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Archive for the ‘Metabolic Immuno-Oncology’ Category


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

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

Greg_AdamsGregory 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_DahanRony 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.

TD2 tagline9:30 Coffee Break

 

MECHANISMS OF ACTION

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

Allison_BetofAllison 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_KanedaMegan 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_QuYan 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.

ProImmune11:30 Epitope Identification and Clinical Immune Monitoring in Immune Oncology Programs

Emilee KnowltonEmilee 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

TARGET DISCOVERY FOR NEXT GENERATION IMMUNOTHERAPIES

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_ThrosbyMark 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_WallisNicola 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.

TD2 tagline3:00 Refreshment Break

 

IMMUNE SYSTEM PRIMING AND ACTIVATION

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

Stephen_BeersStephen 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_LeveyDaniel 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_MansourMarc 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

 

 

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

NON-RESPONDERS, SIDE EFFECTS AND TOXICOLOGY

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_WhitingChan 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_HansenAaron 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.

PROTEIN ENGINEERING

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

Ken_ChangKen 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.

MaxCyte no tagline10:00 Accelerated Production of Immunomodulatory Therapeutic Antibodies & Bispecific Molecules Using Scalable Cell Engineering

James_BradyJames 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_AdlerAdam 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_GuptaRuchi 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

 

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Agios Pharmaceuticals target the metabolism of cancer cells for making drugs that essentially try to repair cancer cells

Reporter: Aviva Lev-Ari, PhD, RN

A small biotech behind a groundbreaking approach to tackling cancer just got its first drug approved

http://www.businessinsider.com/fda-approves-agios-pharmaceuticals-drug-targeting-cancer-cell-metabolism-2017-8

See

Cancer Metabolism

http://www.agios.com/research/cancer-metabolism/

Metabolic Immuno-Oncology

http://www.agios.com/research/metabolic-immuno-oncology/

 

 

The VOICE of Larry H. Bernstein, MD, FCAP

Cancer cells didn’t need as much oxygen to metabolize sugar as normal cells. 

Not correct. Cancer cells metabolize glucose by aerobic glycolysis (4 ATP) with an impaired mitochondrial oxygen utilization (36 ATP). 

There is a reverse Warburg effect in which the underlying stromal cell carries out crosstalk with the epithelial cell. 

There is also a 3rd dimension. Cells undergo a series of adaptive changes tied to proteostasis. This involves the sulfur amino acid cysteine and disulfide bonds, which is involved with protein oligomerization in the ER, and also signaling in the mitochondria with mDNA and the nucleus. 

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