Cambridge Healthtech Institute’s 9th Annual

Preclinical Strategies, Models and Tools in Oncology

Translational Strategies, Novel Therapeutics and Tumor Models

September 17 - 18, 2020 ALL TIMES EDT

The rise of cancer immunotherapy instigated unique preclinical and translational challenges. In addition to immuno-oncology advances, we are witnessing a new wave of targeted and novel therapies that enrich the arsenal of combination cancer therapies. The demand for predictive and robust preclinical models and approaches to minimize translational failures in oncology and immuno-oncology is at an all-time high. The need for leveraging phenotypic features of models, for early identification of predictive biomarkers, for rational design of combination therapies, and for researching the cancer-immune cell interactions adds to the complexity of translational research in oncology and immuno-oncology. Cambridge Healthtech Institute’s 9th Annual Preclinical Strategies, Models and Tools in Oncology conference is designed as a forum for ideas and opinions exchange on how to decrease the rate of clinical failures in oncology and immuno-oncology.

Thursday, September 17

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PLENARY KEYNOTE PANEL DISCUSSION AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall

COMBINATION STRATEGIES, NOVEL MODELS AND THERAPEUTICS

2:05 pm Exploring Novel Immunotherapy Combinations to Overcome Resistance to PD-1 Blockade
Russell Jenkins, MD, PhD, Assistant Professor, Medicine, Center for Cancer Research, Massachusetts General Hospital

Cancer immunotherapy with immune checkpoint blockade has transformed the treatment of patients with advanced melanoma, but strategies to overcome resistance are limited. Using molecular and pharmacologic tools, we have confirmed TANK-binding kinase 1 (TBK1) as a novel target to overcome resistance to PD-1 blockade, further supporting the preclinical and clinical development of this novel combination strategy.

David Langenau, PhD, Associate Chief of Research and Director of Molecular Pathology, Massachusetts General Hospital; Associate Professor, Pathology, Harvard Medical School

We have generated immune-compromised zebrafish that lack T, B and NK cells that robustly engraft human cancers. Capitalizing on the optical clarity of zebrafish and facile imaging approaches, we have documented small-molecule therapy responses and dynamic cell killing by CAR T cell- and bispecific T cell-engager antibodies (BITES) at single-cell resolution. Our studies credential the immune-deficient zebrafish as a new platform for preclinical drug studies.

2:45 pm TGFβ-Blockade Uncovers Stromal Plasticity in Tumors by Revealing the Existence of a Novel Subset of Interferon-Licensed Fibroblasts
Viviana Cremasco, PhD, Senior Principal Scientist, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research Inc.

By performing an unbiased interrogation of tumor mesenchymal cells, our study shows that TGFβ-neutralization leads to a profound remodeling of CAF dynamics, greatly reducing the frequency and activity of myofibroblasts, while promoting the formation of a novel fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes are sufficient to drive productive anti-tumor immunity, laying the foundation for future investigations aimed at defining strategies to reprogram CAF composition for cancer therapy.

Basile Siewe, Director, Business Development, The Jackson Laboratory

The JAX® NSG™ immunocompromised is the perfect host for CD34+ humanization and tumor engraftment, permitting assessment of antibody-based therapy efficacy. The JAX® NSG™ immunocompromised is the perfect host for CD34+ humanization and tumor engraftment, permitting assessment of antibody-based therapy efficacy. 

3:25 pm

Development of a T Cell-Redirecting CD3 Bispecific Antibody for the Treatment of Gastrointestinal Tumors

Lindsay King, PhD, Director, Clinical Pharmacology, Pfizer Inc.

PF-07062119 is a novel T cell-redirecting bispecific against tumors expressing Guanylate Cyclase 2C (GUCY2C), a target expressed in more than 90% of CRC, and in other gastrointestinal cancers. We demonstrate tumor-selective and potent in vitro and in vivo efficacy with PF-07062119 in human xenograft models with T cell adoptive transfer, as well as in an immunocompetent syngeneic model. PF-07062119 shows combination benefits with checkpoint inhibitors and with chemo- and anti-VEGF therapy.

3:45 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Viviana Cremasco, PhD, Senior Principal Scientist, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research Inc.
Panelists:
David Langenau, PhD, Associate Chief of Research and Director of Molecular Pathology, Massachusetts General Hospital; Associate Professor, Pathology, Harvard Medical School
Russell Jenkins, MD, PhD, Assistant Professor, Medicine, Center for Cancer Research, Massachusetts General Hospital
Lindsay King, PhD, Director, Clinical Pharmacology, Pfizer Inc.
Basile Siewe, Director, Business Development, The Jackson Laboratory
4:15 pm Close of Day

Friday, September 18

TARGETING INFLAMMATORY MICROENVIRONMENTS; MASTERING "SMART" RELEASE

10:00 am Friends & Enemies: Spatial Mapping of Regulatory T Lymphocytes in Inflammatory Microenvironments
Shawn O’Neill, DVM, PhD, Senior Director, Global Pathology & Investigative Toxicology, Global Microscopic Imaging Lead, Drug Safety Research & Development, Pfizer Worldwide Research & Development

Tregs are CD4+ T lymphocytes that are central to peripheral immune tolerance, actively inhibiting inflammation upon antigenic stimulation. Tregs thus play a conflicting dual role: as endogenous suppressors of inflammation in autoimmune diseases, while also inhibiting effector CTL from killing tumor cells. In this presentation, we will localize Tregs and CTL by multiplex immunofluorescence and demonstrate spatial mapping of these cells in inflammatory microenvironments by digital pathology using artificial intelligence.

10:20 am

Targeting Tumor-Promoting Inflammation via the Inflammasome Pathway: Lessons Learned

Pushpa Jayaraman, PhD, Senior Principal Scientist, Exploratory Immuno-Oncology, Novartis Institutes for Biomedical Research

Chronic inflammation via the inflammasome pathway plays a key role in carcinogenesis by accelerating tumor invasiveness, growth, and metastatic spread by promoting an immunosuppressive tumor microenvironment. Our work highlights the pathophysiological role of inflammasome mediator, IL-1b, in tumor immunomodulation and that IL-1b blockade might have important consequences on T cell function and checkpoint blockade in cancer.

10:40 am ‘Smart’ Release Therapeutics Target Multi-Drug Resistance in Solid Cancers
Aaron Goldman, PhD, Faculty and Principal Investigator, Goldman Laboratory Drug Resistance Group, Harvard Medical School

The ability for cancer cells to phenotypically switch and survive under drug pressure, referred to as drug-induced resistance or tolerance, is an emerging, yet poorly understood, mechanism of anticancer therapy failure. We discovered a novel metabolic pathway induced by a standard chemotherapy combination, which leads to multi-drug resistance and eventually relapse in patients. To target this mechanism, we engineered small-molecule inhibitors of upstream glucose metabolism with anthracyclines using a ‘smart’ release mechanism that deploys the drugs in highly metabolic cells. This therapeutic improves responses in vitro and in vivo while protecting against systemic toxicity. The result of this novel therapeutic approach means more drug can be distributed into the body while reducing side effects of treatment.

11:00 am

Bispecific Tumor Targeted CD137 Agonism as an Effective Approach for Cancer Immunotherapy

Sailaja Battula, PhD, Director, Immuno-Oncology, Immuneering Corporation

 

CD137 is a validated target for cancer immunotherapy, but antibody approaches targeting CD137 thus far had limited success, likely due to systemic immune activation. I'll discuss how Bispecific tumor targeted modality has been emerging as an effective approach to exploit the beneficial effects of CD137 agonism in cancer immunotherapy.


 

11:20 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Aaron Goldman, PhD, Faculty and Principal Investigator, Goldman Laboratory Drug Resistance Group, Harvard Medical School
Panelists:
Shawn O’Neill, DVM, PhD, Senior Director, Global Pathology & Investigative Toxicology, Global Microscopic Imaging Lead, Drug Safety Research & Development, Pfizer Worldwide Research & Development
Pushpa Jayaraman, PhD, Senior Principal Scientist, Exploratory Immuno-Oncology, Novartis Institutes for Biomedical Research
11:40 am Coffee Break - View Our Virtual Exhibit Hall

NEXT-GENERATION MODELING SYSTEMS AND WHAT WE CAN LEARN WITH THEIR HELP

11:55 am Is There a Key Node in the TME to Tip the Balance?
Zhao Chen, PhD, Investigator III, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, Inc.

The efficacy of the host immune response against cancer largely depends on the behavior of the tumor microenvironment (TME). Many TME components were shown to impact different aspects of cancer immunity, ranging from T cell priming, effector function, and exhaustion to memory. However, the highly heterogeneous TME is often a big hurdle for the clinical translation of TME targets. We are interested in the interplay between components of the TME and the key node that can truly perturb the TME balance.

12:15 pm

In vivo Imaging Techniques for Model Characterization and Guiding Combination Strategies

Tapan Nayak, PhD, Director, Translational Imaging Biomarkers, Merck & Co., Inc.

The success rate of experimental therapy is difficult to predict, as its efficacy often depends upon the characteristics of the preclinical animal models. The presentation will cover different non-invasive imaging techniques to characterize animal models and the information used to guide combination therapies in animal models.

12:35 pm Transplanted Syngeneic Metastasis Models for Preclinical Applications
Vish Muthusamy, PhD, Executive Director, Center for Precision Cancer Modeling, Yale School of Medicine

There is a great need for robust in vivo preclinical models for evaluation of drugs interfering with metastasis. We have developed several transplantable, syngeneic metastasis models and used these to assess: 1) interventions to prevent colonization and growth in distant organs; and 2) treatment-induced abscopal effects on distant metastases. In preliminary studies, an immune-targeting, intratumorally injected drug candidate reduced metastatic burden and improved survival in one such model.

12:55 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Zhao Chen, PhD, Investigator III, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, Inc.

Panelists: Speakers of the Session

Panelists:
Tapan Nayak, PhD, Director, Translational Imaging Biomarkers, Merck & Co., Inc.
Vish Muthusamy, PhD, Executive Director, Center for Precision Cancer Modeling, Yale School of Medicine
1:15 pm Refresh Break - View Our Virtual Exhibit Hall
1:25 pm Brown Bag Lunch and Interactive Breakout Discussions - View Our Virtual Exhibit Hall

Grab your own lunch and 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. Discussion topics and moderators will be listed on the website.


BREAKOUT: Preclinical Strategies for T Cell Therapy

Lindsay King, PhD, Director, Clinical Pharmacology, Pfizer Inc.

•    Preclinical challenges in CAR T Cell therapy development in solid tumors
•    Exploratory assays for T Cell therapy development
•    Major translational challenges
•    Therapy breakthroughs

BREAKOUT: Imaging in Drug Target Research and Preclinical Studies

Tapan Nayak, PhD, Director, Translational Imaging Biomarkers, Merck & Co., Inc.

•    Technology update
•    Novel applications
•    Immuno-oncology insights

IMAGING FOR COMBINATION STRATEGIES, COMPLEX MULTICELLULAR MODELS

2:20 pm

Developing Standards for Potential Prognostic Complex Multicellular Models

Madhu Lal-Nag, PhD, Program Lead, Research Governance Council, Office of Translational Sciences, Center for Drug Evaluation & Research, U.S. Food and Drug Administration
Marc Ferrer, PhD, Leader, Biomolecular Screening and Probe Development, Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health (NIH)

There has been much progress towards the experimental development of robust, scalable, and reproducible 3D cellular models, including spheroids, organoids, biofabricated tissues and microphysiological on chip systems, as assay platforms for preclinical drug testing.  However, there is a need for systematic physiological and pharmacological validation and benchmarking of the different 3D cellular models to establish their true clinical predictability and use for decision making in the drug discovery and development pipeline.

3:00 pm Close of Conference





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