Cambridge Healthtech Institute’s 2nd Annual

Emerging Immuno-Oncology Targets

Novel Targets and Pathways for Cancer Immunotherapy and Combinations

August 30-31, 2018

While cancer immunotherapy has made a giant leap in the past five years, the majority of therapies at advanced stages of development are clustered in a similar target space. The increased investment in immuno-oncology has created an urgent opportunity to discover and populate new target spaces that either present new classes of immunotherapies or can be used in combination with existing products. Cambridge Healthtech Institute’s Second Annual Immuno-Oncology Targets conference will cover the emerging target space, including immunomodulatory inhibitor and agonist targets, stromal and immune cell targets, and strategies for rational combination immunotherapy. Case studies of preclinical and translational approaches to the discovery and validation of new immuno-oncology targets and combinations will be presented.

Final Agenda

THURSDAY, August 30

7:45 am Registration & Morning Coffee (Harbor Level)

TARGETING INNATE AND ADAPTIVE IMMUNITY
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8:25 Chairperson’s Opening Remarks

Steven A. Greenberg, MD, Professor, Neurology, Harvard Medical School; Brigham and Women’s Hospital; Abcuro, Inc.

8:30 Targeting the T and NK Cell Co-Inhibitory Receptor KLRG1: Rationale for Clinical Development

Steven A. Greenberg, MD, Professor, Neurology, Harvard Medical School; Brigham and Women’s Hospital; Abcuro, Inc.

Targeting of lymphocyte co-inhibitory receptors, such as CTLA-4, PD-1, LAG-3, and TIM-3, has gained intense interest for treatment of cancer. KLRG1 is also a lymphocyte co-inhibitory receptor, expressed predominantly on effector memory CD8+ T cells and NK cells, whose ligands E- and N-cadherin are differentially expressed during epithelial-mesenchymal transition. Targeting of KLRG1 has not previously been pursued in murine cancer studies. Here we demonstrate that anti-KLRG1 neutralizing antibody demonstrates efficacy in inhibiting metastases, reducing primary tumor volume, and improving survival as monotherapy and synergistic combination therapy with anti-PD-1 in syngeneic murine cancer models. Humanized anti-KLRG1 antibodies activate T cells and are a promising new approach for cancer immunotherapy.

9:00 Smac Mimetics Can Trigger Immunogenic Cell Death in Cancer Cells

Jürgen Moll, PhD, Director, Pharmacology and Translational Research, Boehringer Ingelheim 

9:30 NKG2D Ligands Regulation of Immune Checkpoint Blockade Therapy of Cancer: Efficacy and Toxicity

Jennifer Wu, PhD, Mary and Patrick Scanlan Professor of Urology, Northwestern University and Robert Lurie Comprehensive Cancer Center

Ligands for the immune activation receptor NKG2D are often induced on the surface of tumor cells in response to genotoxic insults. Surface NKG2D ligand can activate the immune surveillance through activating NK cells and co-stimulating effector T cells. Recent studies demonstrate that advanced tumors shed soluble NKG2D ligands that impair response to immune checkpoint blockade therapy and induce colon toxicity. Therapeutic intervention targeting this pathway will be discussed.

10:00 Coffee Break in the Exhibit Hall (Last Chance for Poster Viewing) (Commonwealth Hall)

10:45 NEW: Polarized Dendritic Cells: Inducers of Tumor-Specific CTLs and Modulators of Tumor Microenvironment

Pawel Kalinski, MD, PhD, Professor, Oncology, Vice-Chair, Translational Research, Roswell Park Cancer Institute

11:15 eFT508: A Highly Selective Inhibitor of MNK1/2 Enhances Anti-Tumor Immune Response

Kevin Webster, PhD, Senior Vice President, Cancer Biology, eFFECTOR Therapeutics

eFT508 is a highly selective inhibitor of MNK1/2, kinases that promote tumor immune evasion downstream of MAPK signaling. eFT508 enhances anti-tumor immune response by establishing a regulatory program that stimulates antigen presentation and T cell priming, expansion of memory T cells, and prevents T cell exhaustion. eFT508 is currently under evaluation in multiple phase 1/2 clinical trials as both a monotherapy and in combination with checkpoint inhibitors.

11:45 Evaluating the Immuno-Oncology Potential of Compounds and Combinations using Human in vitro TME Models

Alison O'Mahony, PhD, Vice President, Translational Biology, Research & Development, Eurofins Pharma Discovery Services

With less than a third of cancer patients responding to immuno-oncology (IO) therapies, the challenge is to develop better and safer IO candidates and combination strategies to achieve improved clinical outcomes. Recent IDO failures illustrate the critical need for more translational target validation for agents and combination strategies. Here we demonstrate the application of human-based in vitro co-culture assays such as the BioMAP® TME phenotypic models, which may prove superior in advancing safer and more effective IO agents than current animal-centric methods.

12:15 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:45 Session Break

NEOANTIGEN TARGETED THERAPIES
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1:40 Chairperson’s Remarks

Philip Arlen, MD, President & CEO, Precision Biologics

1:45 FEATURED PRESENTATION: T Cells against Tumor Neoantigens: How Many Are Likely Needed for Clinical Efficacy and Can Contemporary Vaccines Get Us There?

Andrew Allen, PhD, CEO & President, Gritstone Oncology

Two key challenges in neoantigen-directed therapeutics are: 1) accurate neoantigen identification from “sea” of tumor mutations (achieved with deep learning approach, trained on human tumors); 2) induction of large numbers of polyfunctional neoantigen-specific T cells. Novel vaccine approaches to problem (2), in combination with checkpoint modulators, can drive extremely high and sustained T cell responses in non-human primates. We can compare these to T cell numbers observed in successful adoptive cell therapy.

2:15 The Discovery and Development of Novel Monoclonal Antibodies Targeting Neoantigens

Philip Arlen, MD, President & CEO, Precision Biologics

Immunogenic neoantigens were derived from a membrane preparation of pooled allogeneic colorectal cancer. The membrane was separated into various fractions by molecular weight and screened for immunogenicity. An immunogenic fraction was identified and used as a vaccine in a clinical trial for patients with chemotherapy refractory disease. There was a correlation observed in patients who developed antibody responses to therapy with both antitumor responses as well as prolongation in overall survival. This vaccine was used as a platform to screen monoclonal antibodies as potential therapeutic candidates.

2:45 An Integrated Machine-Learning Approach for Improved Prediction of Clinically Relevant Neoantigens

Trevor Clancy, PhD, CSO, OncoImmunity AS

Current neoantigen discovery algorithms are not optimal to predict antigen presentation to the tumor cell surface. Here, we outline a high-performing machine learning approach, that predicts naturally processed and presented antigens. The predictor is integrated with several immune parameters in a deep learning layer to predict bone fide neoantigens. We illustrate its application to significantly improve the identification of neoantigen targets for personalized cancer immunotherapy.

3:15 Refreshment Break (Commonwealth Hall)

3:45 Improving Checkpoint Blockade by Improving Tumor Antigen Cross-Presentation

Joshua Brody, MD, Assistant Professor, Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai; Director, Lymphoma Immunotherapy Program

Checkpoint blockade therapy of cancer has had tremendous impact, yet only a subset of patients responds. Although increased tumor mutational burden and tumor-associated antigen (TAA) load correlate somewhat with response to checkpoint blockade, we have shown that Hodgkin’s lymphoma, despite a high anti-PD1 response rate, has significantly fewer mutations than highly mutated tumors such as lung cancer. This demonstrates that response to checkpoint blockade is determined by factors beyond mutation burden. Our hypothesis is that checkpoint blockade is limited by suboptimal cross-presentation of TAA by suitably activated dendritic cells.

4:15 Th1 Epitopes for Versatile Tumor- and Patient-Tailored Vaccine Combination Therapies (VCT)

William C. Watt, PhD, President & CEO, EpiThany
Th1 epitopes from overexpressed tumor antigens constitute a rich source of active ingredients for cancer vaccine combination therapies (VCTs). Mining the “Th1 epitoire” for flexibility in vaccine antigen selection enables targeting of diverse tumors, patients and settings. EpiThany is incorporating its a priori validated tumor-specific Th1 epitopes into VCTs using multiple delivery platforms and combination agents to treat breast and ovarian cancers at multiple stages of disease.      

4:45 Induction of Potent Neoantigen Targeted CD8+ T Cell Responses via Optimized DNA-Based Immunotherapy

Niranjan Y. Sardesai, PhD, CEO & President, Geneos Therapeutics

Tumor neoantigen targeting for the development of patient specific immunotherapies has emerged as a viable approach for cancer immunotherapy. Considerable efforts are being directed towards the accurate identification and prediction of targetable neoantigens for each patient. However equally critical is the platform deployed for the administration of the selected neoantigens to generate patient T cell responses in vivo. We will discuss the use of optimized plasmid DNA based approach.

5:15 End of Day

FRIDAY, August 31

7:45 am Registration (Plaza Level)

8:00 Breakout Discussion Groups with Continental Breakfast (Beacon Hill)

This session features discussion groups that are led by a moderator who ensures focused conversations around the key issues listed. Attendees choose to join a specific group, and the small, informal setting facilitates sharing of ideas and active networking. Details on the topics and moderators are available on the conference website.

EMERGING CYTOKINE TARGETS
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9:00 Chairperson’s Remarks

Raymond Tesi, MD, President and CEO, Acting CMO, INmune Bio

9:05 Targeting Soluble TNF in Tumor Microenvironment (TME) to Reverse Resistance to Immunotherapy

Raymond Tesi, MD, President and CEO, Acting CMO, INmune Bio

Checkpoint inhibitors do not work in a majority of patients. The most important predictor of resistance to CPI is MDSC in blood and/or TME. MDSC requires TNF to proliferate. Selective elimination of soluble TNF (with preservation of trans-membrane TNF) in blood and TME will reverse the immunologic factors that cause resistance to CPI and other immunotherapies.

9:35 Preclinical Characterization of a Novel STING Agonist, MK-1454

Saso Cemerski, PhD, Principal Scientist, Merck Research Labs

MK-1454, a novel STING agonist, induces potent cytokine responses and activates several immune cell types in vitro including MDSCs and M2-macrophages, key suppressive myeloid cells in the TME. MK-1454 induces robust anti-tumor activity in mouse syngeneic tumor models and cytokine production and gene expression changes in ex vivo-stimulated human primary tumors. MK-1454 is currently being evaluated in cancer patients both as monotherapy and in combination with Keytruda.

10:05 Novel, High-Potency Sting Agonists Regress Immunotherapy-Resistant Cancers

Michael A. Curran, PhD, Assistant Professor, Immunology, The University of Texas MD Anderson Cancer Center

Working with MD Anderson’s Institute for Applied Cancer Science (IACS), we have developed novel, highly potent agonists of the Stimulator of Interferon Genes (STING) pathway. Not only do these STING agonists outperform existing agents in murine syngeneic melanoma models, but they also synergize with T cell immune checkpoint blockade to treat multi-focal pancreatic cancer which responds poorly, if at all, to weaker agonists.

10:35 Coffee Break (Plaza Level)

11:00 The TNFR2 Immuno-Oncology Target: Elimination through Antibody Antagonism of Infiltrating Tregs and Direct Oncogene Tumor Death

Denise Faustman, MD, PhD, Associate Professor & Director, Immunobiology Lab, Massachusetts General Hospital, Harvard Medical School

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but exhibit variable efficacy and relapse and can induce autoimmunity. Tumor necrosis factor (TNF) receptor 2 (TNFR2) is a signaling molecule found on the surface of a subset of potent regulatory T cells (Tregs) that can activate the proliferation of these cells through nuclear factor kappa B (NF-kB). TNFR2 is also abundantly expressed on the surface of many human tumors. We propose that blocking TNFR2 might target abundant TNFR2+ tumor-infiltrating Tregs and directly kill TNFR2-expressing tumors.

11:30 NKTR-255: Accessing IL-15 Therapeutic Potential through Robust and Sustained Engagement of Innate and Adaptive Immunity

Peiwen Kuo, PhD, Scientist, Nektar Therapeutics

Recognized as a promising immuno-oncology agent, harnessing the full potential of IL-15 has been stymied by poor pharmacokinetics. NKTR-255 overcomes this barrier with dramatically improved bioavailabilty to drive robust proliferation, while supporting function and survival of NK and CD8 T cells. Demonstrating consistent PK, PD and low toxicity in cyno, combined with single and combination efficacy in various preclinical tumor models, NKTR-255 aims to unlock the true potential of IL-15.

12:00 pm Close of Emerging Immuno-Oncology Targets