Cambridge Healthtech Institute’s Fourth Annual
Immunomodulatory Therapeutic Antibodies for Cancer
Recent regulatory approvals and a succession of favorable clinical data from the checkpoint inhibitor programs of major pharmas are now spearheading a new focus on immune system modulating protein therapeutics. These results are now driving interest across the research community in a rapidly evolving landscape of checkpoint blockades, co-stimulatory factors and other emerging target modalities. CHI’s 4th Annual Immunomodulatory Therapeutic Antibodies for Cancer will explore new understandings of target biology in the immunotherapy space and consider applications of protein engineering and novel biotherapeutic design strategies that will result in drug products to be administered as monotherapies and in combinations.
Final Agenda
MONDAY, AUGUST 29
7:30 am Registration & Morning Coffee
8:25 Chairperson’s Opening Remarks
Tariq Ghayur, Ph.D., Distinguished Research Fellow, AbbVie Bioresearch Center
8:30 OPENING KEYNOTE PRESENTATION:
IMMUNOTHERAPY FOR CANCER: THE PROMISE AND CHALLENGES AHEAD
Ronald Herbst, Ph.D., Vice President, R&D; Head, Oncology Research, MedImmune
Immune-evasion is a hallmark of cancer and enhancement of the anti-cancer immune response by targeting checkpoint pathways, such as CTLA-4 and PD-1/PD-L1, is showing significant promise. However, a subset of patients fails to benefit from immune therapy. Going forward it will be key to better understand the immunologic diversity within and across indications, and to identify markers of response (or no response) to therapy to further increase the benefit to patients.
9:00 Lessons Learned from Studies of Checkpoint Blockade Toxicity
Geoffrey T. Gibney, M.D., Medical Oncologist, Georgetown-Lombardi Comprehensive Cancer Center
Recent developments in targeted immune checkpoint blockade have revolutionized treatment approaches in patients with advanced malignancies. While durable responses are seen, checkpoint therapies are associated with a range of immune-related toxicities that can complicate patient care. Combination strategies so far have led to even higher rates of immune events. Most severe toxicities are manageable with corticosteroids and other immunomodulatory agents. The current data on checkpoint blockade toxicities will be reviewed.
9:30 Coffee Break
10:00 Anti-Hypoxia-A2-Adenosinergic Co-Adjuvants to Enable the Full Anti-Tumor Capacities of T- and Natural Killer Cells During Immunotherapies of Cancer
Stephen Hatfield, Ph.D., Research Scientist, New England Inflammation and Tissue Protection Institute, Northeastern University
The presentation introduces the adenosine-generating CD73 ecto-enzyme as a potential drug target and biomarker of the most resistant human tumors. In addition, oxygenation agents join antagonists of A2A Adenosine Receptors as novel checkpoint inhibitors that reprogram the TME away from immunosuppression and have promise if used in combination with existing cancer immunotherapies.
10:30 The Role of Immune Biomarkers in Offering a Standardized Way of Evaluating the in vivo Behavior of Cancer Immunotherapies
Susan R. Slovin, M.D., Ph.D., Medical Oncologist, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center
Major initiatives are ongoing to establish and validate in clinical trials a platform of biomarkers that can be used to assess biologic changes and treatment responses in solid tumors treated with novel immune drugs. The identification and relevance of biomarkers in trials with immunologic agents can vary with the drug used. How to incorporate the metrics of biomarkers into immunotherapy trials and their validation is a major focus of trial design.
Speaker has Cancelled: 11:00 Anti-PD-1 Immunomodulatory Antibodies with Unique Mechanisms of Action
Sheila Ranganath, Ph.D., Director, R&D, Enumeral Biomedical Corporation
Using Enumeral’s proprietary single cell immune-profiling technology, we discovered a distinct anti-PD-1 antibody with a potentially differentiated mechanism of action. This antibody, 244C8, does not compete with currently marketed anti-PD-1 antibodies for PD-1 binding. Further, 244C8 elicits greater T cell activation in ex vivo human cell-based assays than currently marketed anti-PD-1 antibodies. 244C8 has been humanized for preclinical testing in preparation for Phase I clinical studies.
11:00 Tumor-Localized Costimulatory T Cell Engagement with Bispecific CD137-Agonists
Louis Matis, M.D., Senior Vice President, Chief Development Officer, Pieris Pharmaceuticals, Inc.
We describe the generation and characterization of the CD137/HER2 and CD137/GPC-3 bispecifics designed to promote CD137 clustering in the tumor microenvironment by bridging CD137- positive T cells with target positive tumor cells, thereby providing a potent costimulatory signal to tumor antigen-specific T cells.
11:15 Transforming Antibody Discovery with the Benchling Platform
Sajith Wickramasekara, CEO, Benchling
For most antibody discovery R&D, the discovery process is a work in progress. Keeping track of experimental results of just antibody leads, much less managing the entire antibody discovery workflow, can prove difficult. Existing software solutions force users to engage with disparate pieces of software and require time-consuming and error-prone manual input. Benchling unifies experiment workflows in a single, collaborative research platform that was co-developed with scientists, ensuring that cutting-edge science is never held back by archaic software. In this talk we will describe how we work with scientists in antibody discovery to empower them to design, register and optimize antibodies on a single platform.
11:30 pm End of Morning Session (Delegates may attend session of parallel meeting)
12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:30 Session Break
1:25 Chairperson’s Remarks
Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut
1:30 Bi- and Multi-Specific Biologics for Cancer Immunotherapy: Selecting Target Combinations and Designing Biologics to Modulate Anti-Tumor T Cell Functions
Tariq Ghayur, Ph.D., Distinguished Research Fellow, AbbVie Bioresearch Center
The presentation will discuss how high throughput functional bioassays have been used to select combinations of mAbs to either the same target (different epitopes) or different targets for generating dual-specific DVD-Ig molecules with additive and/or synergistic activity. The talk will also describe the application of new multi-specific formats in understanding the biology of T cell activation by co-ligating CD3 and co-receptors and to design molecules to address specific unmet needs.
2:00 T Cell Activation and Pre-Clinical Anti-Tumor Efficacy of Anti-Lag3 Mabs Is Independent of their Lag-3-Mhc Class II Blocking Capacity
Saso Cemerski, Ph.D., Associate Principal Scientist, Merck Research Laboratories
LAG-3 is a MHC-II-interacting receptor that hampers T cell activation. We assessed the relationship between anti-LAG-3 antibody-induced efficacy and the ability to block LAG-3-MHCII interactions. We compared the bioactivity of two distinct anti-mLAG-3 antibodies that differ in their ability to block LAG-3-MHCII interactions. We demonstrated that anti-LAG-3 antibody efficacy is not associated with their ability to disrupt LAG-3-MHCII interaction, suggesting they could enhance both CD4+ and CD8+ T cell function.
2:30 Pathways and Mechanisms Engaged by OX40 Plus 4-1BB Dual Costimulation Immunotherapy
Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut
Dual costimulation with CD134 plus CD137 agonists elicits powerful therapeutic tumor immunity by priming robust CD8+ CTL, and CD4 T cells that are cytotoxic and provide both antigen-linked and non-linked help. Further, dual costimulated T cells can be triggered to elaborate effector functions not only by antigen, but also TCR-independently through cytokine combinations such as IL-12 or IL-2 plus either of the IL-1 family members IL-33 or IL-36.
3:00 Refreshment Break
3:30 High Dimensional Cell Analysis of Early Lung Tumor Immune Contexture
Miriam Merad, M.D., Ph.D., Chair, Cancer Immunology, Oncological Sciences, Tisch Cancer Institute, Mount Sinai Hospital
Despite unprecedented clinical response of advanced NSLC to checkpoint blockade, a comprehensive understanding of the immune microenvironment of early stage NSLC has not been done. Here we will present high dimensional single-cell analysis of immune changes that occurs in the vicinity of early lung NSCLC. Our results provide a rationale for testing whether modulation of the lung tumor immune microenvironment can promote anti-tumor immunity, prevent tumor relapse and transform the outcome of patients with early lung cancer.
4:00 Inducing Neo-Antigen Specific T Cells from the Naïve Repertoire
Marit van Buuren, Ph. D., Scientist, Immunology, Neon Therapeutics
The recognition of neo-antigens on human cancer has strongly been connected to the clinical success of immune therapies. Neon Therapeutics Inc. aims to generate neo-antigen specific vaccines and T cell therapies that are tailored for each individual patient. Here we will present the platform that Neon has developed to generate a neo-antigen specific T cell product for the use of adoptive cell transfer.
4:30 Targeting TIM-3 and LAG-3
Jeffrey Hanke, Ph.D., CSO, Tesaro
Strategies to activate exhausted tumor-specific T cells, including the use of monoclonal antibodies (mAb) that block the negative costimulatory receptors CTLA-4 and PD-1/PDL1, are proving effective in a number of cancer types. However, only a subset of patients respond to these therapies, and resistance is increasingly observed. The role of TIM3 and LAG3 will be discussed.
5:00 End of Day
TUESDAY, AUGUST 30
8:00 am Morning Coffee
8:25 Chairperson’s Opening Remarks
John Desjarlais, Ph.D., CSO, Xencor
8:30 The Role of Antibody Isotype and Fc Receptor Interactions in Engineering Cancer Immunotherapies
Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton
Exciting clinical results with checkpoint-blocking mAb have revived the belief that the immune system holds the key to controlling cancer. Here we show that immunostimulatory mAb can employ multiple mechanisms in tumors, and that the mechanism used depends on mAb isotype and FcgR availability. These data have broad implications for selecting tumor immune targets and engineering immunomodulatory mAb; illustrating the necessity to determine all potential mechanisms of action to maximize activity and potential clinical utility.
9:00 Immune Checkpoint Inhibition by High-Affinity Receptor Decoys: Good Things Come in Small Packages
Aaron Ring, M.D., Ph.D., Assistant Professor, Immunobiology, Yale University School of Medicine
Immune checkpoints have largely been therapeutically targeted using monoclonal antibodies. However, non-antibody biologics may offer potential advantages in the context of tumor immunotherapy. This talk will highlight two engineered ultra high-affinity decoys of PD-1 and SIRPα—checkpoints of the adaptive and innate immune systems, respectively. These agents illustrate the potential for small protein therapeutics as immunotherapeutics, components of cell-based therapies, and diagnostic agents of immune function and tumor immunogenicity.
9:30 Targeting Fc Effector Functions to Tumor-Expressed Integrins for Synergistic Innate and Adaptive Immunotherapy
K. Dane Wittrup, Ph.D., Carbon P. Dubbs Professor, Chemical Engineering and Biological Engineering, Massachusetts Institute of Technology
Anti-tumor antibodies combined with extended-PK IL-2 leads to significant immunotherapeutic responses in large established syngeneic tumors in mice. In order to extend this approach to tumor types for which specific antibodies are not available, we have constructed an Fc fusion to a small knottin protein with broad binding specificity to RGD-binding integrins. This pseudo-mAb exhibits strong efficacy in preclinical models and generates a T-cell dependent protective adaptive immune response.
10:00 Discussion with Session Speakers
10:30 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
11:15 Tumor-Specific Antibodies Engineered to Bind NKG2D Activate both NK and T-Cells
Kyle Landgraf, Ph.D., Senior Scientist, Discovery Research, AvidBiotics
NK and T-cells utilize the NKG2D receptor to destroy cancer cells expressing stress ligands. However, tumors deploy strategies to evade this surveillance pathway. Using structure-guided phage display, NKG2D stress ligands have been engineered as effector domains to convert tumor-specific antibodies into dual NK/T-cell activators through NKG2D engagement. These antibodies can stimulate IFNγ production and degranulation of NK and T-cells, providing rationale for their use in combination with checkpoint therapies.
11:45 Bispecific Antibodies for T Cell Recruitment and Dual Checkpoint Blockade
John Desjarlais, Ph.D., CSO, Xencor
We have optimized a plug-and-play, Fc-containing bispecific antibody platform with high stability, efficient production, and antibody-like pharmacokinetics. This optimized bispecific format resembles a standard monoclonal antibody, with one of the Fab arms replaced by a stability-optimized single-chain Fv (scFv) (scFv-Fab-Fc). We will present application of the platform to generate a broad pipeline of CD3 bispecifics for T cell redirection and dual checkpoint blockade bispecifics for T cell activation.
12:15 pm Close of Immunomodulatory Therapeutic Antibodies for Cancer