The immune system can be programmed to recognize and destroy cancerous cells infected by viruses or affected by transforming genetic or epigenetic alterations. If properly activated, a specific immune attack can lead to a long-term remission or even cure. We are witnessing the renaissance of the concept of immune-mediated cancer therapy, and the need of predictive models for its preclinical assessment is at an all-time high. Cambridge Healthtech Institute’s Part 2: Tumor Models for Cancer Immunotherapy is designed to feature and discuss cutting-edge complex immunocompetent models for cancer immunotherapy research as well as to present case studies of their successful applications.

Final Agenda

Thursday, June 16

11:00 am Registration.

12:00 pm Bridging Luncheon Presentation: Combination Immune Checkpoint Inhibitors for the Treatment of Colon Carcinoma in Humanized NSG Mouse Models

Martin Graf, Ph.D., Director, Charles River Labs

With the increasing success and interest in cancer Immunotherapy, there is a growing need for relevant preclinical models. Our studies with syngeneic tumors, using immune checkpoint inhibitors targeting CTLA-4 and PD-1, showed differential responses across tumor types. Recently, we evaluated the efficacy of these inhibitors in a human colon carcinoma model in CD34-NSG and PBMC-NSG humanized mice. Results from these studies shows significant tumor growth inhibition in response to checkpoint inhibitors associated with T cell activation.

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing

1:45 PLENARY KEYNOTE SESSION

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

MASTERING TRANSLATIONAL IMMUNO-ONCOLOGY

4:15 Chairperson’s Opening Remarks

Zhao Chen, Ph.D., Investigator III, Exploratory Immuno-Oncology, Novartis Institute of Biomedical Research

4:25 In vivo Modeling of Anti-Tumor Immune Response: The Challenges and Opportunities

Zhao Chen, Ph.D., Investigator III, Exploratory Immuno-Oncology, Novartis Institute of Biomedical Research

A faithful modeling system can help to recapitulate, dissect and uncover the dynamic interactions between different tumor immune infiltrates, stromal components and tumor cells at different stages of tumorigenesis, and after various treatment interventions. Special attention should be given to a few key factors that could dictate the tumor immune response. These include location and genomic alterations of the tumor, as well as the status of the host immune system.

4:55 Humanized Mice for Evaluation of Immuno-Oncology Therapeutic.

Rick Huntress, Director, Business Development, In Vivo Services, The Jackson Laboratory

JAX In Vivo Pharmacology Services combined human CD34+ hematopoietic stem cell engrafted NSG & NSG-SGM3 mice with human patient derived xenograft to create 2 new platforms for humanized preclinical studies in immuno-oncology. Non-HLA matched PDX tumors grow well, despite concerns over transplant rejection. When treated with Keytruda®, tumor growth diminished significantly. This showed human T cells could be induced to respond to PDX following treatment with a check-point inhibitor. The humanized mouse platform enables further research into the basic biology and development of therapeutics in human immuno-oncology.

5:25 Leveraging Immunophenotypic Features of Preclinical Models to Minimize Translational Failures

Karuppiah Kannan, Ph.D., Associate Director, Cancer Pharmacology, Takeda Pharmaceuticals International

Syngeneic model systems that provide a wide array of B-cell, Myeloid cell and NK cell mediated tumor-immune milieus with a varying degree of T-cell involvement can help researchers to hone in on the MoA questions. Such a preclinical exploration can then help us with patient selection hypotheses and also potential combination scenarios. The future for IO therapy most likely is going to be targeting multiple facets of immune suppression which could be decided based on prior chemotherapies.

5:55 Microenvironmental Regulation of Anti-Tumor Immune Responses: Immunological Hallmarks of Fibroblastic Cells

Viviana Cremasco, Ph.D., Investigator II, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research

Our data shed light on the mechanisms of FAP-mediated immunomodulation in tumors, highlighting a population of lymphoid-like FAP+stromal cells with fibrogenic and immunosuppressive potential. Moreover, our study demonstrates that modulating the extracellular matrix has profound consequences on the spatial and functional fate of tumor-infiltrating lymphocytes, supporting that targeting stromal determinants represents a promising therapeutic intervention in cancer.

6:25 Close of Day

6:30 Dinner Short Course Registration.

7:00 - 9:30 Dinner Short Courses

Friday, June 17

7:15 am Registration Open

INDUSTRY CASE STUDIES

8:35 Chairperson’s Remarks

Douglas E. Linn, Ph.D., Senior Scientist, Merck Research Laboratories

8:45 Supporting Clinical Development of the Anti-PD1 Antibody Keytruda with Preclinical Models

Douglas E. Linn, Ph.D., Senior Scientist, Merck Research Laboratories

The clinical advancement of immunotherapies like the anti-PD-1 antibody Pembrolizumab (Keytruda) has provided a paradigm shift in the way cancer patients are treated. Preclinical models have been instrumental in understanding how the immune system can be harnessed to attack tumors as well as how therapeutic benefit can be improved with novel combinations.

9:15 Preclinical Characterization and Identification of an Effective Combination Immune Therapy with IDO1 Inhibitor in Syngeneic Mouse Tumor Models

Manfred Kraus, Ph.D., Director, in vivo Pharmacology, Tumor Cell Biology, Pfizer Oncology

This work and talk will cover aspects of several topics such as preclinical studies for combination cancer therapy, criteria for identifying responses to cancer Immunotherapy, biomarkers in cancer Immunotherapy and their preclinical identification, and preclinical assessment of immune-mediated therapy.

9:45 In vivo Evaluation of Human Immuno Oncology Antibody Drugs in Humanized Mouse Models

Howard Li, CSO, Beijing Biocytogen Co. Ltd.

Human therapeutic antibodies for immuno oncology (IO) are growing fast in recent years due to the success of several immune checkpoint drugs. In the R&D of new immunotherapeutic agents, the proper animal models are in high demand. Many human antibody drugs require in vivo pharmacology evaluation before going to further development and human trials. However, these human antibodies could not be directly tested and the surrogates are used for demonstrating the mechanism of action in the immune competent mice. In order to evaluate the in vivo efficacy of these human antibodies, we developed humanized mouse models by engineering the relevant IO target on the immune competent mice and murine tumor cells. The humanized IO targets are functional and recognizable by human antibody drugs. Therefore, the new models are capable to demonstrate clear in vivo efficacy of different IO therapeutics and are promising for studying combination immunotherapy.

10:00 Immunodeficient Rats for Cancer Xenografts and Humanization of the Liver and Immune System

Tseten Yeshi, Vice President, Research & Development, Hera BioLabs

Two immunodeficient rat models presented: One line lacks mature B and T-cells, the other further lacks NK cells. The model demonstrates efficient engraftment of cancer cell lines and work is ongoing to humanize the liver and immune system. Improved utility of this model includes multiple blood draws and larger tumors.

10:15 Coffee Break in the Exhibit Hall. Last Chance for Poster Viewing.

TECHNOLOGY TO ENABLE DRUG DISCOVERY AND BIOMARKER IDENTIFICATION

11:00 Applications of in silico Quantitative Systems Pharmacology (QSP) in Cancer Immunotherapy Drug Discovery CANCELLED

11:30 PD-L1 Expression and Immune Microenvironment in Genetically Annotated Human Cancers

Mari Mino-Kenudson, MD, Associate Pathologist, Massachusetts General Hospital, Associate Professor of Pathology, Harvard Medical School

PD-L1 expression has been associated with improved response rates to PD-1/PD-L1 axis blockade in multiple cancer types. To date, two main mechanisms of PD-L1 upregulation – innate immune resistance and adoptive immune resistance – have been reported. In this talk, I will discuss the PD-L1 expression in association with the immune microenvironment as well as response to PD-1/PD-L1 inhibitors in genetically annotated NSCLC and colorectal cancer.

12:00 pm Molecular Deconstruction of the Tumor Microenvironment

Gus Frangou, Ph.D., Director, Research & Development, Cellecta, Inc.

The tumor microenvironment (TME) plays an important role in cancer development, progression and control. As a result, there is considerable interest to identify new biomarkers and develop therapeutic strategies to remodel the TME and enhance therapy. In this talk, I will describe a novel targeted NGS approach (Driver-Map) to generate comprehensive molecular portraits of the TME. Data demonstrating the utility of our approach to deconstruct tumor cellularity, as well as infer the fraction of infiltrating immune/stromal cells in primary tumors from triple-negative breast cancer patients will be discussed.

12:15 Animal Study Workflow Technology: A Novel Approach for Variable Study Types and Heterogeneous Data Management

Jeffrey Kumer, MSc, Client Services Specialist, Animal Study Workflow Solutions, Studylog Systems, Inc.

Managing animal study workflow and the increasingly-large resultant heterogeneous data sets across multiple disease areas using primarily spreadsheets has been consistently proven ineffective. The power of a database is required to manage and standardize inherently-variable processes and parameters and to efficiently conduct more clinically-relevant multi-arm, multi-site, pre-clinical trials with rolling subject enrollment. Recent software innovations optimize the processes of study design, data acquisition, analysis and interpretation of diverse data types.

12:30 Luncheon Presentation: Precision Research Models of Human Immune System and Metabolic Function: Applications in Oncology Drug Discovery

Michael Seiler, Ph.D., Portfolio Director, Commercial Genetically Engineered Models, Taconic Biosciences

The development of animal models to mimic human immune responses is crucial to study the pathophysiology of cancer. We will focus on the following: Current state of immune system engraftment models; The next generation huNOG-EXL which extends the mechanistic functionality of current systems; Recent advances in immuno-oncology applications with immune system engrafted mice.

1:00 Session Break

PRECLINICAL ASSESSMENT OF CAR T-CELL THERAPY

1:30 Chairperson’s Remarks

Oliver Ghobrial, Ph.D., Senior Scientist III, Translational Modeling and Simulation, AbbVie

1:35 Modeling CAR T Cell Therapies for Solid Tumors

Daniel Abate-Daga, Ph.D., Assistant Member, Immunology Program, H. Lee Moffitt Cancer Center and Research Institute

T cell-based immunotherapies have come of age as a feasible, safe and efficacious approach to treating cancer. At the same time, the use of highly personalized, alive therapeutic agents poses multiple challenges in terms of standardization of treatment protocols. The use of animal and mathematical models will be discussed, in the context of the design and testing of novel therapies involving chimeric antigen receptor (CAR)-T cells.

2:05 Preclinical Modeling of Human Chimeric Antigen Receptor T Cell Therapy In Hematological Malignancies

Saad Kenderian, M.D., Translational Research Program, Center for Cellular Immunotherapy, Laboratory of Dr. Carl June, University of Pennsylvania Medical School

Chimeric antigen receptor T (CART) cell therapy has emerged as a novel and potentially curative approach in hematological malignancies. The responses in refractory B cell malignancies following CD19 directed CARTs are unprecedented. Different preclinical models are employed to assess the activity and toxicity of novel CART cell therapies. The uses and limitation of these preclinical models will be discussed.

2:35 Chimeric Antigen Presenting T Cells that Change the Tumor Microenvironment

Wayne A. Marasco, M.D., Ph.D., Professor of Medicine, Dana-Farber Cancer Institute

Harvard Medical School

The clinical effect of CART cells has been modest for the treatment of solid tumors due to several factors including the difficulty in identifying unique tumor associated antigens, inefficient homing of CART cells to tumor locations, their low persistence after infusion and their functional impairment in the immunosuppressive microenvironment. We will present our latest in vitro and in vivo CART cell data on new technology to overcome these barriers.

3:05 Refreshment Break

3:20 Preclinical Models for Evaluation of Anti-Tumor Activity and Effects on Normal Tissues of CD3 Bispecific Antibodies

Jessica Kirshner, Ph.D., Director, Oncology and Angiogenesis, Regeneron Pharmaceuticals

Using VelocImmune® mice and proprietary bispecific technology, we have generated fully human anti-tumor target xCD3 antibodies. These bispecific antibodies bind to human tumor targets and CD3 and activate T cells in the presence of target-expressing tumors. To evaluate these antibodies, we used Velocigene® technology to engineer immunocompetent mice expressing human CD3 and target. These unique models allow investigation of anti-tumor effects and simultaneous correlation with effects on normal tissues.

3:50 Cancer Vaccines and Immunomodulatory Therapy: Translational Story

Jacalyn Rosenblatt, M.D., Assistant Professor, Department of Medicine, Harvard Medical School

Our group has developed a personalized vaccine whereby patient derived tumor cells are fused to autologous ex-vivo generated dendritic cells. In phase I and II clinical trials, vaccination has resulted in potent immunologic and clinical response. To augment anti-tumor immunity and immune response to vaccination, we have studied the interaction of immune modulatory and vaccination. Importantly, we have described the critical role that the PD1/PDL1 pathway plays in the setting of hematological malignancy, and demonstrated synergy between immune checkpoint blockade and cellular immunotherapy.

4:20 Preclinical Assessment of CAR T Cells Targeting the Alpha V Beta 6 Integrin in Solid Malignancies

Lynsey Whilding, Ph.D., Research Associate, CAR Mechanics Group, Research Oncology, Division of Cancer Studies, King’s College London

Chimeric antigen receptors (CARs) are bespoke fusion molecules that couple the binding of a tumour-associated cell surface target to the delivery of a tailored T cell activating signal. We have re-targeted T cells to the epithelial-specific integrin αvβ6 (termed A20-28z), which is overexpressed in multiple solid tumours. A20-28z T cells demonstrate anti-tumour activity in vitro and elicit tumour regression in preclinical xenograft models of ovarian, pancreatic and breast cancer.

4:50 Close of Conference