Cambridge Healthtech Institute’s Fifth Annual 

Combination Immunotherapy Design Models

Preclinical Approaches and Biomarkers to Bring Combination Therapies to the Clinic

February 20-22, 2017 | Moscone North Convention Center | San Francisco, CA
Part of the 24th International Molecular Medicine Tri-Conference

 

Despite tremendous progress in our understanding of cancer biology, the majority of novel anticancer therapies fail in clinical trials, which indicates deficiencies in conventional translational approaches. In most cases preclinical data have overpredicted clinical efficacy in oncology. With the rise of immuno-oncology the challenge of in vivo pharmacology was enhanced by the differences in mouse and human immune systems that further damages the predictiveness of preclinical data. The phenomenon of cancer heterogeneity and subsequent drug resistance add another dimension to the preclinical cancer research warranting active work on combination cancer regimens. Better models and approaches are clearly in high and urgent demand and has been worked on by industry and academia scientists. Cambridge Healthtech Institute’s Fifth Annual Translational Models in Oncology and Immuno-Oncology conference is designed to highlight cutting edge advances in in vivo, in vitro and in silico modeling and to facilitate a discussion about effective translational approaches in cancer research.



Monday, February 20

10:30 am Conference Program Registration Open

RATIONAL DEVELOPMENT OF COMBINATION THERAPIES

11:50 Chairperson’s Opening Remarks

Terri McClanahan, Ph.D., Executive Director, Molecular Discovery, Biologics, Merck Research Laboratories

12:00 pm KEYNOTE PRESENTATION: Rational Development of Combination Therapies in Immuno-Oncology

Michael Kalos, M.D., CSO, Cancer Immunobiology, Eli Lilly

Treatment of patients with combinations of agents, such as CTLA4 and PD1, has provided additional benefit to patients, along with increased toxicity, highlighting the value for developing combination therapies. In this session, we will discuss preclinical and translational strategies and approaches to support the rational development of more effective combination strategies that lead to increased clinical benefit for patients.

12:30 Biomarker Development for the Era of Combination Cancer Immunotherapy

Terri McClanahan, Ph.D., Executive Director, Molecular Discovery, Biologics, Merck Research Laboratories

Keytruda® (pembrolizumab), a PD-1-specific monoclonal antibody, is approved in the U.S. for advanced melanoma, NSCLC and SCCHN, and is being studied in >30 cancers. Efforts are now underway to extend the benefit of cancer immunotherapy to more patients through the use of anti PD-1-based combination regimens. However, significant challenges remain to identify the best combinations that provide true immune synergy, and to target the right combinations to the right patients who will experience unambiguous clinical benefit. Biomarker and translational research-driven strategies can guide the future state of the field, ultimately allowing for the development of precision medicine approaches to combination cancer immunotherapy.

1:00 Session Break

1:10 Enjoy Lunch on Your Own

2:10 Session Break

PRECLINICAL TO CLINICAL STUDIES: HUMANIZED MODELS TO INFORM TRIALS DESIGN

2:30 Chairperson’s Remarks

Pamela N. Munster, M.D., Professor, Medicine, Program Leader, Development Therapeutics, Director, Early Phase Clinical Trials Program, Helen Diller Cancer Center, University of California, San Francisco

2:40 Designing and Executing Cancer Immunotherapy Clinical Trials

Pamela N. Munster, M.D., Professor, Medicine, Program Leader, Development Therapeutics, Director, Early Phase Clinical Trials Program, Helen Diller Cancer Center, University of California, San Francisco

A breakdown in immune tumor surveillance plays a crucial role in the development of metastatic cancer. Targeting the programmed death receptor (PD-1) and its ligand (PD-L1) have been major breakthroughs in certain cancers such melanoma, lung and other cancers. However, many cancers, including breast cancers, appear less responsive. We are exploring the roles of tumor lymphocyte infiltration, T cell differential, epigenetic modifiers and the co-operative involvement of other immune pathways to induce responses in immune silent tumors. Translating preclinical findings into early phase clinical studies, we will describe recent advances in how to determine safety, feasibility and efficacy of integrating immunotherapy into targeted therapy and chemotherapy.

3:10 Driving Efficiency in I/O Clinical Trials by Leveraging Patient Matched Primary 3D Ex Vivo Cultures
Matthew R. Gevaert, Ph.D., CEO, KIYATEC, Inc. 
KIYATEC’s advances in ex vivo cell culture models are enabling the creation of functional, patient matched tumor-immune 3D co-cultures. Potential benefits of implementing designs to integrate these ex vivo models into immuno-oncology (I/O) clinical trials include: 1) enrichment of study population; 2) informed selection of therapeutic combinations and 3) biomarker discovery. Strategies to achieve these benefits and overall, to drive efficiency in I/O clinical trials, will be discussed.

3:40 Talimogene Laherparepvec in Combination with Checkpoint Inhibitors: From Bench to Bedside

Pedro J. Beltran, Ph.D., Research Director, Oncology Research, Amgen, Inc.

Checkpoint inhibitors and viral immunotherapy with talimogene laherparepvec have shown significant therapeutic benefit in melanoma patients when used as monotherapies. As these two forms of approved immunotherapy act mostly on different parts of the immunity cycle, studying their combination pre-clinically and clinically informs their future development. We have used 3 syngeneic murine models to study the pharmacodynamic and efficacy changes driven by the combination of talimogene laherparepvec and blockade of CTLA-4 or PD-1/PD-L1. Clinical trials testing these combinations in the clinic are currently ongoing.

4:10 Complete Workflows Improve the Isolation and Analysis of Tumor-Infiltrating Immune Cell Subpopulations

Cesar Evaristo, Ph.D., Research & Development Team Coordinator, Research & Development Immune Responses, Tumor Immunology, T cells, Miltenyi Biotec GmbH

Tumor-infiltrating leukocytes (TILs) constitute a fraction of highly complex and variable tumor tissue, complicating the analysis of individual subpopulations. By combining optimized tissue dissociation with specific pre-enrichment of TILs, we significantly increased the quality of data obtained from TIL analysis.

4:40 Refreshment Break and Transition to Plenary Session

5:00 Plenary Keynote Session

6:00 Grand Opening Reception in the Exhibit Hall with Poster Viewing

7:30 Close of Day

Tuesday, February 21

7:30 am Registration Open and Morning Coffee

8:00 Plenary Keynote Session

9:00 Refreshment Break in the Exhibit Hall with Poster Viewing

TUMOR MODELS FOR CANCER IMMUNOTHERAPY

10:05 Chairperson’s Remarks

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

10:15 Mouse Models to Test Human Cancer Immuno-Therapeutics

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

Preclinical in vivo tumor models are essential to test anti-tumor activity and side-effect profiles of novel immunotherapeutics. However, antibody-based therapies often do not cross-react with the corresponding murine targets, making such tests difficult. We have utilized Regeneron’s capabilities in murine genetic engineering to develop several approaches of combining functional immune cells with preclinical tumor models. We have used these approaches for preclinical testing of both checkpoint inhibiting antibodies and T cell-engaging bispecific antibodies.

10:45 Characterization of Molecular and Cellular Properties of Murine Syngeneic Models to Aid Model Selection and Biomarker Discovery for Immune-Oncology Programs

Wenyan Zhong, Ph.D., Senior Principal Scientist, Oncology R&D Group, Pfizer

Preclinical in vivo models for most immuno-oncology (IO) programs require the use of immunocompetent mice bearing syngeneic tumors. To facilitate model selection for use in preclinical efficacy studies, we characterized a panel of mouse tumor cell lines and syngeneic tumor tissues. In this talk, we will discuss molecular and cellular properties of these models.

11:15 Case Study: Blockade of Phosphatidylserine-Mediated Tumor Immune Suppression to Enhance Immune Checkpoint Therapies

Bruce Freimark, Ph.D., Research Director, Pre-Clinical Oncology, Peregrine Pharmaceuticals, Inc.

Phosphatidylserine (PS) exposure in tumors induces non-inflammatory signals which contribute to an immunosuppressive environment. Antibody blockade of PS activates immune responses by promoting M1 macrophages, maturation of dendritic cells and inducing adaptive T-cell responses. PS targeting antibodies enhance the anti-tumor activity of checkpoint antibodies in preclinical tumor models.

MIBioresearch11:45 Methods and Models for Preclinical Immuno-Oncology

Dylan Daniel, Ph.D., Director, Scientific Development, MI Bioresearch

MI Bioresearch has characterized an array of syngeneic immuno-oncology models to support in vivo pharmacology drug discovery. Our characterization includes comprehensive lymphoid and myeloid flow cytometry immune profiling, and model responses to checkpoint inhibitors and focal beam radiotherapy combinations.

12:00 pm Exemplar_GeneticsGenetically Engineered Miniswine Models of Cancer

John Swart, Ph.D., President, Exemplar Genetics

Current preclinical models of cancer fail to accurately recapitulate human disease and do not effectively translated to the clinic. Recently, Exemplar Genetics has developed a genetically engineered miniature swine model that contains a conditional KRAS mutation on the background of TP53-targeted pigs, the ExeGen® TP53+/R167H& KRAS+/G12D miniswine model. This model should allow for the inducement of human-like tumors in a tissue specific manner. Initial characterization of induced tumors demonstrates the transformative nature of this model.

12:30 Session Break

 Mitra Biotech12:35 Luncheon Presentation: A Novel Phenotypic Platform for Therapy Selection and Understanding the Biology of Tumor Immune Response

Parker Cassidy, Chief Commercial Officer, Mitra Biotech

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing

CASE STUDIES OF INDUSTRY-ACADEMIA COLLABORATION

2:00 Chairperson’s Remarks

Lawrence B. Schook, Ph.D., Gutsgell Professor, Animal Sciences and Radiology, University of Illinois

2:10 The Oncopig Cancer Model (OCM): A Platform for Transitional, Translational and Transformative Advances in Cancer Research

Lawrence B. Schook, Ph.D., Gutsgell Professor, Animal Sciences and Radiology,

University of Illinois

Mammalian models are integral components of basic, translational, and clinical cancer research. Recently, there have been advances in creating large animal transitional porcine cancer models, for use in preclinical and translational research studies with transformational impact for human clinical trials. Pigs, due to their anatomy, physiology, metabolism, and genetics, provide an ideal investigational transitional platform for human clinical trials and offer a critical pathway to narrow gaps in cancer therapy.

2:40 Co-Presentation: An Example of a Collaboration between Industry and Academia for Testing Combination Therapies in Preclinical Patient-Derived Xenograft Models of Glioblastoma

Anderson Clark, Ph.D., Director, Translational in vivo Pharmacology, Oncology, EMD Serono Research & Development Institute

John De Groot, Associate Professor, Chair Ad Interim, Neuro-Oncology, The University of Texas MD Anderson Cancer Center

The use of patient-derived xenograft (PDX) models of cancer has increased over the past decade, both in industry and academia, providing preclinical data to support both drug development and basic oncology research.

3:20 Modeling Checkpoint Blockade Using Heterogeneous Chemically-Induced Carcinomas

Rosemary J. Akhurst, Ph.D., Professor and Director, Preclinical Therapeutics Core, UCSF Helen Diller Family Comprehensive Cancer Center

The large majority of patients do not benefit from checkpoint blockade agents when used as monotherapies. It is important to identify agents that accentuate response rates and improve overall survival. We present a novel chemically-induced syngeneic carcinoma model that represents the single nucleotide mutation (SNV) spectra found in environmentally induced human cancers, e.g. melanoma and lung cancer. We tested α-PD-1 and α-pan TGFβ mono- and combination therapies and found responses only in tumors with a high SNV load. This model should be useful to study primary and acquired resistance to α-PD-1.

4:10 Hollywood Oscar Dessert Reception in the Exhibit Hall with Poster Viewing

5:00 Breakout Discussions in the Exhibit Hall

These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion. Pre-registration to sign up for one of the topics will occur a week or two prior to the Event via the App.

Humanized Mouse Models

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

  • Appropriate applications of humanized mouse models in immuno-oncology
  • Limitations of current models
  • Areas of future development

Next Generation Cellular Models

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech Inc.

  • Cancer cell line profiling
  • Large-scale genomic and drug response screening
  • Future directions

Biomarkers for Cancer Combination Therapy Design

Jianda Yuan, M.D., Ph.D., Director, Translational Immuno-Oncology Research, Early Clinical Oncology Development, Merck & Co., Inc.

  • Validation of biomarkers before use in clinical care
  • Using prognostic and predictive biomarkers for enrichment and stratification factors in drug development
  • Challenges and Implementation of biomarkers into clinical practice

6:00 Close of Day

Wednesday, February 22

7:00 am Registration Open

7:00 Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

8:00 Plenary Keynote Session

10:00 Refreshment Break and Poster Competition Winner Announced in the Exhibit Hall

TRANSLATIONAL BIOMARKERS IN CANCER IMMUNOTHERAPY DEVELOPMENT

10:50 Chairperson’s Remarks

Sarah Javaid, Ph.D., Senior Scientist, Discovery Pharmacogenomics, Genetics and Pharmacogenomics, Merck & Co., Inc.

10:55 Next Generation Biomarkers for the Era of Combination Cancer Immunotherapy

Sarah Javaid, Ph.D., Senior Scientist, Discovery Pharmacogenomics, Genetics and Pharmacogenomics, Merck & Co., Inc.

Combination approaches are the keys to improving clinical response. From preclinical immune-oncology mouse models to patients enrolled on clinical trials, novel high throughput technologies enable us to understand the mechanisms underlying the complex interactions between the immune system and cancer, identify predictive biomarkers for the patients who will most likely benefit from current immunotherapies, avoid immune-related adverse events and guide the future combination cancer immunotherapy.

11:20 High-Content Molecular Profiling in Preclinical Immunooncology Research
Ruslan Novosiadly, Ph.D., Senior Research Advisor, Cancer Immunobiology, Biomarkers, Eli Lilly

11:45 Biomarker Strategy to Inform Clinical Development of ImmTACTM Molecules (Immune Mobilising TCRs Against Cancer)

David Krige, Ph.D., Head of Biomarkers, Immunocore

A comprehensive biomarker strategy has been developed to compliment clinical studies with IMCgp100, an ImmTAC that targets malignant melanoma. This biomarker strategy is vital for evaluating ongoing trials as well as informing the clinical development of other ImmTAC molecules, either as single agents or in combination with checkpoint inhibitors.

12:10 pm Utility of Quantifying Circulating Lymphocyte Populations as Pharmacodynamic Biomarkers in Trials of Immune Oncology Therapeutics

Nathan Standifer, Ph.D., Scientist II, Clinical Pharmacology and DMPK, MedImmune

Immune oncology (IO) therapeutics are directed at inducing immune responses against tumor cells. Intrinsic to this mechanism of action is the activation of circulating immune cells, which can be most effectively monitored using flow cytometry-based assays. In this presentation, aspects of assay development, validation, implementation and analysis of clinical flow cytometry datasets will be discussed. Results from clinical trials of IO as single agents or in combination with other IO will be shown and strategies for interpretation and post-hoc analyses will be detailed.

12:35 Session Break

Cellecta 12:45 Luncheon Presentation: Driver-Map™ Genome-Wide Expression Profiling Solution for Biomarker Discovery

Alex Chenchik, Ph.D., President & Scientific Director, Cellecta, Inc.

Driver-Map Genome-Wide Expression Profiling solution combines the sensitivity of multiplex PCR with the dynamic range of NGS. With 10 pg total RNA, a 100-fold greater sensitivity over RNA-Seq. Applications include complex samples like whole blood, tumor microenvironment characterization, xenografts, etc.

1:10 Refreshment Break in the Exhibit Hall and Last Chance for Poster Viewing

CELLULAR MODELS FOR COMBINATION THERAPY DESIGN

1:50 Chairperson’s Remarks

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech

2:00 Understanding and Predicting Cellular Response through Chemical and Functional Genomic Profiling of Well-Characterized Cancer Cell Lines

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech

Determining relationships between genomic features and drug sensitivity is central to the concept of personalized medicine and indication selection. Many studies have highlighted the value of integrating omics data with drug activity across cell lines to identify predictors of response. Here we extend upon these studies with numerous chemical and genetic perturbations to explore such relationships. Data reveals both known and novel correlations, and was also used to explore best experimental and computational practices.

2:30 Beyond Genomics: Identifying Treatment Options for Refractory Cancer Patients Using Real Time Functional Assays and FDA Approved Drug Combinations

Matthew De Silva, CEO, Founder, Notable Labs

Refractory cancer patients often have resistant disease that does not respond to single agent therapy. Combination strategies are promising, but patient heterogeneity makes clinical trial design difficult. Next generation functional phenotypic assays using a patient’s cancer cells can identify potentially synergistic treatments in a matter of days, but the combinatorial space is often larger than the available cells. In silico models that employ ‘omic data from a patient can prioritize which combinations to test ex vivo. If the agent(s) of choice are approved, physicians can then prescribe them

3:00 Generation of ex vivo Tumor Models from PDX Tumors as a Platform for Clinically Relevant Anticancer Drug Discovery

Geoffrey A. Bartholomeusz, Ph.D., Associate Professor and Director, siRNA Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Monolayer cell cultures platforms inadequately represent the complex tumor microenvironment and drugs identified by these systems have failed when translated into the clinics. Clinically relevant PDX systems are both costly and time consuming. We have developed a clinically relevant ex vivo tumor tissue system derived from a PDX tumor, and preliminary data confirms its potential to serve as a platform for clinically relevant drug discovery in a time and cost effective manner.

3:30 Session Break

CRISPR FOR TUMOR MODELING, INTERNATIONAL INITIATIVES

3:40 Chairperson’s Remarks

Monte Winslow, Ph.D., Assistant Professor, Genetics, Stanford University

3:45 Cancer Modeling with in vivo CRISPR/Cas9 Genome Editing

Monte Winslow, Ph.D., Assistant Professor, Genetics, Stanford University

Conventional genetically engineered mouse models of human cancer have been instrumental in our understanding of all aspects of cancer development. However, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately comprehend this disease. I will discuss our ongoing work to employ CRISPR/Cas9-mediated genome editing to generate cancer models and illuminate gene function during cancer progression within the natural in vivo setting.

4:15 Tailored Pre-Clinical Models with CRISPR-Based Genome Editing

Lukas Edward Dow, Assistant Professor, Medicine, Weill Cornell Medicine

CRISPR/Cas9 genome editing has changed the way we design and execute in vivo experiments. We are using CRISPR-based genome editing in stem cells and in adult mice to generate tailored pre-clinical models. This allows both a deeper understanding of the genetic underpinnings of cancer progression and provides a platform to interrogate new therapeutic strategies in specific genetic contexts, which is key for realizing the potential of personalized medicine.

4:45 The Human Cancer Model Initiative

Louis M. Staudt, M.D., Ph.D., Director, Center for Cancer Genomics, Co-Chief, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health

The Human Cancer Model Initiative (HCMI) aims to generate 1000 new cancer cell lines directly from patient biopsy material using a variety of technologies, including organoids and conditionally reprogrammed cells. Each cell line will be genomically characterized and clinical diagnostic and therapeutic data will be gathered from the participating patients. The new cell lines and their associated data will be made available to the research community to promote a deeper understanding of cancer and its response or resistance to therapy.

5:15 Close of Conference Program


Stay on for these Tri-Conference Symposia, taking place at February 23-24, 2017 at Moscone South Convention Center


New Frontiers in CRISPR-Based Gene Editing

Circulating Cell-Free DNA

Biomarkers for Cancer Immunotherapy

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