Cambridge Healthtech Institute’s 4th Annual

Preclinical and Translational Immuno-Oncology

Predictive Preclinical Models and Translational Strategies for Cancer Immunotherapy

August 6-7, 2019

The recent advancements in immunotherapies, such as immune checkpoint modulators, bispecific antibodies, and adoptive T cell transfer, are shifting the way cancer patients are treated. Rapid development of novel immuno-oncology programs is creating the need for predictive preclinical models and translational strategies to understand combination immunotherapy, study responses and resistance to cancer immunotherapy, and identify novel biomarkers and targets. Please join Cambridge Healthtech Institute’s Fourth Annual Preclinical and Translational Immuno-Oncology conference and learn about new clinically-relevant models for screening IO therapies and translational strategies to support clinical IO programs.

Final Agenda

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TUESDAY, AUGUST 6

12:00 pm Registration

CHARACTERIZATION OF RESPONSE AND RESISTANCE TO IMMUNOTHERAPY

1:25 Chairperson’s Opening Remarks

Shahram Salek-Ardakani, PhD, Senior Director, Cancer Immunology, Pfizer

1:30 KEYNOTE PRESENTATION: Defining T Cell States Associated with Response to Combination Immunotherapy

Shahram Salek-Ardakani, PhD, Senior Director, Cancer Immunology, Pfizer

It has remained unclear how simultaneous blockade of PD-1 and co-stimulation of OX40 and 4-1BB receptors synergize for potent T cell-driven anti-tumor efficacy. Using high-dimensional analysis we examined the dynamics of effector CD4 and CD8 T cells responses in the tumor microenvironment (TME) in response to anti-PD-1/OX40/4-1BB treatment. Single-cell profiling of TME revealed distinct CD45+ cells associated with anti-tumor efficacy. Besides exhausted and activated T cells, we identified T cell states with distinct phenotypic, molecular, and functional signatures that were highly predictive of response and survival upon combination immunotherapy. Our findings provide insight into T cell states and biomarkers that underlie the synergy between OX40/4-1BB agonism and PD-1 blockade.

2:00 Mechanisms of Resistance to Anti-CD19 CAR T Therapy

John Rossi, Director, Translational Medicine, Kite Pharma

Limited data has been published describing mechanisms of resistance to CAR T cell therapy. The well-annotated ZUMA-1 clinical trial serves as a benchmark to address outstanding questions. Translational research focusing on the association between CAR T cell product attributes, tumor immune microenvironment and resistance will be presented.

2:30 Characterization of Immune Checkpoint Response and Resistance via Genetic, Transcriptomic, and Epigenetic Analyses

Genevieve Boland, MD, PhD, Assistant Professor, Surgery; Director, Melanoma Surgery Program, Massachusetts General Hospital

Immune checkpoint inhibitors (ICI) have revolutionized treatment for numerous cancer types. However, a significant fraction of patients fails to exhibit a sustainable clinical response. Previous approaches focused on genomic and transcriptomic profiling, yielding promising insights into the mechanisms underlying ICI resistance. The goal here is to discuss epigenomic profiling in parallel with transcriptomic and genomic analyses to confirm existing ICI resistance mechanisms and uncover novel pathways involved in ICI resistance.

3:00 Automated and Decentralized CAR-T Cell Manufacture

Boro Dropulic, PhD, CSO, General Manager, Lentigen Technology, Inc., a Miltenyi Biotec company

Adoptive cell therapy with autologous CAR-T cells has induced remarkable responses in patients with treatment-refractory B cell malignancies. However, limitations exist with commercial CAR-T centralized production. Automation promises to address these issues. Multiple clinical centers are successfully manufacturing CAR-T cells within their institutions. Clinical results shown a high rate of complete remissions upon reaching a threshold dose, with toxicities generally not exceeding grade 2. A decentralized manufacturing network is being established globally.

3:15 Sponsored Presentation (Opportunity Available)

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

4:15 PLENARY KEYNOTE SESSION

PANEL DISCUSSION: Next-Generation Immunotherapies

CHI’s Immuno-Oncology Summit brings you the latest advances in immunotherapy every year. This panel of industry thought leaders will discuss the technology advances and implementation strategies for next-generation immunotherapies, including emerging immunotherapy combinations, bispecific antibodies, oncolytic virotherapy, adoptive cell therapy, personalized vaccines and neoantigen targeted therapies, small molecules and ADCs, cytokines, and innate immunity targeted therapies.

Moderator

Pamela Carroll, PhD

Senior Vice President, Immuno-Oncology, Genocea Biosciences

Panelists

Rakesh Dixit

PhD, DABT, Vice President, R&D; Global Head, Biologics Safety Assessment, MedImmune

Tara Arvedson, PhD

Director, Oncology Research, Amgen

Stephen Doberstein, PhD

Senior Vice President, R&D and Chief Research and Development Officer, Nektar Therapeutics

Raymond Tesi, MD

CEO/CMO, INmune Bio

David Kirn, MD

Co-Founder & Executive Chairman, IGNITE Immunotherapy

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

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WEDNESDAY, AUGUST 7

7:30 am Registration Open and Morning Coffee

CELLULAR MODELS FOR IMMUNOTHERAPY DEVELOPMENT

8:25 Chairperson’s Remarks

Litao Zhang, PhD, Vice President, Leads Discovery and Optimization, Bristol-Myers Squibb

8:30 KEYNOTE PRESENTATION: Dissecting the Tumor Microenvironment Using Multiplex Gene Profiling and Cellular Immune Phenotyping

Litao Zhang, PhD, Vice President, Leads Discovery and Optimization, Bristol-Myers Squibb

Here we will describe and discuss several IO translational models that are regulated by distinct signaling pathways in the tumor microenvironment (TME). Using gene expression and cellular immune-phenotyping profiling as orthogonal and complementary approaches, we uncover network signaling relationships that play a key role in the TME and its critical role in primary and secondary resistance in IO therapy.

9:00 Utilizing 3D Human Immune-Tumor Cell Co-Cultures to Study Immune Oncology Therapies

William Hastings, PhD, Investigator III, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research

To model tumor-immune cell interactions in vitro we have developed a human co-culture model utilizing PBMCs and tumor cell spheroids. We have used this model to probe an unknown mechanism of tumor cell suppression of immune cells. Small molecule and genetic (CRISPR) knockdowns were used to show inhibition of this pathway leads to increased anti-tumor immunity. We observed modulation of IFNg signaling in the tumor by this pathway.

9:30 In vitro CD34-Derived Human Dendritic Cells Provide a Physiologically Relevant System to Evaluate the Potency of Protein Therapeutics That Drive Dendritic Cell Differentiation

Christopher Kemball, PhD, Scientist, Biochemical & Cellular Pharmacology, Genentech

Anti-tumor immunity may be enhanced by therapeutic agents that promote dendritic cell expansion and differentiation, leading to increased antigen presentation and T cell priming. Recent studies identified methods that enable efficient generation of human DCs in vitro from CD34+ progenitor cells; these CD34-derived DCs closely resemble primary human blood DCs. Using this approach, we characterized the activity of a panel of protein therapeutics targeting an antigen expressed by DC progenitors. We evaluated the potency of these agents to drive differentiation of CD141+CLEC9A+ cDC1-like DCs (thought to be important for promoting tumor-specific CD8 T cell responses) and compared this readout with alternative in vitro functional assays that measure receptor-mediated signaling and proliferation of cancer cell lines. Altogether we demonstrate the utility of primary human CD34-derived DC as a more physiologically relevant in vitro system to interrogate the function of protein therapeutics, which could improve translational studies for cancer immunotherapy.

10:00 Lessons Learned From Newly Emergent Humanized Mouse Models for Immune-Oncology

Paula Miliani de Marval, Research Associate Director, Charles River

Given the recent success of cancer immunotherapies, well characterized models are needed to enable drug discovery efforts. The hCD34+ or hPBMC humanized mouse models or the newly developed hPD1 or CTLA-4 knock in mice offer unique tools to assess the anti-tumor response to immune-checkpoint inhibitors in animals bearing a “humanized” immune environment. In this presentation we will discuss the lessons learned from the use of these preclinical models to evaluate human-specific immunotherapies.

10:30 Coffee Break in the Exhibit Hall with Poster Viewing

11:30 Patient-Derived Microtumors for Functional Compound Testing and Therapeutic Response Prediction

Simge G. Yüz, Scientist, NMI Natural and Medical Sciences Institute at the University of Tübingen

Fast and effective functional platforms predicting a patient´s response towards individual treatment after surgery are largely unavailable. We have developed a versatile test platform encompassing patient-derived 3D microtumors (PDMs) and immune cells (including TILs and TAMs) to assess individual responses towards standard-of-care and investigational mono- and combo-treatment approaches for precision oncology assessment and compound efficacy testing.

12:00 pm Ex vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids

Russell W. Jenkins, MD, PhD, Assistant Professor, Medicine, Center for Cancer Research, Massachusetts General Hospital

Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to PD-1 blockade may facilitate efforts in precision immuno-oncology. We have developed a system for ex vivo profiling of PD-1 blockade using 3D microfluidic culture of murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS) using established murine models as well as clinically relevant patient specimens.

12:30 Luncheon Presentation: Capturing Drug-Induced Modulation of the TME Using a Personalized Ex Vivo Histoculture Approach

Mark Paris, PhD, Director, Translational Applications, Biopharma Business Development, Mitra Biotech, Inc.

Delineation of the intra-tumor microenvironment in a dynamic, spatio-temporal setting is critical for investigating the activity and efficacy of candidate oncology drugs. The majority of solid cancers contain unorganized, highly-complex microenvironment wherein a dysregulated phenotypic impacts treatment outcomes at a personalized level. We have developed and validated a fully human ex-vivo platform technology (CANscript™) using patient material (tumor, autologous ligands and immune cells) to explore the mechanism of and predict efficacy for clinically-directed compound.

1:00 Session Break

DEVELOPING CLINICALLY RELEVANT MOUSE MODELS FOR IMMUNO-ONCOLOGY

1:55 Chairperson’s Remarks

Fiona Sharp, PhD, Investigator III, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research

2:00 Exploring Checkpoint Biology in Syngeneic Mouse Models

Fiona Sharp, PhD, Investigator III, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research

The role of checkpoint proteins in regulating anti-tumor immunity has by now been well established for multiple proteins, including, PD-1/PD-L1, LAG-3 and TIM-3. While the cellular and ligand interaction targets for some of these proteins are well defined, our knowledge of these aspects of TIM-3 requires further investigation. Gaining better insight into the key players in TIM-3 biology is central to enhancing the efficacy of this target in the clinic. Our studies have been focused on further exploring the key immune cells involved in TIM-3 controlled anti-tumor immune responses using syngeneic mouse models.

2:30 Using Humanized Mouse Models to Evaluate Cell Engagers

Virna Cortez-Retamozo, PhD, Lab Head, Senior Scientist, Oncology-Pharmacology, Sanofi

3:00 Presentation to be Announced

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

4:15 In vivo Mechanisms Regulating the Activity of BiTE T Cell Engager Molecules in Immuno-Competent Mice

Olivier Nolan-Stevaux, PhD, Principal Scientist, Amgen Research

Despite clinical validation of bispecific T cell engager (BiTE®) molecules against hematological malignancies, the parameters governing their in vivo efficacy remain poorly understood. Here, a new mouse model (huCD3 mouse) in which a human/mouse chimeric CD3ε receptor was engineered into the CD3ε locus is presented. Using syngeneic tumor models, the importance of drug exposure, tumor-infiltrating T cells and immune checkpoints for BiTE® activity in vivo are evaluated.

4:45 Immuno-Competent Mouse Models of Glioma for Preclinical Trials

Eric Holland, MD, PhD, Director, Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center

We have used the RCAS/tva system to generate gliomas in immune competent mice, which mimic the low T cell and high macrophage/microglia environment of human gliomas. The creation of bilateral tumors allows studying the abscopal effect where one side is treated with radiation or oncolytic viruses, and the other is engineered with luciferase expression providing non-invasive readout of viable tumor cell number. We find that the immune system can be trained to recognize untreated tumor areas and that macrophages play a significant role in that response.

5:15 Development and Characterization of a Novel Syngeneic Melanoma Model

Viswanathan Muthusamy, PhD, Director, Center for Precision Cancer Modeling, Yale University

Human melanomas are relatively immunogenic compared to other malignancies. A high somatic mutation burden resulting in immune system recognizable neoantigens result in antitumor responses. A genetically engineered mouse model-derived mouse melanoma line of the genotype: BrafV600E/wt, Pten-/-, Cdkn2a-/- was irradiated with UVB to generate a mutagenized cell line exhibiting a high somatic mutation burden. Compared to the parental cell line, YUMMER1.7 (Yale University Mouse Melanoma Exposed to Radiation) regresses after a brief period of growth when transplanted in low numbers in C57BL/6 wild type mice. This regression phenotype is dependent on T cells as YUMMER1.7 tumors grow significantly faster in immunodeficient Rag1-/-mice and in mice in depleted of CD4 and CD8 T cells. Interestingly, transplantation of higher cell numbers of YUMMER1.7 can overcome regression and result in tumors that grow without effective rejection. Mice that have previously rejected YUMMER1.7 tumors develop immunity against higher doses of YUMMER1.7 tumor challenge. In addition, escaping YUMMER1.7 tumors are sensitive to anti-CTLA-4 and anti-PD-1 therapy, establishing a new model for the evaluation of immune checkpoint inhibition and antitumor immune responses.

5:45 pm Close of Preclinical and Translational Immuno-Oncology

5:45 Dinner Short Course Registration

6:30 Dinner Short Course: Development of Bioassays for Checkpoint Immunotherapy and Other Immuno-Oncology Leads*

*Separate registration required.

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