Cambridge Healthtech Institute’s 5th Annual
Immunomodulatory Therapeutic Antibodies for Cancer
Scientific Strategies for Discovering and Developing Novel Immunotherapies and Agents to Improve the Efficacy and Toxicology Profiles of T Cell-Targeted Biotherapeutics
August 28-29, 2017 Sheraton Boston Hotel | Boston, MA
Recent regulatory approvals and a succession of favorable clinical data from the checkpoint inhibitor programs of major pharmas are spearheading a new focus on immune system modulating protein therapeutics. However, this space has quickly become crowded with agents directed against similar targets, and issues with non-responders and a limited amount of capacity for clinical studies have created barriers for emerging companies wishing to enter this space. CHI’s Fifth Annual Immunomodulatory Therapeutic Antibodies for Cancer will explore the science and strategies behind developing unique approaches to the unmet medical needs in this market and offer important new updates on mechanistic understandings of efficacy, side effects and patient populations.
Final Agenda
MONDAY, AUGUST 28
7:30 am Registration & Morning Coffee
8:25 Chairperson’s Opening Remarks
Yan Qu, Ph.D., Senior Principal Scientist, Pfizer
8:30 KEYNOTE PRESENTATION: Enabling Effective Immuno-Oncology
Gregory Adams, Ph.D., CSO, Eleven Biotherapeutics
Checkpoint inhibitors and other immune-oncology agents have shown significant promise in the treatment of a variety of cancers. However, many of these agents are only effective when an existing host immune response has already been induced by other therapeutic approaches. I will discuss strategies that may be used to effectively set the stage for immune-oncology treatments including Eleven BioTherapeutics’ Targeted Protein Therapeutics.
9:00 Immunomodulatory Antibodies – Potentiation by Fc Receptor Engagement
Rony Dahan, Ph.D., Principal Investigator, Immunology, Weizmann Institute of Science, Israel
Immunomodulatory mAbs are revolutionizing cancer treatment due to their clinical effective stimulation of therapeutic anti-cancer immunity. Recent studies demonstrated the importance of the Fc domain of these types of mAbs. Their optimal activity can be critically depended on their ability to engage defined FcgR pathways. I will discuss our recent characterization of these FcgR-dependent mechanisms, and how they can be exploited for introducing second generation Fc-optimized immunomodulatory mAbs.
9:30 Coffee Break
10:00 The Role of Metabolism in Immune Response in Tumors: Merging the Past and the Present of Tumor Microenvironment
Allison S. Betof, M.D., Ph.D., Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center
Tumors are not simply collections of cancer cells that arise in a vacuum; they are instead complex structures composed of blood vessels, immune cells, and other supporting structures that interact, consume oxygen and other nutrients, and produce waste. Tumor metabolism has long been viewed as a therapeutic target. I will discuss recent data on how metabolism influences immunobiology and our group’s approach to harness these interactions to improve therapeutic outcomes.
10:30 PI3Kgamma Is a Molecular Switch that Controls Immune Suppression
Megan M. Kaneda, Ph.D., Assistant Project Scientist, University of California, San Diego
Macrophages play critical but opposite roles in inflammation and cancer. We have found that the predominant isoform of PI3K in myeloid cells, PI3Kgamma, controls the switch between immune stimulation and immune suppression. Inhibition of macrophage PI3Kgamma activity promotes an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity and synergizes with checkpoint inhibitor therapy to promote tumor regression and extend survival in mouse models of cancer.
11:00 Avelumab (hIgG1 Anti-human PD-L1) Mediates the anti-Tumor Efficacy via Multiple Pathways in Preclinical Models
Yan Qu, Ph.D., Senior Principal Scientist, Pfizer
Analysis of PD-L1 expression on various immune subpopulations in human patient samples showed that PD-L1 is enriched on non-T cells. In tumor-bearing mice, the percentage of splenic NK cells was increased with WT avelumab treatment but not with the Fc isotype variant. Avelumab-induced tumor shrinkage, tumor-infiltrating CD8+ T cell increase, and tumor PD-L1+ immature myeloid cell decrease appear to require NK cells, as such changes were abolished upon NK depletion.
11:30 Epitope Identification and Clinical Immune Monitoring in Immune Oncology Programs
Emilee Knowlton, Ph.D., Immunology Sales Specialist, ProImmune
12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:30 Session Break
1:25 Chairperson’s Remarks
Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom
1:30 Functional Characterization of Macaque Fcr and IgG Subtypes
Margie Ackerman, Ph.D., Assistant Professor, Engineering, Dartmouth College
A number of antibody therapies rely on Fc receptor (FcR)-mediated effector functions for optimal activity, prompting the need to understand how native and IgG domains engineered to differentially bind to the human receptors translate in non-human primate (NHP) models. We report characterization of the affinity between an IgG Fc variant panel (including subclass, Fc mutants and glycosylation) and major human and rhesus FcR allotypic variants.
2:00 Utilizing Patient-Derived Organoids and High-Content Imaging for Screening and Characterization of Bispecific Antibodies
Mark Throsby, Ph.D., EVP & CSO, Merus N.V., The Netherlands
This presentation will provide a case study on how panels of patient-derived organoids grown ex-vivo in 3D culture combined with high-content imaging can be applied to bispecific antibody screening. Lead candidate bispecifics were selected targeting the wnt pathway with novel modes of action including immunomodulation.
2:30 Discovery and Development Strategies for New Small Molecule Immunotherapies
Nicola Wallis, Ph.D., Senior Director, Biology, Astex Therapeutics, Ltd.
Small molecules are of interest as immunotherapies as both single agent and combinations, offering the possibility of modulating different aspects of the immune system to biologics. We are exploring targeting a number of different immunomodulatory mechanisms with small molecules derived using fragment-based drug design and will describe examples in this presentation.
3:00 Refreshment Break
3:30 STING Adjuvants for Immune System Priming for Antibody Therapy
Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom
Successful tumor-targeting antibody approaches appear to rely predominantly on the effector function of Fcγ receptor (FcγR) expressing macrophages. Unfortunately, tumor-associated macrophages (TAM) are frequently poorly cytotoxic, contribute to immune suppression and have suboptimal FcγR expression making treatment less effective. Here we show that STING agonists are able to overcome immunosuppression in the tumour microenvironment effectively reversing the TAM inhibitory FcγR profile and provided strong adjuvant effects to antibody therapy.
4:00 Next-Generation Cancer Vaccines
Daniel L. Levey, Ph.D., Senior Director, Vaccine Research, Agenus
Agenus is advancing two fully synthetic cancer vaccine platforms. The first is based on identification of mutations encoded in the tumor genome while the second relates to a novel class of tumor specific neo-epitopes arising from inappropriate phosphorylation of various proteins in malignant cells. The platforms support the manufacture of both individualized and off-the-shelf cancer vaccines against a range of tumor antigens, increasing the likelihood of immune recognition of tumors.
4:30 Oral T Cell Vaccines Targeting Immune Organs of the Gut for Generating Systemic Antigen Specific T Cells
Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG
We use attenuated Salmonella typhi Ty21 as a vector to deliver a plasmid encoding antigens of interest via the oral route to Peyer’s patches. The bacteria have built in adjuvant properties and induce cross presentation to produce a systemic T cell response. Monotherapy with a candidate targeting VEGFR2 produced clinical responses in GBM, highlighting the unique properties of this T cell vaccine approach.
5:00 End of Day
TUESDAY, AUGUST 29
7:25 am Breakout Discussion Groups with Continental Breakfast
Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below.
New Understandings of the Mechanisms of Action for Immunomodulatory Antibodies
Moderator: Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom
- What are we learning about MOA from clinical trial data?
- Optimizing MOA in next generation immunomodulators
- The role of effector and receptor engagement
- MOA and bispecific antibody design
- Overcoming resistance mechanisms
Target Discovery for Next Generation Immunotherapies
Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG
- Tumor antigen identification: strengths and weaknesses of different methodologies
- Drugable IO targets- using macromolecules versus small molecule
- Novel targets in the tumor microenvironment
8:25 Chairperson’s Opening Remarks
Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut
8:30 Cancer Immunotherapy with Live-attenuated, Double Deleted Listeria Monocytogenes (LADD) Combination Strategies for the Treatment of Malignant Pleural Mesothelioma
Chan C. Whiting, Ph.D., Director, Immune Monitoring and Biomarker Development, Aduro Biotech
We are advancing CRS-207, a clinical LADD strain engineered to express mesothelin, in combinations with various modalities for the treatment of malignant pleural mesothelioma. Data from a Phase 1b study combining CRS-207 with standard chemotherapy demonstrating encouraging clinical and immune responses will be discussed. An overview of the Phase 2 study design and progress of the CRS-207/Pembrolizumab combination study will also be highlighted.
9:00 Tumor and Class-Specific Patterns of Immune-Related Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review
Aaron Hansen, M.D., Ph.D., Assistant Professor, Department of Medicine, University of Toronto; Medical Oncologist, Princess Margaret Cancer Center
Through a systematic review, we identified distinct immune related adverse event (irAE) profiles based on tumor type and immune checkpoint inhibitor class (CTLA-4 and PD-1). CTLA-4 inhibitors have a higher frequency of grade 3/4 irAEs. Furthermore, for patients treated with PD-1 inhibitors, those with melanoma had a higher frequency of gastrointestinal and skin irAEs, and lower rate of pneumonitis compared with patients with NSCLC and RCC. Different immune microenvironments may drive histology-specific irAE patterns.
9:30 Combination Therapy with PD-1 Blockade Enhances the Antitumor Potency of T Cells Redirected by Novel Bispecific Antibodies
Ken Chang, Ph.D., Vice President, Research and Development, Immunomedics
Novel bispecific antibodies that bind bivalently to tumor antigens and monovalently to CD3 can redirect T cells to kill Trop-2- or CEACAM5-expressing solid cancer cells grown in monolayer cultures at low picomolar concentrations. The antitumor efficacy was demonstrated also in a humanized mouse model and in 3D spheroids generated with cells from TNBC and colonic cancers. Combining anti-PD-1 increased cell death in 3D spheroids and prolonged survival of tumor-bearing animals.
10:00 Accelerated Production of Immunomodulatory Therapeutic Antibodies & Bispecific Molecules Using Scalable Cell Engineering
James Brady, Ph.D., Vice President, Technical Applications & Customer Support, MaxCyte
Antibodies and antibody-like molecules are a proven means of modulating effective anti-tumor immune responses. MaxCyte’s delivery platform facilitates rapid, fully scalable, high quality transient protein production in the cell line-of-choice, as well as streamlined stable pool and cell line generation enabling accelerated development of relevant immunomodulatory candidates. Case studies will illustrate the identification and development of antibodies, tribodies & bi-specific T cell engaging molecules (BiTEs) using the MaxCyte platform.
10:30 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
11:15 A Novel, Dual-Specific Antibody Conjugate Targeting CD134 and CD137 Costimulates T Cells and Elicits Antitumor Immunity
Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut
Combining agonists to different costimulatory receptors can be more effective in controlling tumors compared to individual agonists, but presents logistical challenges and increases the potential for adverse events. We developed a novel immunotherapeutic agent by fusing agonists to CD134 and CD137 into a single biologic, OrthomAb, that potentiates cytokine secretion from TCR-stimulated T cells more potently than non-conjugated CD134 + CD137 agonists in vitro, and reduces tumor growth in vivo.
11:45 Targeted Tissue Delivery Using Caveolae Technology Improves Drug Efficacy
Ruchi Gupta, Ph.D., Team Lead Scientist, MedImmune
Current biotherapeutics focus on the molecular targets expressed on cells/tumors. However, less than 10% of the IV administrated biologics can reach the diseased tissues. Tissue targeting using caveolae proteins can allow for specific delivery to organs of interest. This talk will focus on caveolae technology that shows specific delivery to lungs and kidneys and improves drug efficacy. This targeting holds potential for several diseases including fibrosis, COPD, Infections as well as tumors.
12:15 pm Close of Immunomodulatory Therapeutic Antibodies for Cancer