuals and as an organization.

RNActive® Cancer Immunotherapy

Contact us if you are interested in discussing our clinical programs or want to develop new innovative tumor vaccine cocktails based on several full-length antigens to optimally tackle specific tumor types.

RNActive® Prophylactic Vaccines

Contact us if you are interested in identifying or optimizing new antigens for hard-to-treat pathogens, regardless as to whether they are viruses, bacteria or parasites. You want to optimize immunogenicity directly in humans in a Phase I setting? You are interested in a vaccine that doesn’t require a cold chain and can be produced very rapidly in case of an emergency or pandemic setting? Just let us know and we’ll figure out the best way to collaborate.

RNArt® Molecular Therapy

Contact us if you are keen to explore untapped areas for new therapeutics. The limit is your imagination as to how our versatile platform can be tailored to address your therapeutic needs. Are you looking for local or systemic administration? Have you thought about therapeutic proteins acting within the cell? Any ideas about smart combinations of functional protein domains? Get in touch and we’ll explore creative ways to collaborate.

RNAdjuvant® – Innovative Vaccine Booster

Contact us if you need to trigger a long lasting humoral and cellular immune response. Do you need to boost a potent immune response with your peptide- or protein-based vaccine? Are you interested in achieving dose-sparing with your established vaccine? Based on your proposal, we are very open to share our RNAdjuvant® under MTA to enable you to test it in your experimental environment.

Molecular Therapy (2013); 21 3, 506–508. doi:10.1038/mt.2013.26

RNA-Based Vaccination: Sending a Strong Message

David B. Weiner¹

¹Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

Correspondence: David B. Weiner, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 505 SCL-422 Curie Blvd., Philadelphia, Pennsylvania 19104, USA. E-mail: dbweiner@mail.med.upenn.edu

Nucleic acid–based vaccines (NAVs) for induction of antigen-specific immunity have reemerged as important tools in our vaccine/immune therapeutic arsenal. DNA technology appears to more than hold its own alongside viral vectored systems, particularly when the focus is on driving robust T-cell immunity in the clinic.¹ By contrast, studies of vaccines based on RNA in small animals have been disappointing. Instability of the mRNA and manufacturing problems further weakened interest in this platform. However, just as good wine improves with age, cutting-edge technologies can take time to mature, and direct injection of RNA for immunization has recently been shown to be sufficiently improved. Support for RNA delivery as a more effective means of vaccination comes from several very recent reports.^2,3,4

The delivery of DNA or RNA for the in vivo production of antigen was first reported more than two decades ago,^5,6 for both prophylaxis and immune therapy of disease. The attraction of these platforms originated from a paradigm shift engendered by NAV technology.⁷ NAVs enable indefinite repeat boosting because they are not subject to neutralization by the host immune response, thus facilitating boosting even in seropositive individuals. NAVs also drive antigen expression in vivo by the host, and therefore generate antigens that are highly relevant to protection and/or immune treatment of the specific pathogen or cancer. As such, they express host-specific modifications of the relevant antigens that are difficult or impossible to achieve when ex vivo antigen-production systems are used. Although these immunogens are not live, in theory they should induce immunity similar to that following live infection, challenging the vaccine paradigm that only live- or abortive infection–antigen approaches induce diverse CD8 T-cell immunity. NAVs appear to have considerable manufacturing advantages and can easily be combined to form multi-antigen products; this has propelled the platform into clinical studies.

Still, the initial clinical performance of the DNA vaccine platform was surprisingly weak. There were no significant safety issues, but the platform did not induce consistent CD8 T-cell immunity or seroconversion. DNA was subsequently used as a prime-boost modality, a function it served for more than a decade. Within the past few years, however, advances in genetic engineering, delivery, and formulation have resulted in much more robust DNA-based vaccines.^5,8 By contrast, direct RNA vaccination has lagged behind. Reports advancing RNA immunization strategies have relied largely on an ex vivo route^9,10—RNA for antigen expression is transfected into patient-derived dendritic cells (DC) ex vivo, followed by reinfusion of the cells as a way to tailor patient-specific immune responses. This approach is being clinically investigated for immunotherapy against colorectal, lung, prostate, and pancreatic cancer; neuroblastoma; and melanoma, among others.

Improvements in methods for mRNA synthesis and stabilization and development of improved self-amplifying RNA have yielded promising results in animals over the past year. In the study by Petsch et al., protection was observed in both young and old mice, which was encouraging, and combinations of mRNA were effective in as few as one immunization in mice.² Through optimization of the GC content of the synthetic mRNA and by optimizing the untranslated region, as well as complexing the mRNA with protamine, to protect the mRNA from RNase, the in vivo performance of this platform was improved. Furthermore, the vaccines induced immune responses in ferrets and pigs that resulted in disease attenuation upon challenge with virus. The results imply that such an mRNA approach could allow for more rapid generation of new influenza vaccines.

A recent report by Geall et al.³ further extends the direct RNA immunization field using self-amplifying RNA technology. This strategy builds off of early work using alphavirus replicons for in vivo immunization and gene delivery.¹¹ Geall et al. report that, by delivering the alphavirus genes encoding the RNA replication machinery along with the recombinant viral target antigens, which in this case was the respiratory syncytial virus fusion glycoprotein, very low doses of RNA can result in the generation of strong antigen-specific immunity in mice. The responses induced compared favorably with those induced by older, unoptimized DNA vaccines delivered by electroporation and were superior to mRNA vaccines encoding the same F antigen. Further studies in larger animal systems are clearly warranted; these should include evaluation of immune performance in nonhuman primate models such as macaques.

RNA approaches have conceptual advantages as well as disadvantages in relation to other vaccine technologies. They are simple, can be delivered directly into the cytoplasm, and do not require nuclear localization to generate expression. Self-amplifying mRNA vectors expand replication by providing the replication machinery for the RNA to increase copy number, they also provide a unique target for host immunity to home in on in the replication-machinery proteins themselves. It will be important to understand which, if any, of these conceptual issues may limit or help these technologies. In addition, stabilized mRNA approaches have conceptual advantages such as longer half-life, which generates longer expression time, and formulations that are simpler than those of viral vector systems. Conversely, RNA approaches strongly stimulate the host’s innate defense system. They do this, in part, through activation of the TLR3 and 7/8 pathways, which recognize double- and single-stranded RNA, respectively, resulting in inflammatory activation and the generation of type 1 interferon (IFN).¹² Type 1 IFN can either promote or inhibit generation of an adaptive immune response and can have unwanted effects on the host, such as induction of fever or flu-like symptoms and increased expression of autoantigens.

In this regard, a study by Pollard et al.⁴ published recently in Molecular Therapy is enlightening. They reported on the feasibility of using mRNA encoding the HIV gag antigen complexed with DOTAP/DOPE as an immunization strategy. They observed a strong effect of interferon (IFN) on the resulting immunity to this vaccine when delivered into DCs for immunization. Whereas low levels of type 1 IFN may help to drive host immunity, higher levels can shut down the cellular transcriptional machinery, thus negatively impacting mRNA vaccine potency. Pollard et al. investigated this hypothesis by studying their mRNA vaccine in normal DCs as well as DCs derived from IFN-α receptor–deficient mice. They observed that IFN-αR-deficient cells were superior for driving gag-specific T-cell responses in their immune-therapy protocol. These results support the idea that IFN-αR signaling is not required for productive innate immune activation and recruitment of DCs in these mRNA/DOTAP immunized mice, suggesting that new synthetic RNA approaches, modified to reduce innate immunity,¹³ may have important advantages for in vivoimmunization and ex vivo DC applications. It is encouraging that new approaches to building this next generation of RNA immunogens are helping to send their immune message loudly and clearly.

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References

Bagarazzi, ML, Yan, J, Morrow, MP, Shen, X, Parker, RL, Lee, JC et al. (2012). Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci Transl Med 4: 155ra138. | Article | PubMed |
Petsch, B, Schnee, M, Vogel, AB, Lange, E, Hoffmann, B, Voss, D et al. (2012). Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol 30: 1210–1216. | Article | PubMed |
Geall, AJ, Verma, A, Otten, GR, Shaw, CA, Hekele, A, Banerjee, K et al. (2012). Nonviral delivery of self-amplifying RNA vaccines. Proc Natl Acad Sci USA 109: 14604–14609. | Article | PubMed | CAS |
Pollard, C, Rejman, J, De Haes, W, Verrier, B, Van Gulck, E, Naessens, T et al. (2013) Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol Ther 21: 251–259. | Article | PubMed |
Kutzler, MA and Weiner, DB (2008). DNA vaccines: ready for prime time? Nat Rev Genet 9: 776–788. | Article | PubMed | ISI | CAS |
Conry, RM, LoBuglio, AF and Curiel, DT (1996). Polynucleotide-mediated immunization therapy of cancer. Semin Oncol 23: 135–147. | PubMed | ISI | CAS |
Donnelly, JJ, Wahren, B and Liu, MA (2005). DNA vaccines: progress and challenges. J Immunol 175: 633–639. | PubMed | ISI | CAS |
Sardesai, NY and Weiner, DB (2011). Electroporation delivery of DNA vaccines: prospects for success. Curr Opin Immunol 23: 421–429. | Article | PubMed | CAS |
Gilboa, E and Vieweg, J (2004). Cancer immunotherapy with mRNA-transfected dendritic cells. Immunol Rev 199: 251–263. | Article | PubMed | ISI | CAS |
Bringmann, A, Andrea, SA, Held, E, Heine, A and Brossart, P (2010). RNA vaccines in cancer treatment. J Biomed Biotechnol 2010: 623687. | Article | PubMed |
Smerdou, C and Liljestrom, P (1999). Non-viral amplification systems for gene transfer: vectors based on alphaviruses. Curr Opin Mol Ther 1: 244–251. | PubMed | CAS |
Desmet, CJ and Ishii, KJ (2012). Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol 12: 479–491. | Article | PubMed | CAS |
Karikó, K, Muramatsu, H, Welsh, FA, Ludwig, J, Kato, H, Akira, S and Weissman, D (2008). Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 16: 1833–1840. | Article | PubMed | CAS |

SOURCE

http://www.nature.com/mt/journal/v21/n3/full/mt201326a.html

Immunother Cancer. 2015; 3: 26.

Published online 2015 Jun 16. doi: 10.1186/s40425-015-0068-y

PMCID: PMC4468959

Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study

Klinikum rechts der Isar der Technischen Universität München, Munich, Germany

CureVac GmbH, Paul-Ehrlich-Str. 15, Tuebingen, 72076 Germany

Charité University Hospital Berlin, Berlin, Germany

University Hospital Freiburg, Freiburg, Germany

Universitäty Hospital Essen, Essen, Germany

San Raffaele Scientific Institute, Milan, Italy

University Hospital of the Johannes-Gutenberg-University Mainz, Mainz, Germany

Ortenau Klinikum Offenburg-Gengenbach, Offenburg, Germany

University Hospital Göttingen, Göttingen/University Hospital Mannheim, Mannheim, Germany

University Hospital Schleswig-Holstein Campus Luebeck, Luebeck, Germany

Rippin-Consulting, Solingen, Germany

University Hospital Tuebingen, Tuebingen, Germany

Hubert Kübler, Email: ed.nehcneum-ut.zrl@relbeuK.H.

Contributor Information.

Corresponding author.

^#Contributed equally.

Author information ▼ Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

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Abstract

Background

CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer.

Methods

44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3–6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17.

Results

The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a].

Conclusions

The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic.

The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach.

SOURCE

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468959/

Targeted Liposome Based Delivery System to Present HLA Class I Antigens to Tumor Cells: Two papers

Posted in Cancer and Current Therapeutics, Inflammasome, Nanotechnology for Drug Delivery, tagged antigen presentation, Autophagy, cancer immunotherapeutics, endocytosis, HLA, LAMP1, liposomes, Nanotechnology in cancer on July 20, 2016| Leave a Comment »

Targeted Liposome Based Delivery System to Present HLA Class I Antigens to Tumor Cells: Two papers

Reporter: Stephen J. Williams, Ph.D.

Mol Ther. 2015 Jun; 23(6): 1092–1102.

Published online 2015 Apr 14. Prepublished online 2015 Mar 19. doi: 10.1038/mt.2015.42

PMCID: PMC4817760

Modular Three-component Delivery System Facilitates HLA Class I Antigen Presentation and CD8⁺ T-cell Activation Against Tumors

Benjamin J Umlauf,^1,² Chin-Ying Chung,¹ and Kathlynn C Brown^1,^*

Author information ► Article notes ► Copyright and License information ►

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Abstract

Cell-mediated immunotherapies have potential as stand-alone and adjuvant therapies for cancer. However, most current protocols suffer from one or more of three major issues: cost, safety, or efficacy. Here we present a nanoparticle delivery system that facilitates presentation of an immunogenic measles antigen specifically in cancer cells. The delivery system does not contain viral particles, toxins, or biologically derived material. Treatment with this system facilitates activation of a secondary immune response against cancer cells, bypassing the need to identify tumor-associated antigens or educate the immune system through a primary immune response. The delivery system consists of a stealth liposome displaying a cancer-specific targeting peptide, named H1299.3, on its exterior surface and encapsulating H250, an immunogenic human leukocyte antigen class 1 restricted peptide. This targeted-nanoparticle facilitates presentation of the H250 peptide in major histocompatibility complex class I molecules. Activation is dependent on the targeting peptide, previous antigen exposure, and utilizes a novel autophagy-mediated mechanism to facilitate presentation. Treatment with this liposome results in a significant reduction of tumor growth using an aggressive LLC1 model in vaccinated C57BL/6 mice. These data provide proof-of-principle for a novel cell-mediated immunotherapy that is scalable, contains no biologically derived material, and is an efficacious cancer therapy.

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Introduction

Cell-mediated (CM) immunotherapies for cancer treatment are designed to activate the body’s adaptive immune responses against a malignant growth.^1,2 Generally, the goal of a CM response is to activate a cytotoxic T-cell response against a tumor to eliminate cancer cells. The principle of these treatments is straightforward, yet current work studying the complexity of the tumor micro-environment^2,3 as well as methods that attempt to directly activate T cells against tumor antigens^4,5,6 demonstrate the difficulty associated generating an immune response against a tumor.

Several CM cancer immunotherapies exist today. Major examples include PD-1 inhibitors, injection of live virus or viral particles into tumors, and adoptive T-cell therapies.^1,6,7,8 However, concerns regarding efficacy, safety, and/or cost have limited the use of many of these treatments. To address these concerns, we sought to develop a novel treatment based on developing a fully synthetic, minimal delivery system that facilitates presentation of human leukocyte antigen (HLA) class I restricted immunogenic peptides specifically on cancer cells without using live virus, viral subunits, or biologically derived material.

Based on these requirements, we developed a liposomal based agent consisting of a neutral, stealth liposome that encapsulates a synthetically manufactured immunogenic HLA class I restricted peptide derived from measles virus.^1,2,9 In addition, the liposome has a targeting peptide on the external surface that both specifically accumulates in cancer cells and facilitates presentation of the immunogenic peptide in HLA class I molecules (Figure 1a). Thus, this treatment is designed to generate a secondary CM immune response specifically against the tumor if the patient was previously vaccinated against or infected with measles.

Figure 1

The minimal antigen delivery system consists of three components. (a) PEGylated stealth liposomes are loaded with an immunogenic human leukocyte antigen (HLA) class 1 restricted peptide derived from measles virus, named H250. The surface of the liposome …

In this proof-of-concept study, we synthesized a liposome that encapsulates H250,¹ an immunogenic HLA class 1 restricted peptide identified from measles hemagglutinin protein. The liposome is designed to specifically internalize in cancer cells by displaying the recently identified targeting peptide H1299.3 on the exterior surface (Figure 1b).¹⁰ H1299.3 is a 20mer, cancer-specific targeting peptide that was recently identified by our group. The peptide was identified using a novel phage display technique that allows for selection of cancer-specific targeting peptides that preferentially internalize in cancer cells via a defined mechanism of endocytosis. This peptide was dimerized on a lysine core and is fully functional outside the context of the phage particle. The H1299.3 peptide accumulates specifically in a panel of non-small cell lung cancer (NSCLC) cell lines compared to a normal bronchial epithelial cell control cell line via a clathrin-dependent mechanism of endocytosis. In this study, we demonstrate that H1299.3 facilitates functional presentation of an immunogenic antigen in both major histocompatibility complex (MHC) and HLA class I molecules as indicated by CD8⁺-specific interferon (IFN)γ secretion. In addition, H1299.3 facilitated presentation utilizes an autophagy-dependent mechanism. Finally, treatment with H1299.3 targeted liposomes containing H250 substantially reduces the growth rate of subcutaneous LLC1 tumors implanted in vaccinated C57BL/6 mice compared to treatment with vehicle control.

Result summarized:

The H1299.3 targeting ligand specifically accumulates in cancer and facilitates HLA class I presentation: H250 is an immunogenic peptide identified from sequencing peptides present in HLA A*0201 molecules following measles infection. identified two donors that were HLA A*02 positive and had previously been vaccinated against measles virus (the human NSCLC cell line, H1993, which we determined to be HLA A*02 positive)
identified three different cancer-specific targeting peptides that internalize into H1993 that have been previously published: H1299.2, H2009.1, and H1299.3. Each of these peptides specifically internalize in NSCLC cell lines compared to normal bronchial epithelial cells
H1299.3 facilitated HLA class I presentation requires autophagy. H1299.3 peptide colocalizes with Lamp-1 which is a marker of both lysosomes and autolysosomes, therefore it was possible autophagy involved and shown that H1299.3 colocalizes with autophagosomes. Chlorpromazine, which inhibits clathrin coated mediatated endocytosis, decreased the HLA1 presentation of H250.
H1299.3-targeted liposomes encapsulating H250 reduce tumor burden in vivo. Mice were first vaccinated against H250. The J1299.3 targeted liposome encapsulation H250 reduced tumor growth of LLC1 s.c. xenograpfts by 50%.

J Transl Med. 2011 Mar 31;9:34. doi: 10.1186/1479-5876-9-34.

Enhanced presentation of MHC class Ia, Ib and class II-restricted peptides encapsulated in biodegradable nanoparticles: a promising strategy for tumor immunotherapy.

Ma W¹, Smith T, Bogin V, Zhang Y, Ozkan C, Ozkan M, Hayden M, Schroter S, Carrier E, Messmer D, Kumar V, Minev B.

Author information

Abstract

BACKGROUND:

Many peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation. Therefore, the development of suitable and efficient vaccine carrier systems remains a major challenge.

METHODS:

To address this issue, we have engineered polylactic-co-glycolic acid (PLGA) nanoparticles incorporating: (i) two MHC class I-restricted clinically-relevant peptides, (ii) a MHC class II-binding peptide, and (iii) a non-classical MHC class I-binding peptide. We formulated the nanoparticles utilizing a double emulsion-solvent evaporation technique and characterized their surface morphology, size, zeta potential and peptide content. We also loaded human and murine dendritic cells (DC) with the peptide-containing nanoparticles and determined their ability to present the encapsulated peptide antigens and to induce tumor-specific cytotoxic T lymphocytes (CTL) in vitro.

RESULTS:

We confirmed that the nanoparticles are not toxic to either mouse or human dendritic cells, and do not have any effect on the DC maturation. We also demonstrated a significantly enhanced presentation of the encapsulated peptides upon internalization of the nanoparticles by DC, and confirmed that the improved peptide presentation is actually associated with more efficient generation of peptide-specific CTL and T helper cell responses.

CONCLUSION:

Encapsulating antigens in PLGA nanoparticles offers unique advantages such as higher efficiency of antigen loading, prolonged presentation of the antigens, prevention of peptide degradation, specific targeting of antigens to antigen presenting cells, improved shelf life of the antigens, and easy scale up for pharmaceutical production. Therefore, these findings are highly significant to the development of synthetic vaccines, and the induction of CTL for adoptive immunotherapy.

PMID:: 21450109
PMCID:: PMC3078865
DOI:: 10.1186/1479-5876-9-34

[PubMed – indexed for MEDLINE]

Free PMC Article

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Immunotherapy Resistance Rears Its Ugly Head: PD-1 Resistant Metastatic Melanoma and More

Posted in Cancer - General, Cancer and Current Therapeutics, tagged Cancer immunology, cancer immunotherapeutics, cancer resistance, Keytruda, malignant melanoma, PD-1, PD-1 inhibitor, Resistance on July 14, 2016| Leave a Comment »

Immunotherapy Resistance Rears Its Ugly Head Again: PD-1 Resistant Metastatic Melanoma and More

Curator/Reporter: Stephen J. Williams, Ph.D.

From GenomeWeb

Source: https://www.genomeweb.com/sequencing/immune-gene-mutations-found-immunotherapy-resistant-metastatic-melanoma-patients?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20News:%20U%20of%20Texas%20Southwestern%20Medical%20Center%20Licenses%20Exosome%20Tech%20to%20Peregrine%20Pharmaceuticals%20-%2007/14/2016%2011:05:00%20AM

Immune Gene Mutations Found in Immunotherapy-Resistant Metastatic Melanoma Patients

Jul 14, 2016

Andrea Anderson

NEW YORK (GenomeWeb) – Researchers from the US and the Netherlands reported in the New England Journal of Medicine that they have identified mutations in immune system-related genes in individuals who initially responded to anti-PD-1 treatment for metastatic melanoma treatment, but relapsed after six months or more.

A team led by investigators at the University of California at Los Angeles, the Jonsson Comprehensive Cancer Center, and the Netherlands Cancer Institute did exome sequencing on tumor samples from four individuals with metastatic melanoma prior to treatment with pembrolizumab (marketed as Keytruda by Merck). The researchers also assessed protein-coding sequences in tumor samples taken after late relapse, comparing the baseline and relapse tumors to search for mutations related to checkpoint blockade therapy resistance.

They uncovered suspicious mutations in three of the four individuals. In one individual, for example, they saw a truncating mutation affecting the beta-2-microglobulin (B2M) gene, which contributes to expression of class I major histocompatibility complex molecules recognized by the immune system’s CD8 T cells. Two more relapse tumors contained loss-of-function mutations to JAK1 or JAK2 — genes coding for interferon-related kinase enzymes.

“The mutations make the tumor resistant to the way the immune system tries to kill it,” first author Jesse Zaretsky, an MD/PhD student in senior author Antoni Ribas’ University of California at Los Angeles lab, told GenomeWeb. For example, he explained, the JAK mutations “are associated with the interferon receptor and make the tumors insensitive to the signals the immune system sends to slow [tumor] growth and kill the cancer.”

While roughly three-quarters of individuals treated with anti-PD-1 therapies show durable treatment responses, acquired resistance can occur, even long after immunotherapy-mediated tumor regression.

“With the approval of PD-1 checkpoint blockade agents for the treatment of patients with melanoma, lung cancer, and other cancers, it is anticipated that cases of late relapse after initial response will increase,” the study’s authors wrote. “Understanding the molecular mechanisms of acquired resistance … may open options for the rational design of salvage combination therapies or preventative interventions and may guide mechanistic biomarker studies for the selection of patients, before the initiation of treatment, who are unlikely to have a response.”

The team started with 78 metastatic melanoma patients who were treated with pembrolizumab at UCLA. Of the 42 individuals who showed an objective response to the checkpoint blockade therapy, 15 eventually experienced disease progression.

From that group of 15 patients, the researchers focused on four patients with late-acquired resistance — six months or more after response to pembrolizumab as a single agent — for whom there was sufficient biopsy material and clinical information available. Each of the patients had been receiving continuous doses of the drug until relapse, which occurred after a mean of nearly 21 months.

When the investigators scrutinized biopsies from the relapse tumors, they saw enhanced PD-L1 expression at the edges of tumors, along with CD8 T cells attempting to infiltrate the tumors. After capturing protein-coding portions of the genome in baseline and relapse tumor samples with Nimblegen exome kits, the team sequenced the exomes to nearly 150-fold average coverage using the Illumina HiSeq 2000.

“We wanted to capture all of the mutations down to low allele frequencies to get a picture of everything that was going on in the tumors, both before they went on the treatment and after [the tumors] came back,” Zaretsky said.

In the two cases marked by new JAK1 or JAK2 mutations at relapse, the team found that 93 percent to nearly 96 percent of baseline tumor mutations persisted in the relapse tumors.

The researchers suspect resistance mutations arose from clonal populations in the metastatic tumors that expanded after anti-PD-1 treatment. From allele frequency patterns in the relapsed tumors with JAK1/2 mutations, for example, they concluded that “tumors resistant to anti-PD-1 are a relatively homogeneous population derived directly from the baseline tumor and that acquisition of the JAK mutations was an early founder event.”

Even so, they didn’t detect burgeoning resistance mutations in the pre-pembrolizumab-treatment tumors, Zaretsky said, perhaps because such alterations were present in very few cells in the baseline tumors.

In cell lines established from the individual with JAK2 loss-of-function mutations at relapse, the team’s NanoString Technologies’ nCounter expression experiments pointed to loss of JAK2 protein expression after treatment progression, along with a dip in interferon gamma activity and diminished production of proteins involved in antigen presentation and T cell activity.

Vectorisation Of Immune Checkpoint Inhibitor Antibodies

First Drug in Checkpoint Inhibitor Class of Cancer Immunotherapies has demonstrated Superiority over Standard of care in the treatment of First-line Lung Cancer Patients: Merck’s Keytryda

Durable responses with checkpoint inhibitor

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

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Aduro Biotech Phase II Pancreatic Cancer Trial CRS-207 plus cancer vaccine GVAX Fails

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Immunology, Immunotherapy, tagged aduro biotech, Cancer - General, cancer immunotherapeutics, Cancer immunotherapy, cancer vaccine, Clinical trial, immunomodulators, listeria, Pancreatic cancer, PD1 on May 16, 2016| Leave a Comment »

Aduro Biotech Phase II Pancreatic Cancer Trial CRS-207 plus cancer vaccine GVAX Fails

Reporter: Stephen J. Williams, Ph.D

From Biospace News

May 16, 2016
By Alex Keown, BioSpace.com Breaking News Staff

BERKELEY, Calif. – Shares of Aduro Biotech (ADRO) have fallen more than 25 percent this morning following news that the company’s Phase II trial for its combination pancreatic cancer drug, CRS-207 did not meet its primary endpoint of survivability.

Aduro said its Eclipse trial of CRS-207 failed to show an improvement in overall survival for patients with pancreatic cancer who had failed at least two prior therapies in the metastatic setting. Median overall survival was 3.8 months for patients treated with the immunotherapy regimen of CRS-207 and the cancer vaccine GVAX pancreas, 5.4 months for patients treated with CRS-207 alone and 4.6 months for patients administered chemotherapy. Aduro said there were no reported safety concerns during the trial and full study findings will be presented at a later date.

Stephen T. Isaacs, chairman, president and chief executive officer of Aduro, called the findings a disappointing and “unexpected outcome.’

“While we are well aware of the very difficult-to-treat nature of late-stage metastatic pancreatic cancer, we are surprised by the divergence of these data from the results of our Phase IIa study. At the same time, we continue to look forward to the interim results later this year from our ongoing Stellar trial, which is evaluating CRS-207 and GVAX Pancreas with and without the anti-PD1 checkpoint inhibitor nivolumab as a second-line therapy for patients with metastatic pancreatic cancer,” Isaacs said in a statement.

For full story please see http://www.biospace.com/News/aduro-biotechs-stock-craters-after-pancreatic/419628/source=TopBreaking

Also from FierceBiotech

UPDATED: Aduro combo fails in a key pancreatic cancer study

see at http://www.fiercebiotech.com/aduro-combo-fails-a-key-pancreatic-cancer-study

by John Carroll |

May 16, 2016 8:38am

Breaking

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“Median overall survival (MOS) in this third-line and greater setting was 3.8 months for patients treated with the immunotherapy regimen of CRS-207 and GVAX Pancreas, 5.4 months for patients treated with CRS-207 alone and 4.6 months for patients administered chemotherapy,” the company reported.

Aduro’s stock ($ADRO) plunged 30% on the news in premarket trading.

“While we are well aware of the very difficult-to-treat nature of late-stage metastatic pancreatic cancer, we are surprised by the divergence of these data from the results of our Phase 2a study,” said CEO Stephen Isaacs. But the company hasn’t given up hope on its lead program.

“In the overall survival analysis, we were intrigued by activity seen with CRS-207 as a single-agent. While the median duration of 5.4 months appears greater for CRS-207, the overall survival curve of CRS-207 alone was comparable to overall survival seen with chemotherapy. Of note, due to a disproportionately high dropout rate in the single-agent chemotherapy arm, most of these patients instead received a variety of combination treatments, including chemotherapies, immunotherapies and targeted therapies,” said Dirk Brockstedt, executive vice president, research and development for Aduro.

In a conference call with analysts Aduro execs noted that they are now shelving plans for a pivotal Phase III study in pancreatic cancer, focusing on an ongoing study in the pipeline that includes a checkpoint inhibitor.

The history of cancer vaccines not customized to individual patients has been a litany of failure, with programs for Stimuvax and others experiencing a string of defeats in the clinic. Celldex joined that circle of failure recently with a Phase III miss for Rintega. Aduro, though, doubled down on the cancer vaccine strategy and was able to strike some big-money pacts along the way on the basis of some promising midstage data.

GVAX Pancreas is based on a pancreatic cell line modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine known to stimulate the immune system. CRS-207 is made up of attenuated (deactivated) Listeria monocytogenes that express mesothelin, sparking another immune response to a protein concentrated on pancreatic cancer cells. Together, they’re supposed to provide a one-two punch against cancer, with an option to add on additional drugs to continue to build an attack on cancer cells.

That was the only workable strategy with GVAX, which, like other cancer vaccines, wasn’t able to spur a strong enough response to make a significant difference in the fight against cancer as a solo therapy, allowing Aduro to buy it for a song in early 2013. Monday’s conference call included several skeptical remarks from analysts about GVAX’s future, if any.

Aduro was on hand at the 2013 ASCO confab to review the data from a midstage study involving 93 patients with advanced pancreatic cancer. A combination of chemo plus GVAX pancreas and CRS-207 significantly outperformed GVAX and chemo, bumping up overall survival from 3.9 months to 6.1 months. That’s not a big gain, but it was a sign of progress in a very tough field. And it was good enough for the FDA to grant a breakthrough drug designation.

Now the company is forced into a classic defensive crouch, citing its significant cash reserves as it looks to regroup.

– here’s the release

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Issues Need to be Resolved With ImmunoModulatory Therapies: NK cells, mAbs, and adoptive T cells

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Immunology, Immunotherapy, tagged adoptive T cell, Cancer immunology, cancer immunotherapeutics, cancer vaccine, immunomodulation, immunomodulatory, natural killer cells, vaccine on May 1, 2016| Leave a Comment »

Issues Need to be Resolved With Immuno-Modulatory Therapies: NK cells, mAbs, and adoptive T cells

Curator: Stephen J. Williams, PhD

Immunotherapy. 2014;6(3):309-20. doi: 10.2217/imt.13.175.

Optimizing NKT cell ligands as vaccine adjuvants.

Carreño LJ¹, Kharkwal SS, Porcelli SA.

Author information

Abstract

NKT cells are a subpopulation of T lymphocytes with phenotypic properties of both T and NK cells and a wide range of immune effector properties. In particular, one subset of these cells, known as invariant NKT cells (iNKT cells), has attracted substantial attention because of their ability to be specifically activated by glycolipid antigens presented by a cell surface protein called CD1d. The development of synthetic α-galactosylceramides as a family of powerful glycolipid agonists for iNKT cells has led to approaches for augmenting a wide variety of immune responses, including those involved in vaccination against infections and cancers. Here, we review basic, preclinical and clinical observations supporting approaches to improving immune responses through the use of iNKT cell-activating glycolipids. Results from preclinical animal studies and preliminary clinical studies in humans identify many promising applications for this approach in the development of vaccines and novel immunotherapies.

Cancer Res. 2013 Jul 1;73(13):3842-51. doi: 10.1158/0008-5472.CAN-12-1974. Epub 2013 May 23.

Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment.

Baird JR¹, Fox BA, Sanders KL, Lizotte PH, Cubillos-Ruiz JR, Scarlett UK, Rutkowski MR, Conejo-Garcia JR, Fiering S, Bzik DJ.

Author information

Abstract

Reversing tumor-associated immunosuppression seems necessary to stimulate effective therapeutic immunity against lethal epithelial tumors. Here, we show this goal can be addressed using cps, an avirulent, nonreplicating uracil auxotroph strain of the parasite Toxoplasma gondii (T. gondii), which preferentially invades immunosuppressive CD11c(+) antigen-presenting cells in the ovarian carcinoma microenvironment. Tumor-associated CD11c(+) cells invaded by cps were converted to immunostimulatory phenotypes, which expressed increased levels of the T-cell receptor costimulatory molecules CD80 and CD86. In response to cps treatment of the immunosuppressive ovarian tumor environment, CD11c(+) cellsregained the ability to efficiently cross-present antigen and prime CD8(+) T-cell responses. Correspondingly, cps treatment markedly increased tumor antigen-specific responses by CD8(+) T cells. Adoptive transfer experiments showed that these antitumor T-cell responses were effective in suppressing solid tumor development. Indeed, intraperitoneal cps treatment triggered rejection of established ID8-VegfA tumors, an aggressive xenograft model of ovarian carcinoma, also conferring a survival benefit in a related aggressive model (ID8-Defb29/Vegf-A). The therapeutic benefit of cps treatment relied on expression of IL-12, but it was unexpectedly independent of MyD88 signaling as well as immune experience with T. gondii. Taken together, our results establish that cps preferentially invades tumor-associated antigen-presenting cells and restores their ability to trigger potent antitumor CD8(+) T-cell responses. Immunochemotherapeutic applications of cps might be broadly useful to reawaken natural immunity in the highly immunosuppressive microenvironment of most solid tumors.

Oncoimmunology. 2013 Jun 1;2(6):e24677. Epub 2013 Apr 29.

TLR3 agonists improve the immunostimulatory potential of cetuximab against EGFR+ head and neck cancer cells.

Ming Lim C¹, Stephenson R, Salazar AM, Ferris RL.

Author information

Abstract

Toll-like receptor 3 (TLR3) agonists have been extensively used as adjuvants for anticancer vaccines. However, their immunostimulatory effects and precise mechanisms of action in the presence of antineoplastic monoclonal antibodies (mAbs) have not yet been evaluated. We investigated the effect of TLR3 agonists on cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) against head and neck cancer (HNC) cells, as well as on dendritic cell (DC) maturation and cross-priming of epidermal growth factor receptor (EGFR)-specific CD8⁺ T cells. The cytotoxic activity of peripheral blood mononuclear cells (PBMCs) or isolated natural killer (NK) cells expressing polymorphic variants (at codon 158) of the Fcγ receptor IIIa (FcγIIIa) was determined in ⁵¹Cr release assays upon incubation with the TLR3 agonist poly-ICLC. NK cell stimulation was measured based on activation and degranulation markers, while DC maturation in the presence of poly-ICLC was assessed using flow cytometry. The DC-mediated cross priming of EGFR-specific CD8⁺ T cells was monitored upon in vitro stimulation with tetramer-based flow cytometry. TLR3-stimulated, unfractionated PBMCs from HNC patients mediated robust cetuximab-dependent ADCC, which was abrogated by NK-cell depletion. The cytolytic activity of TLR3-stimulated NK cells differed among cells expressing different polymorphic variants of FcγRIIIa, and NK cells exposed to both poly-ICLC and cetuximab expressed higher levels of CD107a and granzyme B than their counterparts exposed to either stimulus alone. Poly-ICLC plus cetuximab also induced a robust upregulation of CD80, CD83 and CD86 on the surface of DCs, a process that was partially NK-cell dependent. Furthermore, DCs matured in these conditions exhibited improved cross-priming abilities, resulting in higher numbers of EGFR-specific CD8⁺ T cells. These findings suggest that TLR3 agonists may provide a convenient means to improve the efficacy of mAb-based anticancer regimens.

Ann Oncol. 2012 Sep; 23(Suppl 8): viii6–viii9.

doi: 10.1093/annonc/mds256

PMCID: PMC4085883

Immuno-oncology: understanding the function and dysfunction of the immune system in cancer

J. Finn^*

Interactions between the Immune System and Cancer

Evidence has been accumulating since the middle of the last century, first from animal models and later from studies in cancer patients, that the immune system can recognise and reject tumours. The goal of tumour immunology has been to understand the components of the immune system that are important for tumour immunosurveillance and tumour rejection to understand how, when, and why they fail in cases of clinical disease. Immunotherapy, which involves strengthening the cancer patient’s immune system by improving its ability to recognise the tumour or providing a missing immune effector function, is one treatment approach that holds promise of a life-long cure [4].

Studies of cancer–immune system interactions have revealed that every known innate and adaptive immune effector mechanism participates in tumour recognition and control [5]. The first few transformed cells are detected by NK cells through their encounter with specific ligands on tumour cells. This leads to the destruction of some transformed cells and the uptake and processing of their fragments by macrophages and dendritic cells. In turn, these macrophages and dendritic cells are activated to secrete many inflammatory cytokines and present tumour cell-derived molecules to T- and B cells. Activation of T- and B cells leads to the production of additional cytokines that further promote activation of innate immunity and support the expansion and production of tumour-specific T cells and antibodies, respectively. The full power of the adaptive immune system leads to the elimination of remaining tumour cells and, importantly, to the generation of immune memory to specific tumour components that will serve to prevent tumour recurrence.

Effectors of adaptive immunity, such as CD4⁺ helper T cells, CD8⁺ cytotoxic T cells, and antibodies, specifically target tumour antigens; i.e. molecules expressed in tumour cells, but not in normal cells. Tumour antigens are normal cellular proteins that are abnormally expressed as a result of genetic mutations, quantitative differences in expression, or differences in posttranslational modifications [5]. In tumour types that have a well-documented viral origin, such as cervical cancer, caused by the human papillomavirus [5], or hepatocellular carcinoma caused by the hepatitis B virus [6], viral proteins can also serve as tumour antigens and targets for antitumour immune response [7].

The first indication that tumours carried molecules distinct from those on the normal cell of origin was derived from immunising mice with human tumours and selecting antibodies that recognised human tumour cells but not their normal counterparts. The major question was whether some, or all, of these molecules would also be recognised by the human immune system. 2011 was an important anniversary for human tumour immunology, marking 20 years since the publication by van der Bruggen et al. [8] that described the cloning of MAGE-1, a gene that encodes a human melanoma antigen recognised by patient’s antitumour T cells. This was not a mutant protein; its recognition by the immune system was due to the fact that it was only expressed by transformed, malignant cells and, with the exception of testicular germ cells, was not expressed in normal adult tissue. Many similar discoveries followed, with each new molecule providing a better understanding of what might be good targets for different forms of cancer immunotherapy. Tumour antigens have been tested as vaccines, as targets for monoclonal antibodies, and as targets for adoptively transferred cytotoxic T cells. There is a wealth of publications from preclinical studies targeting these antigens and results from phase I/II clinical trials. Recently, these studies were critically reviewed and a list of tumour antigens with the largest body of available data compiled [9]. The goal was to encourage faster progress in the design, testing, and approval of immunotherapeutic reagents that incorporate or target the most promising antigens.

As highlighted in the article two scenarios which present problems emerged:

In the past, immunotherapy was referred to as ‘passive’ (e.g. the infusion of preformed immune effectors, such as antibodies, cytokines, or activated T cells, NK cells, or lymphokine-activated killer cells), presumably acting directly on the tumour and independent of the immune system or ‘active’ (e.g. vaccines), designed to activate and therefore be dependent on the patient’s immune system. it has since become clear that both passive and active immunotherapies depend on the patient’s immune system for long-term tumour control or complete tumour elimination. anticancer monoclonal antibodies are a well-established class of immunotherapeutic agent. HOWEVER, The potential of these antibodies is drastically undermined by their administration relatively late in the disease course, when the patient’s immune system is largely compromised. Under more optimal conditions, antibody treatment might result not only in the direct cytostatic or cytotoxic effect on the tumour cell, but also in the loading of antibody-bound tumour antigens onto antigen presenting cells (APC) in the tumour microenvironment. The resultant cross-presentation to antitumour T- and B cells could result in additional antibodies to these antigens being produced, and propagation of the immune response at the tumour site would maintain tumour elimination long after the infused monoclonal antibody is gone.
The same scenario could be predicted for adoptively transferred T cells. Unlike antibodies, transferred T cells persist longer and may provide a memory response [14]; however, as long as the memory response is restricted to one clone, or a limited number of clones, then antigen-negative tumours will be able to escape. In addition, cancer vaccines encounter large numbers of immunosuppressive T_regand MDSC in circulation, as well as immunosuppressive cell-derived soluble products that flood the lymph nodes, preventing maturation of APCs and activation of T cells. Even when vaccines are delivered in the context of ex vivo matured and activated dendritic cells, their ability to activate T cells is compromised by the high-level expression of various molecules on T cells that block this process.

The scenarios proposed above present a rather bleak picture of the potential of immunotherapy to achieve the cure for cancer that has eluded standard therapy [15]. Interestingly, failures of some standard therapies are beginning to be ascribed to their inability to activate the patient’s immune system [16]. However, rather than seeing the picture as a deterrent, it should be considered as a road map, providing at least two major directions for new developments in immunotherapy.

The first direction is to continue using the old classes of immunotherapy that target the cancer directly, but to use them in combination with therapies that target the immune system in the tumour microenvironment, such as cytokines, suppressors of T_reg or MDSC activity, or antibodies that modulate T-cell activity. The recently approved antibody, ipilimumab, which acts to sustain cytotoxic T-cell activity by augmenting T-cell activation and proliferation, is one example of such an immunomodulatory agent [17].

The other direction is to use immunotherapies, both old and new, for preventing cancer in individuals at high risk [18]. Studies of the tumour microenvironment are providing information about immunosurveillance of tumours from early premalignant lesions to more advanced dysplastic lesions to cancer. At each step, tumour-derived and immune system-derived components have a unique composition that will have distinct effects on immunotherapy. Because these premalignant microenvironments are less developed and immunosuppression is less entrenched, it should be easier to modulate towards the elimination of abnormal cells.

Cancer Immunol Immunother. 2011 Sep;60(9):1309-17. doi: 10.1007/s00262-011-1038-y. Epub 2011 May 28.

Tumor immunotherapy using adenovirus vaccines in combination with intratumoral doses of CpG ODN.

Geary SM¹, Lemke CD, Lubaroff DM, Salem AK.

Author information

Abstract

The combination of viral vaccination with intratumoral (IT) administration of CpG ODNs is yet to be investigated as an immunotherapeutic treatment for solid tumors. Here, we show that such a treatment regime can benefit survival of tumor-challenged mice. C57BL/6 mice bearing ovalbumin (OVA)-expressing EG.7 thymoma tumors were therapeutically vaccinated with adenovirus type 5 encoding OVA (Ad5-OVA), and the tumors subsequently injected with the immunostimulatory TLR9 agonist, CpG-B ODN 1826 (CpG), 4, 7, 10, and 13 days later. This therapeutic combination resulted in enhanced mean survival times that were more than 3.5× longer than naïve mice, and greater than 40% of mice were cured and capable of resisting subsequent tumor challenge. This suggests that an adaptive immune response was generated. Both Ad5-OVA and Ad5-OVA + CpG IT treatments led to significantly increased levels of H-2 K(b)-OVA-specific CD8+ lymphocytes in the peripheral blood and intratumorally. Lymphocyte depletion studies performed in vivo implicated both NK cells and CD8+ lymphocytes as co-contributors to the therapeutic effect. Analysis of tumor infiltrating lymphocytes (TILs) on day 12 post-tumor challenge revealed that mice treated with Ad5-OVA + CpG IT possessed a significantly reduced percentage of regulatory T lymphocytes (Tregs) within the CD4+ lymphocyte population, compared with TILs isolated from mice treated with Ad5-OVA only. In addition, the proportion of CD8+ TILs that were OVA-specific was reproducibly higher in the mice treated with Ad5-OVA + CpG IT compared with other treatment groups. These findings highlight the therapeutic potential of combining intratumoral CpG and vaccination with virus encoding tumor antigen.

Adv Drug Deliv Rev. 2009 Mar 28;61(3):268-74. doi: 10.1016/j.addr.2008.12.005. Epub 2009 Jan 7.

CpG oligonucleotide as an adjuvant for the treatment of prostate cancer.

Lubaroff DM¹, Karan D.

Author information

Abstract

The use of an adenovirus transduced to express a prostate cancer antigen (PSA) as a vaccine for the treatment of prostate cancer has been shown to be active in the destruction of antigen-expressing prostate tumor cells in a pre-clinical model, using Balb/C or PSA transgenic mice. The destruction of PSA-secreting mouse prostate tumors was observed in Ad/PSA immunized mice in a prophylaxis study with 70% of the mice surviving long term tumor free. This successful immunotherapy was not observed in therapeutic studies in which tumors were established before vaccination and the development of anti-PSA immune response was not as easily generated in PSA transgenic mice. Immunization of conventional and transgenic animals was enhanced by incorporating a collagen matrix into the immunizing injection. Therefore the need to strengthen anti-PSA and anti-prostate cancer immunity was an obvious next step in developing a successful prostate cancer immunotherapy. Because the use ofimmunostimulatory CpG motifs was shown to enhance immune responses to a wide variety of antigens, our studies incorporated CpG into the Ad/PSA vaccine experimental plans. The results of the subsequent studies demonstrated a dichotomy where Ad/PSA plus CpG enhanced the in vivo destruction of PSA-secreting tumors and the survival of experimental animals, but revealed that the number and in vitro activities of antigen specific CD8+ T cells was decreased as compared to the values observed when the vaccine alone was used for immunization. The dichotomous observations were confirmed using another antigen system, OVA also incorporated into a replication defective adenovirus. Despite the reduction in antigen-specific CD8+ cells after vaccine plus CpG immunization the enhanced destruction of sc and systemic tumors was shown to be mediated entirely by CD8+ T cells. Finally, the reduction of the CD8+ T cells was the result of an observed decrease in the proliferation of the antigen specific cell population.

J Invest Dermatol. 2004 Aug;123(2):371-9.

CpG motifs are efficient adjuvants for DNA cancer vaccines.

Schneeberger A¹, Wagner C, Zemann A, Lührs P, Kutil R, Goos M, Stingl G, Wagner SN.

Author information

Abstract

DNA vaccines can induce impressive specific cellular immune response (IR) when taking advantage of their recognition as pathogen-associated molecular patterns (PAMP) through Toll-like receptors (TLR) expressed on/in cells of the innate immune system. Among the many types of PAMP,immunostimulatory DNA, so-called CpG motifs, was shown to interact specifically with TLR9, which is expressed in plasmacytoid dendritic cells(pDC), a key regulatory cell for the activation of innate and adaptive IR. We now report that CpG motifs, when introduced into the backbone, are a useful adjuvant for plasmid-based DNA (pDNA) vaccines to induce melanoma antigen-specific protective T cell responses in the Cloudman M3/DBA/2 model. The CpG-enriched pDNA vaccine induced protection against subsequent challenge with melanoma cells at significantly higher levels than its parental unmodified vector. Preferential induction of an antigen-specific, protective T cell response could be demonstrated by (i) induction of antigen-dependent tumor cell protection, (ii) complete loss of protection by in vivo CD4+/CD8+T cell- but not NK cell-depletion, and (iii) the detection of antigen-specific T cell responses but not of relevant NK cell activity in vitro. These results demonstrate that employing PAMP in pDNA vaccines improves the induction of protective, antigen-specific, T cell-mediated IR.

J Biomed Sci. 2016 Jan 25;23(1):16. doi: 10.1186/s12929-016-0238-3.

Combination of the toll like receptor agonist and α-Galactosylceramide as an efficient adjuvant for cancer vaccine.

Gableh F¹, Saeidi M², Hemati S³, Hamdi K⁴, Soleimanjahi H⁵, Gorji A^6,7,8, Ghaemi A^9,10,11.

Author information

Abstract

BACKGROUND:

DNA vaccines have emerged as an attractive approach for the generation of cytotoxic T lymphocytes (CTL). In our previous study, we found That Toll like receptor (TLR) ligands are promising candidates for the development of novel adjuvants for DNA vaccine. To improve the efficacy of DNA vaccine directed against human papillomavirus (HPV) tumors, we evaluated whether co-administration of a TLR4 ligand, monophosphoryl lipid A (MPL), and Natural Killer T Cell Ligand α-Galactosylceramide(α-GalCer) adjuvants with DNA vaccine would influence the anti-tumor efficacy of DNA vaccinations.

METHODS:

We investigated the effectiveness of α-GalCer and MPL combination as an adjuvant with an HPV-16 E7 DNA vaccine to enhance antitumor immune responses.

RESULTS:

By using adjuvant combination for a DNA vaccine, we found that the levels of lymphocyte proliferation, CTL activity, IFN- γ, IL-4 and IL-12 responses, and tumor protection against TC-1 cells were significantly increased compared to the DNA vaccine with individual adjuvants. In addition, inhibition of IL-18 signaling during vaccination decreased IFN-γ responses and tumor protection, and that this inhibition suggested stimulatory role of IL-18 in adjuvant effects of α-GalCer and MPL combination.

CONCLUSION:

The strong adjuvanticity associated with α-GalCer/MPL combination may to be an important tool in the development of novel and strong cancer immunotherapy.

Cancer Sci. 2015 Dec;106(12):1659-68. doi: 10.1111/cas.12824. Epub 2015 Nov 18.

Adjuvant for vaccine immunotherapy of cancer – focusing on Toll-like receptor 2 and 3 agonists for safely enhancing antitumor immunity.

Seya T¹, Shime H¹, Takeda Y¹, Tatematsu M¹, Takashima K¹, Matsumoto M¹.

Author information

Abstract

Immune-enhancing adjuvants usually targets antigen (Ag)-presenting cells to tune up cellular and humoral immunity. CD141(+) dendritic cells (DC) represent the professional Ag-presenting cells in humans. In response to microbial pattern molecules, these DCs upgrade the maturation stage sufficient to improve cross-presentation of exogenous Ag, and upregulation of MHC and costimulators, allowing CD4/CD8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival. These DCs also facilitate natural killer-mediated cell damage. Toll-like receptors (TLRs) and their signaling pathways in DCs play a pivotal role in DC maturation. Therefore, providing adjuvants in addition to Ag is indispensable for successful vaccine immunotherapy for cancer, which has been approved in comparison with antimicrobial vaccines. Mouse CD8α(+) DCs express TLR7 and TLR9 in addition to the TLR2 family (TLR1, 2, and 6) and TLR3, whereas human CD141(+) DCs exclusively express the TLR2 family and TLR3. Although human and mouse plasmacytoid DCs commonly express TLR7/9 to respond to their agonists, the results on mouse adjuvant studies using TLR7/9 agonists cannot be simply extrapolated to human adjuvant immunotherapy. In contrast, TLR2 and TLR3 are similarly expressed in both human and mouse Ag-presenting DCs. Bacillus Calmette-Guerin peptidoglycan and polyinosinic-polycytidylic acid are representative agonists for TLR2 and TLR3, respectively, although they additionally stimulate cytoplasmic sensors: their functional specificities may not be limited to the relevant TLRs. These adjuvants have been posted up to a certain achievement in immunotherapy in some cancers. We herein summarize the history and perspectives of TLR2 and TLR3 agonists in vaccine-adjuvant immunotherapy for cancer.

Adv Exp Med Biol. 2015;850:81-91. doi: 10.1007/978-3-319-15774-0_7.

Molecular Programming of Immunological Memory in Natural Killer Cells.

Beaulieu AM¹, Madera S, Sun JC.

Author information

Abstract

Immunological memory is a hallmark of the adaptive immune system. Although natural killer (NK) cells have traditionally been classified as a component of the innate immune system, they have recently been shown in mice and humans to exhibit certain features of immunological memory, including an ability to undergo a clonal-like expansion during virus infection, generate long-lived progeny (i.e. memory cells), and mediate recall responses against previously encountered pathogens–all characteristics previously ascribed only to adaptive immune responses by B and T cells in mammals. To date, the molecular events that govern the generation of NK cell memory are not completely understood. Using a mouse model of cytomegalovirus infection, we demonstrate that individual pro-inflammatory IL-12, IL-18, and type I-IFN signaling pathways are indispensible and play non-redundant roles in the generation of virus-specific NK cell memory. Furthermore, we discovered that antigen-specific proliferation and protection by NK cells is mediated by the transcription factor Zbtb32, which is induced by pro-inflammatory cytokines and promotes a cell cycle program in activated NK cells. A greater understanding of the molecular mechanisms controlling NK cell responses will provide novel strategies for tailoring vaccines to target infectious disease.

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Real Time Coverage and eProceedings of 2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, Scientific & Biotech Conferences: Press Coverage, tagged Cancer Care, cancer immunotherapeutics on April 28, 2016| Leave a Comment »

Real Time Coverage and eProceedings of 2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

Curator: Aviva Lev-Ari, PhD, RN

Director & Founder

Leaders in Pharmaceutical Business Intelligence Group, Boston

Editor-in-Chief

http://pharmaceuticalintelligence.com

e-Mail: avivalev-ari@alum.berkeley.edu

SkypeID: HarpPlayer83

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Top Three among Disruptive Dozen Technologies: The Future of Cancer Therapies @2016 World Medical Innovation Forum

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CANCER IMMUNOTHERAPY

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Clinical & Translational, Curation, Cytokines, Cytoskeleton, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Immunology, Immunotherapy, Monoclonal Immunotherapy, tagged cancer immunotherapeutics, JAK/STAT pathway, PDL1/PD1 pathway, targets for immunotherapy on April 12, 2016| Leave a Comment »

CANCER IMMUNOTHERAPY

Larry H. Bernstein, MD, FCAP, Curator

LPBI

KNOWLEDGE-BASED APPROACHES FOR CANCER IMMUNOTHERAPY TARGETS

BY RICHARD K. HARRISON

http://stateofinnovation.thomsonreuters.com/knowledge-based-approaches-for-cancer-immunotherapy-targets

The field of cancer immunotherapy is in its infancy but has already led to a major shift in the treatment of cancer – and this is only the beginning

Cancer is the second leading cause of death in the US, accounting for almost a quarter of US deaths.¹ The American Cancer Society estimates the total worldwide economic impact of cancer at $900 billion annually.² Until recently, treatments largely relied on nonspecific toxic compounds that showed limited success. But treatment paradigms are beginning to change and an old observation about tumors and the immune system may be responsible for a new wave of cancer treatments.

Using the immune system to regulate cancer progression traces its roots back to the 1890s when William B. Coley observed that bacterial infection often coincided with cancer regression. Coley developed the theory that post-surgical infections had helped patients to recover better from their cancer by provoking an immune response. He later reported the successfully creation of a filtered mixture of bacteria and bacterial lysates to treat tumors.³ The field progressed little over the following century until the comparatively recent explosion of research which has identified the mechanisms by which cancer cells evade detection by the immune system. Armed with this knowledge, researchers have identified several protein targets, most notably Programmed Cell Death-1 (PD-1)⁴ and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)⁵, and more importantly, antibodies that act on these targets resulting in the activation of the immune system towards the targeting of cancer cells.

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FIGURE 1: Cause of Death in the US, 2013

These findings have yielded unprecedented success in the treatment of certain cancers and ushered in the era of cancer immunotherapy.⁶ However, several cancers have proven refractory to PD-1 and CTLA-4 targeted therapies. For these diseases new classes of targets and new mechanisms must be identified. ⁷

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FIGURE 2: Components of the Immune System with targets for Cancer Immunotherapy

Identifying these new targets is arguably the most important step in the multimillion dollar drug discovery process. Fewer than 1 in 10 compounds that enter clinical trials becomes a medicine.⁸ Most fail because they are not effective against the disease they are designed to combat.⁹ Often these failures can be traced back to not selecting the right target to drug.¹⁰

To address this challenge Thomson Reuters analysts are applying knowledge based approaches and scouting biological pathways for potential new targets for immune based therapies for cancer. Our knowledge comes from a combination of retrospective analysis of ongoing development programs coupled with information extracted from the literature. We use this evidence to better understand the role of the immune system in fighting cancer.

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FIGURE 3: Targets for cancer immunotherapy

Better Targets For Existing Approaches

Scouting known targets for cancer immunotherapy and interrogating the regulators of these targets is one method to identify new potential targets. As an example we researched PD-1, the well-known checkpoint protein mentioned above. Analysis of the known transcriptional regulators of PD-1 highlighted that the majority of PD-1 expression is centered on activation of the JAK/STAT pathway and that targeting these proteins may represent a novel way to modulate the activity of PD-1. In addition, we uncovered interesting biomarkers for patient stratification or combination drug targets such as IFN-, NOTCH1, and the STATs.

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FIGURE 4: Signaling Pathways leading to the expression of PD-1

Novel Targets for New Approaches

For novel targets we performed analysis of publically available gene sets of cancer patients to identify differentially regulated genes. Interrogating the differentially expressed genes and superimposing these onto proprietary canonical pathway maps for immune response we are able to identify several targets that can serve as starting points for immunotherapy drug discovery, biomarkers for disease progression, and for stratifying patients for clinical trials.

The field of cancer immunotherapy is in its infancy but has already led to a shift in the treatment of cancer. Instead of treating the cancer, researchers are treating the immune system which in turn specifically targets only the cancer. And that is just the beginning. The knowledge gained from this research can be applied to diseases other than cancer, ushering in a new era of immunotherapy. Not a bad outcome even if it took over 100 years to come about.

For more detail on this topic, download the slide presentation given by author Richard K. Harrison, Thomson Reuters Chief Scientific Officer, at the Molecular Med Tri-Con 2016: “Knowledge Based Approaches to New Targets in Cancer Immunotherapy.”

To learn more about themes covered at the Molecular Med Tri-Con 2016, read the BioWorld special report.

References:

^1. Globacan, International Agency for Research on Cancer; “Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. (2012).

^2. American Cancer Society Cancer Facts and Figures. (2013).

^3. Coley WB, The Treatment of Malignant Tumors By Repeated Inoculations of Erysipelas: With A Report of Ten Original Cases.
The American Journal of Medical Sciences 10, 487-511 (1893).

^4. H. Nishimura, M. Nose, H. Hiai, N. Minato, T. Honjo, Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying
immunoreceptor. Immunity 11, 141-151 (1999).

^5. K. M. Lee et al., Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263-2266 (1998).

^6. A. Swaika, W. A. Hammond, R. W. Joseph, Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol. Immunol. 67, 4-17 (2015).

^7. A. C. Anderson, Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res 2, 393-398 (2014).

^8. J. Arrowsmith, A decade of change. Nat. Rev. Drug. Discov. 11, 17-18 (2012).

^9. J. Arrowsmith, P. Miller, Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug. Discov. 12, 569 (2013).

^10. P. Morgan et al., Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival.
Drug Discov.Today 17, 419-424 (2012).

CLINICAL TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY

BY BETH KIERNAN http://stateofinnovation.thomsonreuters.com/clinical-trends-and-challenges-in-immuno-oncology

Within immuno-oncology, checkpoint inhibitors and therapeutic cancer vaccines exhibit unique trends and challenges

Immunotherapy trials comprise more than one third of the current clinical oncology space. As innovators race to market, challenges inherent in immuno-oncology (I/O) are being met. Predictive and prognostic biomarkers have become notoriously difficult to pinpoint and regulatory bodies are struggling to maintain pace with the burgeoning field.

In taking a closer look at the 2,500 active I/O clinical trials in Cortellis Clinical Trials Intelligence, there are two classes experiencing interesting trends, each with their unique challenges. Therapeutic cancer vaccine trials have seen a shift in sponsors while steadily decreasing in number. Checkpoint inhibitors, meanwhile, have been rapidly gaining momentum.

Therapeutic Cancer Vaccines

Specialized biotech companies and research institutions have taken on the challenge of therapeutic cancer vaccine development. Following Dendreon’s success in 2010 with Provenge (sipuleucel-T), the only therapeutic cancer vaccine approved by the FDA thus far, drug developers are employing diverse strategies to effectively introduce cancer vaccines to immuno-compromised patients while mitigating adverse or unintended effects. Although the majority of therapeutic cancer vaccine studies are in the early stages, approximately 10 percent are those that have progressed to late-stage trials. These numbers indicate both an interest in the class as well as modest success with trial candidates.

FIGURE 1: Active, commercial immuno-oncology trials. (SOURCE: Cortellis Clinical Trials)

Checkpoint Inhibitors

On the opposite end of the spectrum, checkpoint inhibitor trials are exhibiting a rapid-fire growth pattern and tremendous success. Since 2010, they have experienced a twenty-fold increase in the number of commercially relevant trials as compared to those started in 2015. Anti-CTLA-4 trials comprise a quarter of the current space, while target newcomers, PD-1 and PD-L1, make up the remainder, with PD-1 being studied in more than half of current trials.

PD-1 is a receptor on T-cells and binds ligands PD-L1 and PD-L2 to prevent T-cell activation. Upregulation of these proteins causes cancer cells to go unnoticed by the immune system. Inhibiting this checkpoint, however, lifts the veil, allowing the immune system to launch an attack. Both big pharma and biotech companies are active in the space and are taking on trials at almost double the rate of therapeutic vaccines.

BMS, following up on their success with Yervoy (CTLA-4) and Opdivo (PD-1), are at the top of the space, followed by Merck (Keytruda, PD-1) and Roche. Early and late phase trials are split down the middle indicating both interest in the space and successful progression to phase III trials. Until recently, melanoma has been the top indication in the space; however it has since been surpassed by lung cancer.

Advanced metastatic cancers, those where other treatments have failed, remain the top patient segments in checkpoint inhibitor trials. Challenges in this space lie in identifying predictive and prognostic biomarkers. Correlating response rate to the PD-L1 biomarker, which is currently seen in 39 percent of checkpoint inhibitor trials measuring biomarkers, is not always possible.

Conclusion

Immuno-oncology is a highly marketable and dynamic space currently led by checkpoint inhibitors. However, as niches become saturated, developers must look to identify novel approaches. Immunotherapy and cross-class combinations are proving to be successful, and the recent approval of Amgen’s oncolytic virus (T-vec) for inoperable melanoma is giving hope that there are opportunities beyond T-cells. Our immune system is a complex defense structure full of cells ready to take on the fight against cancer – they just need the right orders.