Metabolic Immuno-Oncology | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

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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An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression

Posted in Apoptosis, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Cell Biology, Cell Biology, Signaling & Cell Circuits, Metabolic Immuno-Oncology, Monoclonal Immunotherapy, Oligonucleotide Therapeutics & Delivery, Precision Cancer Medicine, RNA Biology, Cancer and Therapeutics, Signaling & Cell Circuits, tagged Cancer, gene expression, HApt, HER2, Nanorobot, tFNA, Therapy on July 24, 2019| Leave a Comment »

An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

3.2.9

3.2.9 An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

HER2 is an important prognostic biomarker for 20–30% of breast cancers, which is the most common cancer in women. Overexpression of the HER2 receptor stimulates breast cells to proliferate and differentiate uncontrollably, thereby enhancing the malignancy of breast cancer and resulting in a poor prognosis for affected individuals. Current therapies to suppress the overexpression of HER2 in breast cancer mainly involve treatment with HER2-specific monoclonal antibodies. However, these monoclonal anti-HER2 antibodies have severe side effects in clinical trials, such as diarrhea, abnormal liver function, and drug resistance. Removing HER2 from the plasma membrane or inhibiting the gene expression of HER2 is a promising alternative that could limit the malignancy of HER2-positive cancer cells.

DNA origami is an emerging field of DNA-based nanotechnology and intelligent DNA nanorobots show great promise in working as a drug delivery system in healthcare. Different DNA-based nanorobots have been developed as affordable and facile therapeutic drugs. In particular, many studies reported that a tetrahedral framework nucleic acid (tFNA) could serve as a promising DNA nanocarrier for many antitumor drugs, owing to its high biocompatibility and biosecurity. For example, tFNA was reported to effectively deliver paclitaxel or doxorubicin to cancer cells for reversing drug resistance, small interfering RNAs (siRNAs) have been modified into tFNA for targeted drug delivery. Moreover, the production and storage of tFNA are not complicated, and they can be quickly degraded in lysosomes by cells. Since both free HApt and tFNA can be diverted into lysosomes, so, combining the HApt and tFNA as a novel DNA nanorobot (namely, HApt-tFNA) can be an effective strategy to improve its delivery and therapeutic efficacy in treating HER2-positive breast cancer.

Researchers reported that a DNA framework-based intelligent DNA nanorobot for selective lysosomal degradation of tumor-specific proteins on cancer cells. An anti-HER2 aptamer (HApt) was site-specifically anchored on a tetrahedral framework nucleic acid (tFNA). This DNA nanorobot (HApt-tFNA) could target HER2-positive breast cancer cells and specifically induce the lysosomal degradation of the membrane protein HER2. An injection of the DNA nanorobot into a mouse model revealed that the presence of tFNA enhanced the stability and prolonged the blood circulation time of HApt, and HApt-tFNA could therefore drive HER2 into lysosomal degradation with a higher efficiency. The formation of the HER2-HApt-tFNA complexes resulted in the HER2-mediated endocytosis and digestion in lysosomes, which effectively reduced the amount of HER2 on the cell surfaces. An increased HER2 digestion through HApt-tFNA further induced cell apoptosis and arrested cell growth. Hence, this novel DNA nanorobot sheds new light on targeted protein degradation for precision breast cancer therapy.

It was previously reported that tFNA was degraded by lysosomes and could enhance cell autophagy. Results indicated that free Cy5-HApt and Cy5-HApt-tFNA could enter the lysosomes; thus, tFNA can be regarded as an efficient nanocarrier to transmit HApt into the target organelle. The DNA nanorobot composed of HApt and tFNA showed a higher stability and a more effective performance than free HApt against HER2-positive breast cancer cells. The PI3K/AKT pathway was inhibited when membrane-bound HER2 decreased in SK-BR-3 cells under the action of HApt-tFNA. The research findings suggest that tFNA can enhance the anticancer effects of HApt on SK-BR-3 cells; while HApt-tFNA can bind to HER2 specifically, the compounded HER2-HApt-tFNA complexes can then be transferred and degraded in lysosomes. After these processes, the accumulation of HER2 in the plasma membrane would decrease, which could also influence the downstream PI3K/AKT signaling pathway that is associated with cell growth and death.

However, some limitations need to be noted when interpreting the findings: (i) the cytotoxicity of the nanorobot on HER2-positive cancer cells was weak, and the anticancer effects between conventional monoclonal antibodies and HApt-tFNA was not compared; (ii) the differences in delivery efficiency between tFNA and other nanocarriers need to be confirmed; and (iii) the confirmation of anticancer effects of HApt-tFNA on tumors within animals remains challenging. Despite these limitations, the present study provided novel evidence of the biological effects of tFNA when combined with HApt. Although the stability and the anticancer effects of HApt-tFNA may require further improvement before clinical application, this study initiates a promising step toward the development of nanomedicines with novel and intelligent DNA nanorobots for tumor treatment.

References:

https://pubs.acs.org/doi/10.1021/acs.nanolett.9b01320

https://www.ncbi.nlm.nih.gov/pubmed/27939064

https://www.ncbi.nlm.nih.gov/pubmed/11694782

https://www.ncbi.nlm.nih.gov/pubmed/27082923

https://www.ncbi.nlm.nih.gov/pubmed/25365825

https://www.ncbi.nlm.nih.gov/pubmed/26840503

https://www.ncbi.nlm.nih.gov/pubmed/29802035

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Newly Found Functions of B Cell

Posted in Adaptive Immune Response to Biomaterials and Tissue Repair, Allergy and Infectious Diseases, Autoimmune Inflammatory DIseases, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, CNS-Immune Interface, combination immunotherapies., Cytokine Receptor Structure, Cytokines, Diagnostic Immunology, Human Immune System in Health and in Disease, Human Naive B Cell Repertoire, Immune Engineering, Immune Modulatory, Immuno-Oncology & Genomics, Immunodiagnostics, Immunology, Immunotherapy, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Integrin-targeted Combination Immunotherapy, Metabolic Immuno-Oncology, Modulating Macrophages in Cancer Immunotherapy, Monoclonal Immunotherapy, NK Cell-Based Cancer Immunotherapy, Protection Against Autoimmune Disease, Synergistic Innate and Adaptive Immunotherapy, Synthetic Immunology: Hacking Immune Cells, Tolerance-inducing Autoimmune Disease Therapeutics, Universal Immune Cell Therapies (uICT), tagged Allergy, autoimmunity, B cell receptor, B-cell, Cancer, immune system, immunosuppression on May 23, 2019| Leave a Comment »

Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

4.1.8

4.1.8 Newly Found Functions of B Cell, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 4: Single Cell Genomics

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

Other advances that are providing insight include:

single-cell approaches to define B cell heterogeneity,
glycomic approaches to study effector sugars on antibodies,
new methods to study human B cell responses including CRISPR-based manipulation, and
the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

References:

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

https://www.pnas.org/content/115/18/4743

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

https://cshperspectives.cshlp.org/content/10/5/a028795

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

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Immunoediting can be a constant defense in the cancer landscape

Posted in Anticancer Resistance, Apoptosis, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Surgery of the Heart, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Cell Processing System in Cell Therapy Process Development, cell-based therapy, Childhood cancer, Circulating Tumor Cells (CTC), combination immunotherapies., Efficacy of Anti-Tumor T Cells, Engineering Better T Cells, Engineering Enhanced Cancer Vaccines, Funding Opportunities for Cancer Research, Human Immune System in Health and in Disease, Imaging-based Cancer Patient Management, Immune Modulatory, Immuno-Oncology & Genomics, Immunology, Immunotherapy, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Integrin-targeted Combination Immunotherapy, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood, Liquid Biopsy: Circulating Tumor Cells in Urine and Blood, Metabolic Immuno-Oncology, Microbiome and Responses to Cancer Therapy, MicroEngineering Cell-Tissue & Systems, Modulating Macrophages in Cancer Immunotherapy, Monoclonal Immunotherapy, NK Cell-Based Cancer Immunotherapy, Pancreatic cancer, Pharmacotherapy and Cell Activity, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Precision Cancer Medicine, Prostate Cancer: Monitoring vs Treatment, RNA Biology, Cancer and Therapeutics, Signaling & Cell Circuits, Single Cell Genomics, stem cell biology and patient-specific, Stem Cells for Regenerative Medicine, Synergistic Innate and Adaptive Immunotherapy, Synthetic Immunology: Hacking Immune Cells, Universal Immune Cell Therapies (uICT), Voices of Patients and Healthcare Providers, tagged Cancer, cancer vaccine, DNA, HLA, immunoediting on March 16, 2019| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

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Immunotherapy may help in glioblastoma survival

Posted in Anticancer Resistance, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Cell Biology, Childhood cancer, CNS-Immune Interface, combination immunotherapies., Efficacy of Anti-Tumor T Cells, Engineering Better T Cells, Glioblastoma, Imaging-based Cancer Patient Management, Immune Engineering, Immune Modulatory, Immuno-Oncology & Genomics, Immunodiagnostics, Immunology, Immunotherapy, Inflammasome, Innovation in Immunology Diagnostics, Integrin-targeted Combination Immunotherapy, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood, Metabolic Immuno-Oncology, Metastasis Process, Modulating Macrophages in Cancer Immunotherapy, Monoclonal Immunotherapy, Neuronal Circuits, NK Cell-Based Cancer Immunotherapy, Pancreatic cancer, Population genetics, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Precision Cancer Medicine, Prostate Cancer: Monitoring vs Treatment, RNA Biology, Cancer and Therapeutics, Synergistic Innate and Adaptive Immunotherapy, Synthetic Immunology: Hacking Immune Cells, Universal Immune Cell Therapies (uICT), tagged Cancer, Glioblastoma, Immunotherapy, pembrolizumab, survival, Therapy on March 16, 2019| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. But, in a glimmer of hope, a recent study found that a drug designed to unleash the immune system helped some patients live longer. Glioblastoma powerfully suppresses the immune system, both at the site of the cancer and throughout the body, which has made it difficult to find effective treatments. Such tumors are complex and differ widely in their behavior and characteristics.

A small randomized, multi-institution clinical trial was conducted and led by researchers at the University of California at Los Angeles involved patients who had a recurrence of glioblastoma, the most common central nervous system cancer. The aim was to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab (checkpoint inhibitor) in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone.

Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhanced both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

Immunotherapy has not proved to be effective against glioblastoma. This small clinical trial explored the effect of PD-1 blockade on recurrent glioblastoma in relation to the timing of administration. A total of 35 patients undergoing resection of recurrent disease were randomized to either neoadjuvant or adjuvant pembrolizumab, and surgical specimens were compared between the two groups. Interestingly, the tumoral gene expression signature varied between the two groups, such that those who received neoadjuvant pembrolizumab displayed an INF-γ gene signature suggestive of T-cell activation as well as suppression of cell-cycle signaling, possibly consistent with growth arrest. Although the study was not powered for efficacy, the group found an increase in overall survival in patients receiving neoadjuvant pembrolizumab compared with adjuvant pembrolizumab of 13.7 months versus 7.5 months, respectively.

In this small pilot study, neoadjuvant PD-1 blockade followed by surgical resection was associated with intratumoral T-cell activation and inhibition of tumor growth as well as longer survival. How the drug works in glioblastoma has not been totally established. The researchers speculated that giving the drug before surgery prompted T-cells within the tumor, which had been impaired, to attack the cancer and extend lives. The drug didn’t spur such anti-cancer activity after the surgery because those T-cells were removed along with the tumor. The results are very important and very promising but would need to be validated in much larger trials.

References:

https://www.washingtonpost.com/health/2019/02/11/immunotherapy-may-help-patients-with-kind-cancer-that-killed-john-mccain/?noredirect=on&utm_term=.e1b2e6fffccc

https://www.ncbi.nlm.nih.gov/pubmed/30742122

https://www.practiceupdate.com/content/neoadjuvant-anti-pd-1-immunotherapy-promotes-immune-responses-in-recurrent-gbm/79742/37/12/1

https://www.esmo.org/Oncology-News/Neoadjuvant-PD-1-Blockade-in-Glioblastoma

https://neurosciencenews.com/immunotherapy-glioblastoma-cancer-10722/

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Tumor Ammonia Recycling: How Cancer Cells Use Glutamate Dehydrogenase to Recycle Tumor Microenvironment Waste Products for Biosynthesis

Posted in Breast Cancer - impalpable breast lesions, Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, cancer metabolism, Cancer-Immune Interactions, Glioblastoma, Immunology, Inflammasome, Metabolic Immuno-Oncology, Oxidative phosphorylation, tumor microenvironment, Warburg effect, tagged alpha ketoglutarate, ammonia metabolism, biomass, Biosynthesis, breast cancer, cancer metabolic pathways, cancer metabolism, ER positive breast cancer, estrogen receptor positive cancer, glutaminolysis, IDH1 and IDH2, metabolic reprogramming, tumor microenvironment, Warburg Effect on February 13, 2019| Leave a Comment »

Tumor Ammonia Recycling: How Cancer Cells Use Glutamate Dehydrogenase to Recycle Tumor Microenvironment Waste Products for Biosynthesis

Reporter: Stephen J. Williams, PhD

A feature of the tumorigenic process is the rewiring of the metabolic processes that provides a tumor cell the ability to grow and thrive in conditions of limiting nutrients as well as the ability to utilize waste products in salvage pathways for production of new biomass (amino acids, nucleic acids etc.) required for cellular growth and division ^1-8. A Science article from Spinelli et al. ⁹ (and corresponding Perspective article in the same issue by Dr. Chi V. Dang entitled Feeding Frenzy for Cancer Cells ¹⁰) describes the mechanism by which estrogen-receptor positive (ER+) breast cancer cells convert glutamine to glutamate, release ammonia into the tumor microenvironment, diffuses into tumor cells and eventually recycle this ammonia by reductive amination of a-ketoglutarate by glutamate dehydrogenase (GDH) to produce glutamic acid and subsequent other amino acids needed for biomass production. Ammonia can accumulate in the tumor microenvironment in poorly vascularized tumor. Thus ammonia becomes an important nitrogen source for tumor cells.

Mammalian cells have a variety of mechanisms to metabolize ammonia including

Glutamate synthetase (GS) in the liver can incorporate ammonia into glutamate to form glutamine
glutamate dehydrogenase (GDH) converts glutamate to a-ketoglutarate and ammonia under allosteric regulation (discussed in a post on this site by Dr. Larry H. Berstein; subsection Drugging Glutaminolysis)
the reverse reaction of GDH, which was found to occur in ER+ breast cancer cells, a reductive amination of a-ketoglutarate to glutamate¹¹, is similar to the reductive carboxylation of a-ketoglutarate to citrate by isocitrate dehydrogenase (IDH) for fatty acid synthesis (IDH is overexpressed in many tumor types including cancer stem cells ^12-15), and involved in immune response and has been developed as a therapeutic target for various cancers. IDH mutations were shown to possess the neomorphic activity to generate the oncometabolite, 2-hydroxyglutarate (2HG) ^16-18. With a single codon substitution, the kinetic properties of the mutant IDH isozyme are signiﬁcantly altered, resulting in an obligatory sequential ordered reaction in the reverse direction ¹⁹.

In the Science paper, Spinelli et al. report that ER+ breast cancer cells have the ability to utilize ammonia sources from their surroundings in order to produce amino acids and biomass as these ER+ breast cancer cells have elevated levels of GS and GDH with respect to other breast cancer histotypes.

GDH was elevated in ER+ luminal cancer cells and the quiescent epithelial cells in organoid culture

However proliferative cells were dependent on transaminases, which transfers nitrogen from glutamate to pyruvate or oxaloacetate to form a-ketoglutarate and alanine or aspartate. a-ketoglutarate is further metabolized in the citric acid cycle.

Figure 1. Reductive amination and transamination reactions of glutamic acid. Source http://www.biologydiscussion.com/organism/metabolism-organism/incorporation-of-ammonia-into-organic-compounds/50870

Spinelli et al. showed GDH is necessary for ammonia reductive incorporation into a-ketoglutarate and also required for ER+ breast cancer cell growth in immunocompromised mice.

In addition, as commented by Dr. Dang in his associated Perspectives article, (quotes indent)

The metabolic tumor microenvironment produced by resident cells, such as fibroblasts and macrophages, can create an immunosuppressive environment ²⁰. Hence, it will be of great interest to further understand whether products such as ammonia could affect tumor immunity or induce autophagy (end quote indent)

Figure 2. Tumor ammonia recycling. Source: From Chi V. Dang Feeding Frenzy for cancer cells. Rights from RightsLink (copyright.com)

Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

Jessica B. Spinelli¹,², Haejin Yoon¹, Alison E. Ringel¹, Sarah Jeanfavre², Clary B. Clish², Marcia C. Haigis¹ *

1. ¹Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. 2. ²Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

* ↵*Corresponding author. Email: marcia_haigis@hms.harvard.edu

Science 17 Nov 2017:Vol. 358, Issue 6365, pp. 941-946 DOI: 10.1126/science.aam9305

Abstract

Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We found that ammonia is not merely a toxic waste product but is recycled into central amino acid metabolism to maximize nitrogen utilization. In our experiments, human breast cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. These data show that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.

References

1 Strickaert, A. et al. Cancer heterogeneity is not compatible with one unique cancer cell metabolic map. Oncogene 36, 2637-2642, doi:10.1038/onc.2016.411 (2017).

2 Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115-118, doi:10.1038/nature24057 (2017).

3 Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614, doi:10.1016/j.cell.2014.11.025 (2014).

4 Sousa, C. M. et al. Erratum: Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 540, 150, doi:10.1038/nature19851 (2016).

5 Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479-483, doi:10.1038/nature19084 (2016).

6 Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633-637, doi:10.1038/nature12138 (2013).

7 Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).

8 Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, doi:10.1016/j.cell.2011.02.013 (2011).

9 Spinelli, J. B. et al. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science 358, 941-946, doi:10.1126/science.aam9305 (2017).

10 Dang, C. V. Feeding frenzy for cancer cells. Science 358, 862-863, doi:10.1126/science.aaq1070 (2017).

11 Smith, T. J. & Stanley, C. A. Untangling the glutamate dehydrogenase allosteric nightmare. Trends in biochemical sciences 33, 557-564, doi:10.1016/j.tibs.2008.07.007 (2008).

12 Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380-384, doi:10.1038/nature10602 (2011).

13 Garrett, M. et al. Metabolic characterization of isocitrate dehydrogenase (IDH) mutant and IDH wildtype gliomaspheres uncovers cell type-specific vulnerabilities. Cancer & metabolism 6, 4, doi:10.1186/s40170-018-0177-4 (2018).

14 Calvert, A. E. et al. Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. Cell reports 19, 1858-1873, doi:10.1016/j.celrep.2017.05.014 (2017).

15 Sciacovelli, M. & Frezza, C. Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. The FEBS journal 284, 3132-3144, doi:10.1111/febs.14090 (2017).

16 Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739-744, doi:10.1038/nature08617 (2009).

17 Gross, S. et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. The Journal of experimental medicine 207, 339-344, doi:10.1084/jem.20092506 (2010).

18 Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer cell 17, 225-234, doi:10.1016/j.ccr.2010.01.020 (2010).

19 Rendina, A. R. et al. Mutant IDH1 enhances the production of 2-hydroxyglutarate due to its kinetic mechanism. Biochemistry 52, 4563-4577, doi:10.1021/bi400514k (2013).

20 Zhang, X. et al. IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. Neuro-oncology 18, 1402-1412, doi:10.1093/neuonc/now061 (2016).

2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Circulating Tumor Cells (CTC), Efficacy of Anti-Tumor T Cells, Engineering Better T Cells, Engineering Enhanced Cancer Vaccines, Genomic Expression, Human Antibody Response, Human Circulating Antibody Repertoire, Immuno-Oncology & Genomics, Immunotherapy, Metabolic Immuno-Oncology, NK Cell-Based Cancer Immunotherapy, Synergistic Innate and Adaptive Immunotherapy on October 1, 2018| Leave a Comment »

2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan

Reporter: Aviva Lev-Ari, PhD, RN

See

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/01/immune-system-stimulants-articles-of-note-pharmaceuticalintelligence-com/

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

Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/11/articles-on-immune-oncology-molecules-in-development-pharmaceuticalintelligence-com/

Monday, October 1, 2018

NIH grantees win 2018 Nobel Prize in Physiology or Medicine.

The Nobel Prize medallion.Nobel Foundation

The 2018 Nobel Prize in Physiology or Medicine has been awarded to National Institutes of Health grantee James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan, for their discovery of cancer therapy by inhibition of negative immune regulation.

The Royal Swedish Academy of Sciences said, “by stimulating the inherent ability of our immune system to attack tumor cells this year’s Nobel Laureates have established an entirely new principle for cancer therapy.”

Dr. Allison discovered that a particular protein (CTLA-4) acts as a braking system, preventing full activation of the immune system when a cancer is emerging. By delivering an antibody that blocks that protein, Allison showed the brakes could be released. The discovery has led to important developments in cancer drugs called checkpoint inhibitors and dramatic responses to previously untreatable cancers. Dr. Honjo discovered a protein on immune cells and revealed that it also operates as a brake, but with a different mechanism of action.

“Jim’s work was pivotal for cancer therapy by enlisting our own immune systems to launch an attack on cancer and arrest its development,” said NIH Director Francis S. Collins, M.D., Ph.D. “NIH is proud to have supported this groundbreaking research.”

Dr. Allison has received continuous funding from NIH since 1979, receiving more than $13.7 million primarily from NIH’s National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID).

“This work has led to remarkably effective, sometime curative, therapy for patients with advanced cancer, who we were previously unable to help,” said NCI Director Ned Sharpless, M.D. “Their findings have ushered in the era of cancer immunotherapy, which along with surgery, radiation and cytotoxic chemotherapy, represents a ‘fourth modality’ for treating cancer. A further understanding of the biology underlying the immune system and cancer has the potential to help many more patients.”

“Dr. Allison’s elegant and groundbreaking work in basic immunology over four decades and its important applicability to cancer is a vivid demonstration of the critical nature of interdisciplinary biomedical research supported by NIH,” says NIAID Director Anthony S. Fauci, M.D.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-grantees-win-2018-nobel-prize-physiology-or-medicine

Dr. Lev-Ari covered in person the following curated articles about James Allison, PhD since his days at University of California, Berkeley, including the prizes awarded prior to the 2018 Nobel Prize in Physiology.

2018 Albany Medical Center Prize in Medicine and Biomedical Research goes to NIH’s Dr. Rosenberg and fellow immunotherapy researchers James P. Allison, Ph.D., and Carl H. June, M.D.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/15/2018-albany-medical-center-prize-in-medicine-and-biomedical-research-goes-to-nihs-dr-rosenberg-and-fellow-immunotherapy-researchers-james-p-allison-ph-d-and-carl-h-june-m-d/

Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston

REAL TIME Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/09/08/lectures-by-the-2017-award-recipients-of-warren-alpert-foundation-prize-in-cancer-immunology-october-5-2017-hms-77-louis-paster-boston/

Cancer-free after immunotherapy treatment: Treating advanced colon cancer – targeting KRAS gene mutation by tumor-infiltrating lymphocytes (TILs) and Killer T-cells (NK)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/08/cancer-free-after-immunotherapy-treatment-treating-advanced-colon-cancer-targeting-kras-gene-mutation-by-tumor-infiltrating-lymphocytes-tils-and-killer-t-cells-nk/

New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN): Shrink Tumors and bolster Vaccines, re-arm the Immune System’s Natural Killer Cells, which attack Cancer Cells and Virus-infected Cells

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/24/new-class-of-immune-system-stimulants-cyclic-di-nucleotides-cdn-shrink-tumors-and-bolster-vaccines-re-arm-the-immune-systems-natural-killer-cells-which-attack-cancer-cells-and-virus-inf/

UC Berkeley research led to Nobel Prize-winning immunotherapy

By Robert Sanders, Media relations| OCTOBER 1, 2018

Immunologist James P. Allison today shared the 2018 Nobel Prize in Physiology or Medicine for groundbreaking work he conducted on cancer immunotherapy at UC Berkeley during his 20 years as director of the campus’s Cancer Research Laboratory.

James Allison, who for 20 years was a UC Berkeley immunologist conducting fundamental research on cancer, is now at the M.D. Anderson Cancer Center in Houston, Texas.

Now at the University of Texas M.D. Anderson Cancer Center in Houston, Allison shared the award with Tasuku Honjo of Kyoto University in Japan “for their discovery of cancer therapy by inhibition of negative immune regulation.”

Allison, 70, conducted basic research on how the immune system – in particular, a cell called a T cell – fights infection. His discoveries led to a fundamentally new strategy for treating malignancies that unleashes the immune system to kill cancer cells. A monoclonal antibody therapy he pioneered was approved by the Food and Drug Administration in 2011 to treat malignant melanoma, and spawned several related therapies now being used against lung, prostate and other cancers.

“Because this approach targets immune cells rather than specific tumors, it holds great promise to thwart diverse cancers,” the Lasker Foundation wrote when it awarded Allison its 2015 Lasker-DeBakey Clinical Medical Research Award.

Allison’s work has already benefited thousands of people with advanced melanoma, a disease that used to be invariably fatal within a year or so of diagnosis. The therapy he conceived has resulted in elimination of cancer in a significant fraction of patients for a decade and counting, and it appears likely that many of these people are cured.

“Targeted therapies don’t cure cancer, but immunotherapy is curative, which is why many consider it the biggest advance in a generation,” Allison said in a 2015 interview. “Clearly, immunotherapy now has taken its place along with surgery, chemotherapy and radiation as a reliable and objective way to treat cancer.”

“We are thrilled to see Jim’s work recognized by the Nobel Committee,” said Russell Vance, the current director of the Cancer Research Laboratory and a UC Berkeley professor of molecular and cell biology. “We congratulate him on this highly deserved honor. This award is a testament to the incredible impact that the fundamental research Jim conducted at Berkeley has had on the lives of cancer patients”

“I don’t know if I could have accomplished this work anywhere else than Berkeley,” Allison said. “There were a lot of smart people to work with, and it felt like we could do almost anything. I always tell people that it was one of the happiest times of my life, with the academic environment, the enthusiasm, the students, the faculty.”

In this video about UC Berkeley’s new Immunotherapeutics and Vaccine Research Initiative (IVRI), Allison discusses his groundbreaking work on cancer immunotherapy.

In fact, Allison was instrumental in creating the research environment of the current Department of Molecular and Cell Biology at UC Berkeley as well as the department’s division of immunology, in which he served stints as chair and division head during his time at Berkeley, said David Raulet, director of Berkeley’s Immunotherapeutics and Vaccine Research Initiative (IVRI).

“His actions helped create the superb research environment here, which is so conducive to making the fundamental discoveries that will be the basis of the next generation of medical breakthroughs,” Raulet said.

Self vs. non-self

Allison joined the UC Berkeley faculty as a professor of molecular and cell biology and director of the Cancer Research Laboratory in 1985. An immunologist with a Ph.D. from the University of Texas, Austin, he focused on a type of immune system cell called the T cell or T lymphocyte, which plays a key role in fighting off bacterial and viral infections as well as cancer.

Supercharging the immune system to cure disease: immunotherapy research at UC Berkeley. (UC Berkeley video by Roxanne Makasdjian and Stephen McNally)

At the time, most doctors and scientists believed that the immune system could not be exploited to fight cancer, because cancer cells look too much like the body’s own cells, and any attack against cancer cells would risk killing normal cells and creating serious side effects.

“The community of cancer biologists was not convinced that you could even use the immune system to alter cancer’s outcome, because cancer was too much like self,” said Matthew “Max” Krummel, who was a graduate student and postdoctoral fellow with Allison in the 1990s and is now a professor of pathology and a member of the joint immunology group at UCSF. “The dogma at the time was, ‘Don’t even bother.’ ”

“What was heady about the moment was that we didn’t really listen to the dogma, we just did it,” Krummel added. Allison, in particular, was a bit “irreverent, but in a productive way. He didn’t suffer fools easily.” This attitude rubbed off on the team.

Trying everything they could in mice to tweak the immune system, Krummel and Allison soon found that a protein receptor called CTLA-4 seemed to be holding T cells back, like a brake in a car.

Postdoctoral fellow Dana Leach then stepped in to see if blocking the receptor would unleash the immune system to actually attack a cancerous tumor. In a landmark paper published in Science in 1996, Allison, Leach and Krummel showed not only that antibodies against CTLA-4 released the brake and allowed the immune system to attack the tumors, but that the technique was effective enough to result in long-term disappearance of the tumors.

“When Dana showed me the results, I was really surprised,” Allison said. “It wasn’t that the anti-CTLA-4 antibodies slowed the tumors down. The tumors went away.”

After Allison himself replicated the experiment, “that’s when I said, OK, we’ve got something here.”

Checkpoint blockade

The discovery led to a concept called “checkpoint blockade.” This holds that the immune system has many checkpoints designed to prevent it from attacking the body’s own cells, which can lead to autoimmune disease. As a result, while attempts to rev up the immune system are like stepping on the gas, they won’t be effective unless you also release the brakes.

James Allison in 1993, when he was conducting research at UC Berkeley on a promising immunotherapy now reaching fruition. (Jane Scherr photo)

“The temporary activation of the immune system though ‘checkpoint blockade’ provides a window of opportunity during which the immune system is mobilized to attack and eliminate tumors,” Vance said.

Allison spent the next few years amassing data in mice to show that anti-CTLA-4 antibodies work, and then, in collaboration with a biotech firm called Medarex, developed human antibodies that showed promise in early clinical trials against melanoma and other cancers. The therapy was acquired by Bristol-Myers Squibb in 2011 and approved by the FDA as ipilimumab (trade name Yervoy), which is now used to treat skin cancers that have metastasized or that cannot be removed surgically.

Meanwhile, Allison left UC Berkeley in 2004 for Memorial Sloan Kettering research center in New York to be closer to the drug companies shepherding his therapy through clinical trials, and to explore in more detail how checkpoint blockade works.

“Berkeley was my favorite place, and if I could have stayed there, I would have,” he said. “But my research got to the point where all the animal work showed that checkpoint blockade had a lot of potential in people, and working with patients at Berkeley wasn’t possible. There’s no hospital, no patients.”

Thanks to Allison’s doggedness, anti-CTLA-4 therapy is now an accepted therapy for cancer and it opened the floodgates for a slew of new immunotherapies, Krummel said. There now are several hundred ongoing clinical trials involving monoclonal antibodies to one or more receptors that inhibit T cell activity, sometimes combined with lower doses of standard chemotherapy.

Antibodies against one such receptor, PD-1, which Honjo discovered in 1992, have given especially impressive results. Allison’s initial findings can be credited for prompting researchers, including Allison himself, to carry out the studies that have demonstrated the potent anti-cancer effects of PD-1 antibodies. In 2015, the FDA approved anti-PD-1 therapy for malignant melanoma, and has since approved it for non-small-cell lung, gastric and several other cancers.

Science magazine named cancer immunotherapy its breakthrough of 2013 because that year, “clinical trials … cemented its potential in patients and swayed even the skeptics. The field hums with stories of lives extended: the woman with a grapefruit-size tumor in her lung from melanoma, alive and healthy 13 years later; the 6-year-old near death from leukemia, now in third grade and in remission; the man with metastatic kidney cancer whose disease continued fading away even after treatment stopped.”

Allison pursued more clinical trials for immunotherapy at Sloan-Kettering and then in 2012 returned to his native Texas.

Born in Alice, Texas, on Aug. 7, 1948, Allison earned a B.S. in microbiology in 1969 and a Ph.D. in biological science in 1973 from the University of Texas, Austin.

RELATED INFORMATION

Nobel Prize website

Lasker-DeBakey Clinical Medical Research Award

The story of Yervoy (ipilimumab)

Activator Puts the Brakes on Cancer (technology transfer and ipilimumab, by Mary Roberts Henderson)

Antibodies stimulate tumor rejection and confer subsequent immunity, UC Berkeley scientists report (1996 UC Berkeley press release)

Hot new immune therapy from UC Berkeley is being readied for clinical trials against prostate cancer and melanoma (1999 UC Berkeley press release)

SOURCE

http://news.berkeley.edu/2018/10/01/uc-berkeley-research-led-to-nobel-prize-winning-immunotherapy/

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Original Tweets Re-Tweets and Likes by @pharma_BI and @AVIVA1950 at #kisymposium for 17th annual Summer Symposium: Breakthrough Cancer Nanotechnologies: Koch Institute, MIT Kresge Auditorium, June 15, 2018, 9AM-4PM

Posted in BioTechnology - Venture Creation, Cancer Genomics, Conference Coverage with Social Media, CRISPR/Cas9 & Gene Editing, Metabolic Immuno-Oncology, Monoclonal Immunotherapy, Nanotechnology for Drug Delivery on June 17, 2018| Leave a Comment »

Original Tweets Re-Tweets and Likes by @pharma_BI and @AVIVA1950 at #kisymposium for 17th annual Summer Symposium: Breakthrough Cancer Nanotechnologies: Koch Institute, MIT Kresge Auditorium, June 15, 2018, 9AM-4PM

Aviva Lev-Ari‏ @AVIVA1950 Jun 15

2.1.3.6 Original Tweets Re-Tweets and Likes by @pharma_BI and @AVIVA1950 at #kisymposium for 17th annual Summer Symposium: Breakthrough Cancer Nanotechnologies: Koch Institute, MIT Kresge Auditorium, June 15, 2018, 9AM-4PM, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

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Aviva Lev-Ari Retweeted Anne E Deconinck

Enjoyed his comment on the Panel #KISymposium

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Anne E Deconinck @AEDeconinck

Awesome interview with @NoubarAf. Can’t wait to see him on our panel at next week’s #KISymposium @kochinstitute @KI_Nanomedicine @MIT https://twitter.com/MrJeffKarp/status/1005176997063086081 …
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Patrice Milos‏ @milospm1206 Jun 15

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A reminder of the increasing cancer burden #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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SG: molecular micro bubbles for molecular targeting to understand human cancer #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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SG: First micro bubble targeting KDR for human cancer detection to assess clinical safety in breast and ovarian lesions and feasibility to detect via ultrasound. Molecular imaging to histology #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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SG: dosing up to 0.08 ml/kg well tolerated, well tolerated, 40 subjects, defining malignant and benign disease #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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SG: important signal imaging differentiating cancer lesions #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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Ralph Weissleder (Harvard): the three pillars of cancer diagnostics #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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RW: Challenges nicely highlighted #kisymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Patrice Milos

two technologies will lead the way

Aviva Lev-Ari added,

Patrice Milos @milospm1206

RW: Describing extracellular vessicles which are shed from cancer cells, contain RNA and Perrin reflecting cell of origin and the analysis tools to study #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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AB: amazing to see data on using the M13 phage with carbon nanotube homing to tumors prior to surgery allowing localization of tumors <1mm in size! #kisymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Patrice Milos

Great talk by @MarkDavis @Caltech

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Patrice Milos @milospm1206

Mark Davis (Caltech): Nano particles for therapeutic delivery. Advantages #kisymposium
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Patrice Milos

Great technology emerging

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Patrice Milos @milospm1206

MD: Nanoparticle delivery in human studies for safety and early efficacy indications #kisymposium –
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Anne E Deconinck

Enjoyed the talk very much

Aviva Lev-Ari added,

Anne E Deconinck @AEDeconinck

Great slide (and talk!) by Dan Anderson @kochinstitute @MIT_IMES #kisymposium combining many of our favorite things #CRISPR #RNAThx #nanomedicine
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Patrice Milos‏ @milospm1206 Jun 15

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AB: Great props to present her virus and strategies for genetically engineering virus to bind to carbon nanotubes! #kisymposium

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Patrice Milos‏ @milospm1206 Jun 15

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Suzie Pun (Univ of Washington): targeting tumor associated macrophage as way to potentiate targeted therapies #KISymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Julien C. Senécal

cutting edge

Aviva Lev-Ari added,

Julien C. Senécal @jul_cs

Daniel Anderson @KI_Nanomedicine uses NPs to deliver siRNA or mRNA to silence or edit genes at a specific location in-vivo! #mindblown #KIsymposium
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Patrice Milos‏ @milospm1206 Jun 15

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Daniel Anderson (Koch): Can nanoparticles be used for delivery of Genome editing tools? Inside cells? #KIsymposium

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Aviva Lev-Ari‏@AVIVA1950Jun 15

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Aviva Lev-Ari Retweeted Anne E Deconinck

Great visualization in Angie Belcher’s presentation

Aviva Lev-Ari added,

Anne E Deconinck@AEDeconinck

Angie Belcher @kochinstitute @KI_Nanomedicine @MIT and her model of bacteriophage for detecting tiny tumors (<2mm) #KISymposium https://twitter.com/milospm1206/status/1007627821634740224…
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Patrice Milos‏ @milospm1206 Jun 15

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DA: wow, fascinating delivery of gene editing machinery to liver or lungs to correct gene defects, AAV for sgRNA and repair DNA plus nanoparticle containing Cas9 mRNA – and it worked in animal model to correct metabolic defect. #Kisymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Patrice Milos

I agree

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Patrice Milos @milospm1206

DA: interesting approaches to consider for cancer utility #KIsymposium
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Julien C. Senécal‏ @jul_cs Jun 15

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Sangeeta Bhatia stresses the importance of #nano for early detection of #cancer especially in low-resource setting. Also promoting the launch of #MITnano this year #KIsymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Omar Costilla Reyes

Was so impressed by @MIT.nano

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Omar Costilla Reyes @konet

Director of @mit nano Vladimir Bulovic says that nanoscale technology will advance every area of research at MIT through scientific collaboration. Looking forward to the discoveries it will enable! @kochinstitute …

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Marble Center

Combination drug therapy one biologics and one nano

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Marble Center @KI_Nanomedicine

New ways of thinking about combo therapies using #nanomedicine with Dr. Mark E. Davis @kochinstitute #KISymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Koch Institute at MIT

Cutting Edge

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Koch Institute at MITVerified account @kochinstitute

Holography and nanoplasmodics are just two examples of what the @WeisslederLab is working on to make cancer detection and diagnosis more accurate, affordable, and accessible, not to mention less invasive. Stay tuned for #KIsymposium videos later this summer!
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Anne E Deconinck‏ @AEDeconinck Jun 15

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Adherence to medicine is another area where #nanomedicine will likely be very important @JMaraganore #kisymposium. Indeed, area of great interest @kochinstitute w/ both nano and drug delivery devices

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Leny Gocheva‏ @gocheval Jun 15

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Always love @KI_Nanomedicine’s Angela Belcher’s demos during her talks! @kochinstitute #KISymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted John Maraganore

Great Presentations at #BIO2018 and great opinions expressed #KISYMPOSIUM

Aviva Lev-Ari added,

John Maraganore @JMaraganore

My first panel since #BIO2018 and VERY glad it had diverse members and opinions. It was better as a result! Thanks to @kochinstitute and my co-panelists for a great discussion! #KIsymposium https://twitter.com/kochinstitute/status/1007686581753405440 …

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Anne E Deconinck‏ @AEDeconinck Jun 15

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Amazing early detection/diagnostics technology from Ralph’s Weissleder lab @MGHCancerCenter: single cell, treatment informing Dx w/machine learning, as efficient as FACS but 1000x cheaper! #kisymposium @kochinstitute @KI_Nanomedicine

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Vimisha Dharamdasani‏ @Vimishaaa Jun 15

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Learning how to translate technology from an incredible panel @Alnylam @kochinstitute @KI_Nanomedicine #KIsymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Anne E Deconinck

i agree

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Anne E Deconinck @AEDeconinck

“I think there’s almost no area that #nano medicine won’t reach” Bob Langer @kochinstitute @MIT #kisymposium
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Anne E Deconinck

Amazing panel

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Anne E Deconinck @AEDeconinck

Super excited about today’s #kisymposium panel discussion w/ @JMaraganore @Alnylam, @NoubarAf @FlagshipPioneer, Paula Hammond & Bob Langer @kochinstitute, Rijcken @cristaltherap, Bradbury …
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Anne E Deconinck

Kendall square and Silicon Valley

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Anne E Deconinck @AEDeconinck

IP and patents really matter for translation, valley of death still a problem, but look @MIT & @Stanford: Not about short term gains or royalties. It’s about IMPACT. Bob Langer @kochinstitute (doing good in the world) #kisymposium
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Anne E Deconinck‏ @AEDeconinck Jun 15

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Tour-de-force talk by Jim Heath @ISBUSA. Glad we recorded so many of today’s talks, definitely watching this one again! #kisymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Koch Institute at MIT

A leader in n-dimensions

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Koch Institute at MITVerified account @kochinstitute

Time to kick off Session III: Nanosystems & Devices with @snbhatia, director of @KI_Nanomedicine. “Protease Nanosensors for Cancer Detection, Classification and Monitoring” Sounds like a sensitive subject! …
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Anne E Deconinck

Great role model, Paula Hammond

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Anne E Deconinck @AEDeconinck

Paula Hammond: One of my main roles as a PI @kochinstitute is creating an environment in which creativity can thrive, and new ideas result in new platforms & new solutions #kisymposium
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Koch Institute at MIT

Best talk

Aviva Lev-Ari added,

Koch Institute at MITVerified account @kochinstitute

Might need a tissue for this next talk, but that’s ‘cule. All will be (micro)well. Rashid Bashir from @eceILLINOIS presents “Micro and Nanotechnologies for Analysis of Tissues and Molecules” So fab! #KIsymposium
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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Na no na no, na no na no, hey hey, goodbye! Thanks to @KI_Nanomedicine, our amazing speakers, our wonderful sponsors, and everyone who came out to learn about Breakthrough Cancer Nanotechnologies at #KIsymposium 2018. See you on June 14, 2019 for AI/machine learning in cancer!

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Aviva Lev-Ari Retweeted Koch Institute at MIT

Amazing man

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Koch Institute at MITVerified account @kochinstitute

Vladimir Bulović, founding director of #MITnano, presents “Nanoscale Discoveries for Transformative Breakthroughs” in the final session of #KIsymposium 2018. Through the ages, the lesson is clear: Dream…

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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This next one’s going to get personal. James Heath of @ISBUSA is taking “A Molecular View of Immuno-Oncology” with insight on how to personalize the field. We’re T-sold! (past tense of T-cell) #KIsymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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SYNOPSIS – 17th annual Summer Symposium: Breakthrough Cancer Nanotechnologies: Koch Institute, MIT Kresge Auditorium, June 15, 2018, 9AM-4PM #kisymposium @PHARMA_BI @AVIVA1950 https://pharmaceuticalintelligence.com/2018/06/14/17th-annual-summer-symposium-breakthrough-cancer-nanotechnologies-koch-institute-mit-kresge-auditorium-june-15-2018-9am-4pm-2/ … via @wordpressdotcom

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Nanoscale will define many future discoveries 51% of the recently tenured SOS faculty – use nano 67% of the recently tenured SOE faculty with benefits – use nano #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @VladimirBulović
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Analytical Chemistry challenge:Fundamental Immunology Challenge CRISPR knocking out genes not for knocking in genes Mutated proteins and NEO antiagens: mostly computational task #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @JamesHeath

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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ON CHIP RT-LAMP CONTROL: CANCER (red) VS NON-CANCER (blue) – FTIR Single cell spatial RNA Seq Hematology Analyzer – complete blood celll count vs Flow cytometry #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @RashidBashir,
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Cryo-section on microwell array, pixelate and fix tissue inside wells amplification reagents loaded on chip flow on chip On-chip RT-LAMP: Spatial fluorescence analysis #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @RashidBashir,
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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liquid biopsy, molecualar analysis of the tumor spatial map of nuclei acids in tissue – Intra tumor heterogeniety subclonal genetic diversity in situ hybridization #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @RashidBashir,
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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@SangeetaBhatia #Massbarcodes enable #multiplexing #Massencoded #synthetic #biomarkers Differentiating similar diseases with #proteaseactivity #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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@SangeetaBhatia multi-compartment modeling for predicting #PK Enhancing sensitivity by #nanosensorengineering for #ovariancancer #detection #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Endoprotease Cancer: MMP9, MMP4 Synthetic Biomarkers Enzyme-responsive nanosensors PK switch Synthetic Biomarker paradigm for clinical decisions – Exogenous, multiples, urine #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @SangeetaBhatia,
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Team Science approache to effect the community @MichelleBradbury #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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@PaulaHammond @NoubarAfeyan Science must lead the way for translation and implementations, innovations IMPACT in academia on economy: MIT and Stanford in Sillicon Valley are leading the way #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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durability of nanoparticles in the body area we need more knowing FDA is developing new guidelines for nanotechnology policies will come from FDA soon #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @JohnMaraganore
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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@JohnMaraganore company made decision to celebrate science by publishing research @alnylam #augmentedreality @NOUBARAFEYAM: BIOLOGY DEVELOPED TOOL SETS THEY ARE EXAMPLES FOR NANO PARTICLES #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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potential becoming reality is in the hands of very able people working with people and other istitutionscreate robust designs partnering among roles #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @PaulaHammond @MichelleBradbury
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Notion of founding a company Investors some are scientists help develop companies while pursing science lip faith vs facts and quantification #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @NoubarAfeyan,
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Bringing therapeutics to tumor tissue @BobLanger platform technology companies committed to bring cure #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @RobertLanger @johnmataganore @Alnylam @CristianneRijcken @CristalTherapeutics
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Diagnostics use of nanopartics by 7 developing companies #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @NoubarAfeyan
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Highly engineered particle encapsulated used in OR microdose in the past hospital setting finding optimal oncologies subtherapeutic properties cell death #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @MichelleSBradbury @MemorialSloan
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Panel on #translations of #Nanomedicine to #patients #kisymposium @pharma_BI @AVIVA1950 @BobLanger transformation of Biotech industry around @MIT like no elsewhere in the World

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Flagship Pioneering‏ @FlagshipPioneer Jun 14

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Are you going to @kochinstitute‘s #KIsymposium tomorrow? Hear from @FlagshipPioneer CEO @NoubarAf, Bloomberg’s @beccabiotech, Alnylam’s @jmaraganore, @MIT‘s Robert Langer, and others. https://ki.mit.edu/news/symposium/2018 …

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Angela Belcher (@MITdeptofBE @KI_Nanomedicine) is sharing the stage with her portable, light-up bacteriophage to share “New Approaches for Finding Tiny Tumors: Towards Early Detection and Treatment of #ovariancancer” Ready, set, glow! #KIsymposium

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Omar Costilla Reyes‏ @konet Jun 15

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Attending the 17th annual Cancer research symposium organized by @kochinstitute. Interesting talk by Angela Belcher on finding tiny tumors. #KIsymposium @MIT

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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(gene) Silence, everyone! It’s time for @KI_Nanomedicine member Dan Anderson (@MITChemE) to tell us about “Nanoparticle Formulations for RNA Therapy and Gene Editing.” #KIsymposium

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Julien C. Senécal‏ @jul_cs Jun 15

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@ben_ouyang and @TheChanLab taught me the importance of TAMs in tumour growth and NP delivery. The peptide developed by Suzie Pun that specifically targets M2 Mø has the potential to increase the efficiency of cancer nanotherapies #KIsymposium

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Session II: Therapeutics continues with Suzie Pun (@UW researcher and @KI_Nanomedicine scientific advisor) presenting on “Modulating Tumor-Associated Macrophages.” (Wait, was that a “macro” in the title? We thought #Kisymposium was all nano all the time this year!)

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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KI Director Tyler Jacks thanks this year’s #KISymposium co-chairs: KI members Angela Belcher @MITdeptofBE, @snbhatia, director of @KI_Nanomedicine & Paula Hammond @MITChemE Dept head

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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50% HER2 positive will have brain metastesis BBB TfP Receptor-mediate Transcytosis: Antibody affinity Nanoparticles behave similarity to antibodies in the brain #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @MarkEDavis @Caltech

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Marble Center‏ @KI_Nanomedicine Jun 15

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It is happening!! @snbhatia @kochinstitute #KIsymposium

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Excitement is “bubbling” after that first talk, but hold your questions for the break, please! #KIsymposium

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Julien C. Senécal‏ @jul_cs Jun 15

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S.S. Gambhir from @StanfordMed uses ultrasound imaging of nanobubbles (with gas core and active targeting) to image cancer at molecular level. Q: Do changes in pressure in body affect quality of imaging? #KIsymposium

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Heads up! @Caltech‘s Mark Davis is talking about “Designing Nanoparticles to Safely Cross the Blood-Brain Barrier for Treating Brain Cancers” #KIsymposium

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Yup, definite “props” to Angie for a dynamic engaging talk. Good science too. Very promising technology, data. Lots to discuss during the break. #KIsymposium

MIT Dept of BE, Marble Center and MGH Cancer Center

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Patrice Milos‏ @milospm1206 Jun 15

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MD: Now moving into combo delivery with nanoparticle. Topo I and PARP toxicity so high when delivered in drug form, toxicity so high dosing had to be reduced to sub-efficacious levels. Now NCI study using delivery with nanoparticles to avoid tox #KISymposium

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Welcome and Intro to NanoMedicine with @snbhatia @KI_Nanomedicine #kisymposium.

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EBioMedicine‏ @EBioMedicine Jun 15

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EBioMedicine Retweeted Claudia Schaefer

Our editor is at the #kisymposium today @marblecenter @kochinstitute. This is what’s going on right now:

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Claudia Schaefer @Claudia_Editor

Great talk from Prof. Weissleder on the development of cancer diagnostics with actionable consequences ⁦@harvardmed⁩ ⁦@WeisslederLab⁩ ⁦@kochinstitute⁩ ⁦@EBioMedicine⁩

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Koch Institute at MIT‏Verified account @kochinstitute Jun 15

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Our first speaker, Sanjiv Sam Gambhir @Stanford talks Bubble Based Nanodiagnostics. Early detection = Prevention = deserves intense focus so we can save lives #kisymposium

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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@DanielAnderson e-sgRNA – edited PCKS9- hyperlipidemia — Nanoparticle for in vivo Genome Editing RNA NANOTHERAPEUTICS AND CANCER Delivery to Immune system – Genome editing in vivo of CAR-Ts #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Chylomicron metabolism: Mechanism of APoE mediated iLNP delivery siRNA in hypatocytes 5 genes silencing in lung endothelial cells IMMUNE CELLS AS A TARGET FOR siRNA #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @DanielGAnderson @IOM
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Immunomodulation – Macrophage targeting for TAM for Humans improve drug potency synthetic Nucleocapsids Biomaterials for modulating tumor extracellular matrix #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @SusieHPun @uwashington
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Gail Thornton‏ @GailThornt Jun 14

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17th annual Summer Symposium: Breakthrough Cancer Nanotechnologies: Koch Institute, MIT Kresge Auditorium, June 15, 2018, 9AM-4PM https://pharmaceuticalintelligence.com/2018/06/14/17th-annual-summer-symposium-breakthrough-cancer-nanotechnologies-koch-institute-mit-kresge-auditorium-june-15-2018-9am-4pm-2/ … via @wordpressdotcom @aviva1950 @pharma_BI

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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#translational #diagnostics: #Precisiononcology (1) Imaging (2) Tumor biopsy (3) Liquid biopsy Enable earlier detection Visualization affordable cost @MGH #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @RalphWeissleder @MGHCancerCenter

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Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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#Fallopiantubes maximum #reduction in #tumor better #survivalrate Pre-surgical planning locates hard-to-detect #ovariantumor – find tumors that are hidden #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @AngelaBelcher
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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#Rapidcellular #proteinprofiling #Exosome #POCtesting #AI #DefractionAnalysis #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @RalphWeissleder @MGHCancerCenter
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Bubble based Nanodiognostics: cancer location molecular events, atomical modelity Bubble size nanobubbles microbubbles targeted for Vascular Endothilium In vivo #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @SanjivSamGambhir @Stanford
Aviva Lev-Ari‏ @AVIVA1950 Jun 15

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Nanotech, Diagnostics, Therapeutics, Cancer Care, Cancer Biology New Center for NanoMedicine @MIT Prevention and early detection of Cancer for improved outcomes #Cancer #Nanotechnologies @kochinstitute #Kresge @MIT @Pharma_BI @AVIVA1950 #KISYMPOSIUM @TylerJacks @SangeetaBhatia
Aviva Lev-Ari‏ @AVIVA1950 Jun 14

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17th annual #Summer #Symposium: Breakthrough #Cancer #Nanotechnologies: @KochInstitute, @MIT #KresgeAuditorium, June 15, 2018, 9AM-4PM https://pharmaceuticalintelligence.com/2018/06/14/17th-annual-summer-symposium-breakthrough-cancer-nanotechnologies-koch-institute-mit-kresge-auditorium-june-15-2018-9am-4pm-2/ … via @wordpressdotcom

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Knowing the genetic vulnerability of bladder cancer for therapeutic intervention

Posted in Anticancer Resistance, Apoptosis, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Biological Networks, Gene Regulation and Evolution, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Cell Processing System in Cell Therapy Process Development, Childhood cancer, Clinical Diagnostics, Clinical Genomics, Gene Regulation, Gene Therapy & Gene Editing Development, Genome Biology, Genomic Endocrinology, interventional oncology, Metabolic Immuno-Oncology, Metastasis Process, Microbiome and Responses to Cancer Therapy, mRNA Therapeutics, Mutagenesis, Personalized and Precision Medicine & Genomic Research, Population genetics, Population Health Management, Population Health Management, Genetics & Pharmaceutical, RNA Biology, RNA Biology, Cancer and Therapeutics, Signaling, tagged bladder, Cancer, classification, invasive, Ral, Ras, therapeutic on November 21, 2017| Leave a Comment »

Knowing the genetic vulnerability of bladder cancer for therapeutic intervention

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

References:

https://www.ncbi.nlm.nih.gov/pubmed/29117162

https://www.ncbi.nlm.nih.gov/pubmed/27321955

https://www.ncbi.nlm.nih.gov/pubmed/28583312

https://www.ncbi.nlm.nih.gov/pubmed/24476821

https://www.ncbi.nlm.nih.gov/pubmed/28988769

https://www.ncbi.nlm.nih.gov/pubmed/28753430

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CHI’s 5th ImmunoModulatory Therapeutic Antibodies for Cancer Conference, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Immuno-Oncology & Genomics, Immunodiagnostics, Immunotherapy, Innovation in Immunology Diagnostics, Metabolic Immuno-Oncology, Monoclonal Immunotherapy on August 28, 2017| Leave a Comment »

CHI’s 5th ImmunoModulatory Therapeutic Antibodies for Cancer Conference, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

Reporter: Aviva Lev-Ari, PhD, RN

ANNOUNCEMENT

Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover the event in

REAL TIME

Aviva Lev-Ari, PhD, RN will be streaming live from the floor of the Sheraton Hotel in Boston on August 28 and August 29, 2017

@pharma_BI

@AVIVA1950

Cambridge Healthtech Institute’s 5th Annual

Immunomodulatory Therapeutic Antibodies for Cancer

Scientific Strategies for Discovering and Developing Novel Immunotherapies and Agents to Improve the Efficacy and Toxicology Profiles of T Cell-Targeted Biotherapeutics
August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

http://www.immuno-oncologysummit.com/Immunomodulatory-Antibodies-Cancer/

MONDAY, AUGUST 28

7:30 am Registration & Morning Coffee

8:25 Chairperson’s Opening Remarks

Yan Qu, Ph.D., Senior Principal Scientist, Pfizer

8:30 KEYNOTE PRESENTATION: Enabling Effective Immuno-Oncology

Gregory Adams, Ph.D., CSO, Eleven Biotherapeutics

Checkpoint inhibitors and other immune-oncology agents have shown significant promise in the treatment of a variety of cancers. However, many of these agents are only effective when an existing host immune response has already been induced by other therapeutic approaches. I will discuss strategies that may be used to effectively set the stage for immune-oncology treatments including Eleven BioTherapeutics’ Targeted Protein Therapeutics.

9:00 Immunomodulatory Antibodies – Potentiation by Fc Receptor Engagement

Rony Dahan, Ph.D., Principal Investigator, Immunology, Weizmann Institute of Science, Israel

Immunomodulatory mAbs are revolutionizing cancer treatment due to their clinical effective stimulation of therapeutic anti-cancer immunity. Recent studies demonstrated the importance of the Fc domain of these types of mAbs. Their optimal activity can be critically depended on their ability to engage defined FcgR pathways. I will discuss our recent characterization of these FcgR-dependent mechanisms, and how they can be exploited for introducing second generation Fc-optimized immunomodulatory mAbs.

9:30 Coffee Break

10:00 The Role of Metabolism in Immune Response in Tumors: Merging the Past and the Present of Tumor Microenvironment

Allison S. Betof, M.D., Ph.D., Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center

Tumors are not simply collections of cancer cells that arise in a vacuum; they are instead complex structures composed of blood vessels, immune cells, and other supporting structures that interact, consume oxygen and other nutrients, and produce waste. Tumor metabolism has long been viewed as a therapeutic target. I will discuss recent data on how metabolism influences immunobiology and our group’s approach to harness these interactions to improve therapeutic outcomes.

10:30 PI3Kgamma Is a Molecular Switch that Controls Immune Suppression

Megan M. Kaneda, Ph.D., Assistant Project Scientist, University of California, San Diego

Macrophages play critical but opposite roles in inflammation and cancer. We have found that the predominant isoform of PI3K in myeloid cells, PI3Kgamma, controls the switch between immune stimulation and immune suppression. Inhibition of macrophage PI3Kgamma activity promotes an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity and synergizes with checkpoint inhibitor therapy to promote tumor regression and extend survival in mouse models of cancer.

11:00 Avelumab (hIgG1 Anti-human PD-L1) Mediates the anti-Tumor Efficacy via Multiple Pathways in Preclinical Models

Yan_Qu Yan Qu, Ph.D., Senior Principal Scientist, Pfizer

Analysis of PD-L1 expression on various immune subpopulations in human patient samples showed that PD-L1 is enriched on non-T cells. In tumor-bearing mice, the percentage of splenic NK cells was increased with WT avelumab treatment but not with the Fc isotype variant. Avelumab-induced tumor shrinkage, tumor-infiltrating CD8+ T cell increase, and tumor PD-L1+ immature myeloid cell decrease appear to require NK cells, as such changes were abolished upon NK depletion.

11:30 Epitope Identification and Clinical Immune Monitoring in Immune Oncology Programs

Emilee Knowlton, Ph.D., Immunology Sales Specialist, ProImmune

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 Session Break

1:25 Chairperson’s Remarks

Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom

1:30 Functional Characterization of Macaque Fcr and IgG Subtypes

Margie Ackerman, Ph.D., Assistant Professor, Engineering, Dartmouth College

A number of antibody therapies rely on Fc receptor (FcR)-mediated effector functions for optimal activity, prompting the need to understand how native and IgG domains engineered to differentially bind to the human receptors translate in non-human primate (NHP) models. We report characterization of the affinity between an IgG Fc variant panel (including subclass, Fc mutants and glycosylation) and major human and rhesus FcR allotypic variants.

2:00 Utilizing Patient-Derived Organoids and High-Content Imaging for Screening and Characterization of Bispecific Antibodies

Mark Throsby, Ph.D., EVP & CSO, Merus N.V., The Netherlands

This presentation will provide a case study on how panels of patient-derived organoids grown ex-vivo in 3D culture combined with high-content imaging can be applied to bispecific antibody screening. Lead candidate bispecifics were selected targeting the wnt pathway with novel modes of action including immunomodulation.

2:30 Discovery and Development Strategies for New Small Molecule Immunotherapies

Nicola Wallis, Ph.D., Senior Director, Biology, Astex Therapeutics, Ltd.

Small molecules are of interest as immunotherapies as both single agent and combinations, offering the possibility of modulating different aspects of the immune system to biologics. We are exploring targeting a number of different immunomodulatory mechanisms with small molecules derived using fragment-based drug design and will describe examples in this presentation.

3:00 Refreshment Break

3:30 STING Adjuvants for Immune System Priming for Antibody Therapy

Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom

Successful tumor-targeting antibody approaches appear to rely predominantly on the effector function of Fcγ receptor (FcγR) expressing macrophages. Unfortunately, tumor-associated macrophages (TAM) are frequently poorly cytotoxic, contribute to immune suppression and have suboptimal FcγR expression making treatment less effective. Here we show that STING agonists are able to overcome immunosuppression in the tumour microenvironment effectively reversing the TAM inhibitory FcγR profile and provided strong adjuvant effects to antibody therapy.

4:00 Next-Generation Cancer Vaccines

Daniel L. Levey, Ph.D., Senior Director, Vaccine Research, Agenus

Agenus is advancing two fully synthetic cancer vaccine platforms. The first is based on identification of mutations encoded in the tumor genome while the second relates to a novel class of tumor specific neo-epitopes arising from inappropriate phosphorylation of various proteins in malignant cells. The platforms support the manufacture of both individualized and off-the-shelf cancer vaccines against a range of tumor antigens, increasing the likelihood of immune recognition of tumors.

4:30 Oral T Cell Vaccines Targeting Immune Organs of the Gut for Generating Systemic Antigen Specific T Cells

Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG

We use attenuated Salmonella typhi Ty21 as a vector to deliver a plasmid encoding antigens of interest via the oral route to Peyer’s patches. The bacteria have built in adjuvant properties and induce cross presentation to produce a systemic T cell response. Monotherapy with a candidate targeting VEGFR2 produced clinical responses in GBM, highlighting the unique properties of this T cell vaccine approach.

5:00 End of Day

Day 1 | Day 2 | Short Courses | Download Brochure

TUESDAY, AUGUST 29

7:25 am Breakout Discussion Groups with Continental Breakfast

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below.

New Understandings of the Mechanisms of Action for Immunomodulatory Antibodies

Moderator: Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom

What are we learning about MOA from clinical trial data?
Optimizing MOA in next generation immunomodulators
The role of effector and receptor engagement
MOA and bispecific antibody design
Overcoming resistance mechanisms

Target Discovery for Next Generation Immunotherapies

Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG

Tumor antigen identification: strengths and weaknesses of different methodologies
Drugable IO targets- using macromolecules versus small molecule
Novel targets in the tumor microenvironment

8:25 Chairperson’s Opening Remarks

Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut

8:30 Cancer Immunotherapy with Live-attenuated, Double Deleted Listeria Monocytogenes (LADD) Combination Strategies for the Treatment of Malignant Pleural Mesothelioma

Chan C. Whiting, Ph.D., Director, Immune Monitoring and Biomarker Development, Aduro Biotech

We are advancing CRS-207, a clinical LADD strain engineered to express mesothelin, in combinations with various modalities for the treatment of malignant pleural mesothelioma. Data from a Phase 1b study combining CRS-207 with standard chemotherapy demonstrating encouraging clinical and immune responses will be discussed. An overview of the Phase 2 study design and progress of the CRS-207/Pembrolizumab combination study will also be highlighted.

9:00 Tumor and Class-Specific Patterns of Immune-Related Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review

Aaron Hansen, M.D., Ph.D., Assistant Professor, Department of Medicine, University of Toronto; Medical Oncologist, Princess Margaret Cancer Center

Through a systematic review, we identified distinct immune related adverse event (irAE) profiles based on tumor type and immune checkpoint inhibitor class (CTLA-4 and PD-1). CTLA-4 inhibitors have a higher frequency of grade 3/4 irAEs. Furthermore, for patients treated with PD-1 inhibitors, those with melanoma had a higher frequency of gastrointestinal and skin irAEs, and lower rate of pneumonitis compared with patients with NSCLC and RCC. Different immune microenvironments may drive histology-specific irAE patterns.

9:30 Combination Therapy with PD-1 Blockade Enhances the Antitumor Potency of T Cells Redirected by Novel Bispecific Antibodies

Ken Chang, Ph.D., Vice President, Research and Development, Immunomedics

Novel bispecific antibodies that bind bivalently to tumor antigens and monovalently to CD3 can redirect T cells to kill Trop-2- or CEACAM5-expressing solid cancer cells grown in monolayer cultures at low picomolar concentrations. The antitumor efficacy was demonstrated also in a humanized mouse model and in 3D spheroids generated with cells from TNBC and colonic cancers. Combining anti-PD-1 increased cell death in 3D spheroids and prolonged survival of tumor-bearing animals.

10:00 Accelerated Production of Immunomodulatory Therapeutic Antibodies & Bispecific Molecules Using Scalable Cell Engineering

James Brady, Ph.D., Vice President, Technical Applications & Customer Support, MaxCyte

Antibodies and antibody-like molecules are a proven means of modulating effective anti-tumor immune responses. MaxCyte’s delivery platform facilitates rapid, fully scalable, high quality transient protein production in the cell line-of-choice, as well as streamlined stable pool and cell line generation enabling accelerated development of relevant immunomodulatory candidates. Case studies will illustrate the identification and development of antibodies, tribodies & bi-specific T cell engaging molecules (BiTEs) using the MaxCyte platform.

10:30 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

11:15 A Novel, Dual-Specific Antibody Conjugate Targeting CD134 and CD137 Costimulates T Cells and Elicits Antitumor Immunity

Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut

Combining agonists to different costimulatory receptors can be more effective in controlling tumors compared to individual agonists, but presents logistical challenges and increases the potential for adverse events. We developed a novel immunotherapeutic agent by fusing agonists to CD134 and CD137 into a single biologic, OrthomAb, that potentiates cytokine secretion from TCR-stimulated T cells more potently than non-conjugated CD134 + CD137 agonists in vitro, and reduces tumor growth in vivo.

11:45 Targeted Tissue Delivery Using Caveolae Technology Improves Drug Efficacy

Ruchi Gupta, Ph.D., Team Lead Scientist, MedImmune

Current biotherapeutics focus on the molecular targets expressed on cells/tumors. However, less than 10% of the IV administrated biologics can reach the diseased tissues. Tissue targeting using caveolae proteins can allow for specific delivery to organs of interest. This talk will focus on caveolae technology that shows specific delivery to lungs and kidneys and improves drug efficacy. This targeting holds potential for several diseases including fibrosis, COPD, Infections as well as tumors.

12:15 pm Close of Immunomodulatory Therapeutic Antibodies for Cancer