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 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 11

12:00 pm Registration

TRANSLATIONAL IMMUNO-ONCOLOGY

2:00 Chairperson’s Opening Remarks

John Maher, M.D., Ph.D., Senior Lecturer in Immunology, NIHR Biomedical, Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London

2:05 Preclinical Tumor Models for Evaluating Bispecific Redirected T Cell Therapeutics

Chad May, Ph.D., Director, Oncology Research Unit, Pfizer

Strong evidence exists supporting the important role T-cells play in the immune response against tumors. Still, the ability to initiate tumor specific immune responses remains a challenge. We have developed a bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of tumors expressing target antigens.

2:35 Joint Presentation: Preclinical to Clinical Translation of Anti-PD-1 Blockade

David Kaufman, M.D., Ph.D., Director/Senior Principal Scientist, Oncology/Immunotherapy Clinical Research, Merck

Elaine Pinheiro, Ph.D., Associate Principal Scientist, In vivo Pharmacology – Oncology, Merck Research Laboratories

Keytruda® (pembrolizumab), a PD-1-specific monoclonal antibody, is approved in the U.S. for advanced melanoma, and is being studied in >30 cancers. We have generated a murine surrogate antibody (muDX400) and determined mechanistic features of PD-1 inhibition in preclinical tumor models. Gene and protein expression signatures reveal determinants of response and resistance. In addition, muDX400 has been combined with chemotherapies, targeted therapies, and other immunotherapies, and the systemic and intratumoral immune landscape has been evaluated. These data will facilitate the clinical development of both pembrolizumab monotherapy and combination therapies. In particular, these data will support the development of novel mechanistic biomarkers that will aid in the customization of immunotherapeutic regimens, elucidation of novel determinants of response, and identification of early indicators of on-treatment response. In turn, data from clinical trials can be used to improve the predictive power of the nonclinical workstream and speed the preclinical development of novel immunotherapeutic agents.

3:35 Studies of Immunotherapy Agents Using Patient-derived Tumor Xenografts in Humanized Mice

Walter Ausserer, Ph.D., Business Director, Clinical and In Vivo Services, The Jackson Laboratory

We will report on our program to establish in vivo preclinical models of human tumor immunotherapy by engrafting immunodeficient mice expressing a partial human immune system with human tumor implants. Humanized NOD-scid IL2Rγ (null) (hu-NSG™) mice initially were generated by transplanting NSG mice with human CD34+ hematopoietic stem and progenitor cells (HSPCs) which support human hematopoietic and immune system development. Several types of patient-derived tumors (non small cell lung cancer, sarcoma, triple negative breast cancer and invasive bladder cancer) were successfully implanted into HLA-mismatched hu-NSG mice. Growth rates for all PDX tumors were similar between hu-NSG and non-humanized NSG models. In addition, tumor growth was observed in hu-NSG mice implanted with human ovarian tumor cell line SKOV3-Luc-D3. Treatment with the anti-PD-1 receptor agent pembrolizumab produced significant tumor growth inhibition in both solid tumor and cell line xenografts, suggesting that co-engrafted hu-NSG mice may represent an important new model for preclinical immunotherapy research.

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

4:45 Translational Approaches to Preclinical Evaluation of Immune Oncology Agents

Brett Hall, Ph.D., Senior Director & Head, Translational Medicine-Oncology, MedImmune

An expanding body of basic and translational research has established a solid framework for how the tumor microenvironment (TME) influences cancer biology. The TME influences tumor immune recognition as well as metabolic activity, tumor survival, genomic instability, epigenetic state, metastatic progression, tumor proliferation and therapeutic resistance. For effective clinical translation of immune mediated therapies, it is essential that preclinical models adequately address key immuno-modulatory aspects of the human TME.

ENHANCING IMMUNE RESPONSE

5:15 Adoptive Immunotherapy of Cancer Using ex vivo Expanded Vg9Vd2 T Cells

John Maher, M.D., Ph.D., Senior Lecturer in Immunology, NIHR Biomedical, Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London

Vg9Vd2 T-cells recognize phosphoantigen intermediates of mevalonate metabolism and thereby play an important role in tumor immunosurveillance. We have developed systems to expand these cells ex-vivo by over 2000-fold in 2 weeks, enhancing the feasibility of clinical immunotherapy using this approach. Expanded cells exhibit potent anti-tumor activity in xenograft models of ovarian cancer and acute myeloid leukemia in a manner that is potentiated by either free or liposome-encapsulated aminobisphosphonates.

5:45 Enhancing Immune Response to DC/Tumor Fusion Cell Vaccination for the Treatment of Hematologic Malignancies

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

DC/tumor fusion cell vaccination has demonstrated potent immune responses, and clinical responses in a subset of patients. Strategies to augment immune response to vaccination depend on overcoming the immunosuppressive milieu characteristic of patients with malignancy. Combining vaccination with checkpoint blockade and immunomodulatory drugs are being evalauted in clinical trials. In pre-clinical models, we have demonstrated that MUC1 plays a critical role in mediating immune tolerance. Strategies to block MUC1 mediated signalling are being evaluated as a means of augmenting response to immunotherapy.

6:15 Close of Day

Friday, June 12

DESIGNING AND ASSESSING COMBINATIONS

8:35 Chairperson’s Remarks

Daniela Cipolletta, Ph.D., Research Investigator, Clinical Translational Oncology, TCO, Novartis Oncology

8:45 Identification of Novel Immune-Modulatory Combination though Transcriptomic and Proteomic-Based Analysis of Tumor Models

Daniela Cipolletta, Ph.D., Research Investigator, Clinical Translational Oncology, TCO, Novartis Oncology

We have used transcriptomic and proteomic approaches to monitor the immune response following perturbation of key onco-pathway and immune-checkpoint nodes in preclinical tumor models. This approach has enabled our understanding of tumor induced immune modulation and the identification of novel combinatorial strategies in specific cancer settings

9:15 Combining Radiation Therapy and Cancer Immunotherapy: Preclinical Assessment and Translational Approaches

Maria Angelica Cortez, Ph.D., Postdoctoral Fellow, Experimental Radiation Oncology, UT MD Anderson Cancer Center

The immune-modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. However, additional pre-clinical studies are needed to demonstrate the antigen-specific nature of radiation induced immune responses and elucidate potential mechanisms of synergy withimmunotherapy. Here we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy.

9:45 Personalized Mouse Model for Preclinical Testing of Drugs Targeting Immune Checkpoints

Keren Paz, Ph.D., CSO, Champions Oncology

The blockade of immune checkpoints is a promising therapeutic avenue for cancer therapy, with durable objective responses observed in patients with various solid tumors. However, current animal models often fail to accurately identify immunotherapies with the greatest clinical potential and there exists a need for reliable preclinical tools to test these drugs directly against human cancers. To circumvent this limitation, Champions Oncology has developed the ImmunoGraft, whereby two innovative technologies, the Champions TumorGraft (a type of patient-derived xenograft) and humanized mice (immunodeficient mice reconstituted with a human immune system), are combined in a single platform.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 Developing and Deploying Novel Experimental Model Systems in Ovarian Cancer for Improved Drug Discovery

Ronny I. Drapkin, M.D., Ph.D., Director, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania

The emergence of the fallopian tube as a dominant site of origin for high-grade serous ovarian carcinomas has sparked the development of novel model systems, including PDX and GEM models, that are impacting development of novel drug therapies, methods for early detection and approaches to chemo- and immuno-prevention. Examples of how these models are being integrated to address key clinical issues will be discussed.

11:30 A Rapid Establishment of Patient Derived Tumor Xenograft Microenvironments that Enable Preclinical Evaluations of Chemo-Immune Therapeutic Strategies

Richard B. Bankert, V.M.D., Ph.D., Professor, Department of Microbiology and Immunology, State University of NY at Buffalo, School of Medicine and Biomedical Sciences

We report here a simple and reliable model system in which ovarian tumor cell aggregates implanted intraperitoneally into severely immunodeficient NSG mice establish tumor microenvironments within the omentum within one week. The rapid establishment of tumor xenografts within this small anatomically well-defined site enables the recovery, characterization, and quantification of tumor and tumor-associated T cells.

  12:00 pm Modulation of Tumor Progression by Immune Check Point Inhibitors (anti-PD-1/CTLA-4) in Murine Tumor Models

Martin R. Graf, Ph.D., Associate Research Director, In Vivo Oncology, Charles River

With the increasing success and subsequent interest in tumor immunology, there is a growing need for well-characterized preclinical models. We evaluated the responsiveness of nine syngeneic tumor models to antibody based, immune checkpoint inhibitor therapeutics, targeting CTLA-4 and PD-1. Our results clearly show a differential response across tumors when these inhibitors were used individually or in combination. This differential allows one to match efficacy with model and expands the models available for evaluating combination therapies.

12:30 LUNCHEON PRESENTATION: Humanized Immune System Mice for Immuno-Oncology Applications

Leon L. Hall, Ph.D., Senior Director, Global Scientific Development and Translational Discovery Services, Taconic Biosciences, Inc.

Mouse models are widely used in preclinical oncology research but species differences can limit efficacy predictions for clinical translation. Taconic Biosciences’ Immune system humanization program is being leveraged to accelerate efficacy and safety testing of novel immunotherapies. An overview of Taconic’s humanization program will include data showing the utility of humanized mice in PDX applications for immuno-oncology drug development. Additionally, recent advances utilizing next generation humanized mice will be presented.

1:15 Session Break

TOOLS AND TECHNOLOGIES

1:30 Chairperson’s Remarks

Gavin Thurston, Ph.D., Vice President, Oncology & Angiogenesis Research, Regeneron Pharmaceuticals

 1:35Genetic Engineering of the Mouse Immune System to Test Novel Cancer Immuno-Therapuetics

Gavin Thurston, Ph.D., Vice President, Oncology & Angiogenesis Research, Regeneron Pharmaceuticals

One of the challenges in developing clinical immuno-therapeutics is testing these agents in relevant preclinical tumor models. A particular issue has been the lack of cross-reactivity of human-specific therapeutic monoclonal antibodies to murine targets. We have used VelociGene® technology to humanize a variety of targets within the immune system, allowing us to test and compare novel immuno-therapeutics. Examples will be provided for immune modulatory antibodies and bispecific antibodies.

2:05 ImmunoPET Imaging in the Development of Therapeutic Antibodies

Jan Marik, Ph.D., Department of Biomedical Imaging, Genentech, Inc.

Positron emission tomography with radiolabeled monoclonal antibodies (ImmunoPET) is becoming a valuable tool in translational development of therapeutic antibodies. The half-life of positron emitting radionuclide 89Zr (3.3d) matches well the pharmacokinetics of monoclonal antibodies (mAb) hence good quality images can be obtained and inform about the biodistribution of the drug and/or the targeted antigen. Examples of pre-clinical and clinical use of 89Zr-mAbs in the development of targeted cancer therapeutics will be discussed.

2:35 Imaging the Immune Response to Cancer

Michael Dougan, M.D., Ph.D., Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute

Appropriate surrogate endpoints for monitoring immune therapy to cancer are currently lacking. My talk will cover work we are doing in the lab to use single domain camelid derived antibodies conjugated to radioisotypes to image the response to anti-cancer immune therapy by positron emission tomography. We envision this strategy as potentially providing a novel means for tracking immune therapies for cancer, with the potential to guide therapy as well as assist in the generation of new treatment.

3:45 Close of Conference