Agonist Immunotherapy Targets

The immunotherapies industry is currently dominated by antagonist antibodies such as PD-1 and CTLA-4, however, agonist targets play an equally critical role in improving the immune response across various types of cancer. CHI’s Agonist Immunotherapy Targets conference brings together leading industry scientists and academics to examine the most promising agonist targets in development, supported by cutting-edge data and lessons learnt. Key targets include 4-1BB, OX40, CD137, CD40 and GITR, as well as developments in TNFR receptors, ICOS, STING, and VISTA – as monotherapies and in combination.

Thursday, September 3

ADVANCES IN ICOS AGONISTS

12:45 pm KEYNOTE PRESENTATION:

ICOS Agonism – The Next Generation of Immune Checkpoint Modulation for Cancer

Axel Hoos, PhD, Senior Vice President, Therapeutic Area Head, Oncology, GSK

GSK3359609 is a non-T cell depleting ICOS costimulatory receptor agonist antibody. In non-clinical systems, it enhances immune-stimulatory and anti-tumor properties as monotherapy and in combination with other anti-cancer agents. INDUCE-1 study has demonstrated the pharmacology and anti-cancer properties of GSK3359609 including clinical activity as monotherapy and in combination with PD1 blockade in r/mHNSCC warranting randomized trials to evaluate overall survival.

1:05 pm

Reverse Translational Approaches in Development of ICOS Agonist Vopratelimab

Elizabeth Tréhu, MD, CMO, Jounce Therapeutics Inc.

Vopratelimab is an investigational ICOS agonist monoclonal antibody that results in activation and proliferation of CD4 T effector cells with high levels of ICOS. In the ICONIC trial, emergence of these cells was associated with improved ORR, PFS, and OS. An RNA signature in baseline tumor samples appears to predict for emergence of ICOS high CD4 T cells and improved clinical outcomes.

1:25 pm

LIVE Q&A: Session Wrap-up

Panel Moderator:
Peter Ellmark, PhD, Vice President, Discovery, Alligator Bioscience AB
Panelists:
Axel Hoos, PhD, Senior Vice President, Therapeutic Area Head, Oncology, GSK
Elizabeth Tréhu, MD, CMO, Jounce Therapeutics Inc.
1:45 pm Refresh Break - View our Virtual Exhibit Hall

ADVANCES IN CD137 AGONISTS

2:30 pm

A CD137 Antibody with Differential Agonist Properties that Promotes Antitumor Immunity

Helen Kotanides, PhD, Senior Research Advisor, Oncology Biologics Discovery, Loxo Oncology at Lilly

We developed the CD137 agonist, 7A5, a fully human IgG1 Fc effector null monoclonal antibody, and characterized its biological properties. 7A5 binds CD137, and the binding epitope overlaps with the CD137L binding site. 7A5 engages the CD137 receptor in cell-based function assays and inhibits tumor growth in human tumor xenograft mouse models reconstituted with human immune cells. Collectively, the preclinical data support further development of 7A5 as a cancer immunotherapy.

2:50 pm

A CD137 Bispecific Antibody Targeting the Tumor Microenvironment

Patrick Mayes, PhD, Executive Director, Head, IO Antibody Research, Incyte

We have identified a CD137xPD-L1 bispecific antibody (MCLA-145) which drives transactivation of CD137, specifically in the vicinity of cells expressing PD-L1. MCLA-145 treatment resulted in significant immune cell activation in primary human immune cell assays as well as antitumor immune responses in two separate humanized mouse tumor models. These data support the clinical evaluation of MCLA-145 as a novel, PD-L1 dependent CD137 agonist immune therapy and clinical studies are ongoing (NCT03922204).

3:10 pm

IGM Antibodies with Very Potent Agonism to DR-5 Induced Apoptosis and as Anti-Tumor Agents

Bruce Keyt, PhD, CSO, R&D, IGM Biosciences, Inc.

DR5 is broadly expressed on tumors and multimerization induces apoptosis. However, anti-DR5 agonistic IgG and TRAIL molecules have been unsuccessful in clinical trials. We have engineered a multivalent IgM antibody IGM-8444 containing 10 binding sites for efficient DR5 multimerization and agonism. IGM-8444 was cytotoxic across cell lines from 18 solid and hematologic malignancies in vitro though did not induce cytotoxicity of primary hepatocytes. In vivo, IGM-8444 induced complete and durable dose-dependent tumor regressions in a gastric PDX model and tumor growth inhibition in other CDX and PDX models. IGM-8444 combined well with chemotherapeutics and targeted agents in vitro and in vivo. IGM-8444 is expected to be in Phase 1 clinical testing later in 2020.

3:30 pm

LIVE Q&A: Session Wrap-up

Panel Moderator:
Peter Ellmark, PhD, Vice President, Discovery, Alligator Bioscience AB
Panelists:
Helen Kotanides, PhD, Senior Research Advisor, Oncology Biologics Discovery, Loxo Oncology at Lilly
Patrick Mayes, PhD, Executive Director, Head, IO Antibody Research, Incyte
Bruce Keyt, PhD, CSO, R&D, IGM Biosciences, Inc.
3:50 pm Close of Day

Friday, September 4

ADVANCES IN OX-40, 4-1BB, CD40 AGONISTS

9:05 am

Overcoming the Resistance to Agonist Immunotherapy

Bin Zhang, PhD, Professor, Department of Medicine, Division of Hematology/Oncology Department of Microbiology-Immunology Director, Cancer Immunotherapy Initiative Co-Director, Immune Assessment Core Facility Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine

The underlying mechanisms of agonist immunotherapy remain incompletely understood. We recently demonstrated an inhibitory role of ecto-enzyme CD73 (generating extracellular adenosine) for agonistic anti-4-1BB/CD137 Ab therapy. In particular, the TGF-β-rich tumor milieu confers resistance to anti-4-1BB therapy by sustaining CD73 expression primarily on infiltrating CD8+ T cells across several tumor models. Thus, our findings identify a novel resistance mechanism targeting of 4-1BB and other costimulatory molecules.

9:25 am

Elucidating How Nonlinked CD4+ Help Augment OX40 plus 4-1BB Agonist Immunotherapy

Adam Adler, Professor, Department of Immunology, UConn Health School of Medicine

Engaging tumor-unrelated CD4 T cells can boost the efficacy of costimulatory receptor agonist immunotherapy through a previously uncharacterized process termed "nonlinked help". The ability of the unrelated CD4 T cells to provide nonlinked help appears to be conferred via a TCR-independent, "innate-like" response that involves stimulation with a JAK/STAT activating cytokine plus an IL-1 family member.

9:45 am

Fc-Silenced Bispecific Antibodies Targeting PD-L1 and 4-1BB Combine Checkpoint Blockade and T Cell Co-Stimulation to Promote Anti-Tumor Activity

Alexander Muik, PhD, Head, Immunomodulators, BioNTech SE

DuoBody®-PD-L1x4-1BB [GEN1046] was designed to combine ICB and conditional T cell co-stimulation through dual targeting of PD-L1 and 4-1BB. This distinctive mechanism of action triggers potent anti-tumor immunity without inducing hepatotoxicity in mice. Correspondingly, the clinical candidate, DuoBody®-PD-L1x4-1BB, enhances human primary T cell function and TIL expansion.

10:05 am

LIVE Q&A: Session Wrap-up

Panel Moderator:
Adam Adler, Professor, Department of Immunology, UConn Health School of Medicine
Panelists:
Bin Zhang, PhD, Professor, Department of Medicine, Division of Hematology/Oncology Department of Microbiology-Immunology Director, Cancer Immunotherapy Initiative Co-Director, Immune Assessment Core Facility Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Alexander Muik, PhD, Head, Immunomodulators, BioNTech SE
10:30 am Speed Networking Coffee Break - View our Virtual Exhibit Hall

ADVANCES IN OX-40, 4-1BB, CD40 AGONISTS

10:50 am

Developing Novel Combinations to Enhance the Therapeutic Efficacy of OX40 Agonists

William Redmond, PhD, Associate Member and Director, Immune Monitoring Laboratory, Earle A. Chiles Research Institute, Providence Cancer Institute

Novel combinatorial approaches are needed to improve the efficacy of cancer immunotherapy. Therefore, we investigated the efficacy of combined therapy with pegzilarginase, a human arginase 1 enzyme engineered to have superior stability and enzymatic activity relative to native human arginase 1, plus anti-PD-L1 or agonist anti-OX40 mAb. Combined pegzilarginase/immunotherapy induced robust anti-tumor immunity characterized by increased intratumoral CD8+ T cells and M1-polarization of tumor-associated macrophages and provides a strong rationale for clinical translation of this approach.

11:10 am

CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade to Bridge Innate and Adaptive Immunity

Taylor H. Schreiber, PhD, CEO, Shattuck Labs Inc.

CD47/SIRPa blockade enhances macrophage-mediated phagocytosis of tumor cells that are dying, or have been tagged with an ADCP-competent antibody, however this event does not enhance anti-tumor immunity in the absence of antigen presentation to CD8+ T cells. SIRPa-Fc-CD40L (SL-172154) links these two mechanisms via a Type I interferon response, and has shown profound activity in both mouse and non-human primate studies.

11:30 pm

Targeting CD40 to Unleash Dendritic Cells in Immuno-Oncology – Expanding the Tumor Specific T Cell Repertoire

Peter Ellmark, PhD, Vice President, Discovery, Alligator Bioscience AB

Tumors that lack tumor infiltrating T cells, so called cold tumors, do not respond to checkpoint therapies. In many cases, the lack of T cell infiltration is a result of insufficient activation of dendritic cells. Alligator Bioscience develops therapies targeting CD40, including the Phase II ready CD40 agonistic antibody (Mitazalimab) that activates dendritic cells. Activation of dendritic cells can increase the frequency and activation of tumor infiltrating T cells resulting in anti-tumor responses.

11:50 pm

LIVE Q&A: Session Wrap-up

Panel Moderator:
Adam Adler, Professor, Department of Immunology, UConn Health School of Medicine
Panelists:
Taylor H. Schreiber, PhD, CEO, Shattuck Labs Inc.
Peter Ellmark, PhD, Vice President, Discovery, Alligator Bioscience AB
William Redmond, PhD, Associate Member and Director, Immune Monitoring Laboratory, Earle A. Chiles Research Institute, Providence Cancer Institute
12:15 pm Lunch Break - View our Virtual Exhibit Hall
1:35 pm Close of Summit





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