Despite immense clinical benefits, many immunotherapies have been associated with a number of immune-related adverse events (irAEs) including cytokine storm/cytokine release syndrome, macrophage activation syndrome, or autoimmunity. This risk increases when combinations are introduced, yet these are some of the most promising therapies currently in development. irAEs can lead to severe setbacks and the question for many pharmaceutical and biotech companies becomes, “how can we advance our clinical trials and keep our patients safe?” Cambridge Healthtech Institute’s Second Annual Preventing Toxicity in Immunotherapy conference will examine effective preclinical models, biomarkers, and dosing considerations. The usefulness of preclinical models will also be debated with regards to humanized models vs. standard mouse models and cross reactivity. Finally, potential toxicity issues in combination therapies will be addressed. Overall, this event will enable researchers to continue moving forward rapidly, but safely.
Final Agenda
Recommended Short Courses*
SC3: Genomics in the Service of Cancer Immunotherapy - Detailed Agenda
SC11: Adoptive Therapy with CAR T Cells - Detailed Agenda
*Separate registration required
MONDAY, MAY 1
7:00 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
Wayne Marasco, Professor, Cancer Immunology and Virology, Dana-Farber Cancer Institute
8:40 Immune Intact Preclinical Models to Understand Efficacy and Toxicity of CAR T Cells
Charles Sentman, Ph.D., Director, Center for Synthetic Immunity, The Geisel School of Medicine, Dartmouth College
The mechanisms involved in the efficacy of CAR T cells can be investigated using syngeneic tumor models with intact immune systems. CAR receptors designed to target murine tumor ligands can be used to understand the key mechanisms of action against tumors and the nature of toxicity observed in immune intact and deficient mice.
9:10 Chimeric Antigen Presenting T Cells That Change the Tumor Microenvironment
Wayne Marasco, M.D., Ph.D., Professor, Cancer Immunology and Virology, Dana-Farber Cancer Institute
The clinical effect of CART cells has been modest for the treatment of solid tumors due to several factors including the difficulty in identifying unique tumor associated antigens, inefficient homing of CART cells to tumor locations, their low persistence after infusion and their functional impairment in the immunosuppressive microenvironment. We will present our latest in vitro and in vivo CART cell data on new technology to overcome these barriers.
9:40 A Higher-Affinity Variant of a GD2-Specific CAR That Significantly Enhances Potency in vivo and Allows for a Novel Model of On-Target Off-Tumor Toxicity
Sarah Richman, M.D., Ph.D., Instructor, Cancer Center, The Children’s Hospital of Philadelphia
On-target/off-tumor toxicity poses a major challenge in chimeric antigen receptor (CAR) T cell immunotherapy, particularly for solid tumors. The glycolipid tumor antigen GD2 is an attractive antigen with which to study on-target/off-tumor toxicity owing to its shared expression between rodents and humans and its presence on some vital normal tissues. By incorporating an affinity-enhancing mutation into a GD2-specific CAR, we have developed a model for studying on-target/off-tumor toxicity.
10:10 Coffee Break
10:45 Chairperson’s Remarks
Michael Postow, M.D., Medical Oncologist, Department of Medicine, Memorial Sloan Kettering Cancer Center
10:50 ImmTACTM Platform: Delivering Novel Bi-functional TCR-based Biologics for Targeted Immunotherapy
Stephen Hearty, Group Leader, Autoimmune Group, Immunocore Ltd.
Immunocore has developed a unique biologic platform through the creation of ImmTAC reagents. The ability of ImmTAC molecules to bind intracellular peptides presented in the context of HLA significantly expands the addressable antigenic landscape beyond that currently accessible to antibody based therapies. One thing that is essential to the development of ImmTAC molecules is a robust pre-clinical testing package. This presentation will expand upon how Immunocore is diversifying the ImmTAC platform to deliver novel immunotherapeutics.
11:20 Preventing Self-Reactivity of Engineered TCRs
Andrew Sewell, Ph.D., Distinguished Research Professor and Wellcome Trust Senior Investigator, Cardiff University School of Medicine
The αβ TCR repertoire is dwarfed by the vast array of potential foreign peptide-MHC complexes. Comprehensive immunity requires that each T-cell recognizes numerous peptides and thus be extremely cross-reactive. Natural central tolerance culls T-cells that have a high affinity for self peptide-MHC. TCR engineering bypasses this process and can result in dangerous self-reactivity. These toxicities can be predicted and engineered out without loss of specificity for the target antigen.
11:50 A Different Way of Thinking about Toxicities of Combination Immune Checkpoint Blockade
Michael Postow, M.D., Medical Oncologist, Department of Medicine, Memorial Sloan Kettering Cancer Center
Immune checkpoint inhibition results in immune-related adverse events. We will briefly review the spectrum of toxicities seen with these agents and how clinicians approach their treatment. We will then discuss toxicity issues arising when CTLA-4 and PD-1 immune checkpoint inhibitors have been combined and how clinicians and researchers can think differently about best strategies to deliver these medications safely.
12:20 pm Human in vitro Skin Explant Assays for Predicting Immunotoxicity of Drugs and Cellular Therapies
Shaheda Ahmed, Ph.D, Senior Scientific Officer, Alcyomics Limited, Haematological Sciences, Institute of Cellular Medicine, The Medical School, Newcastle University
There are currently no reliable human in vitro assays which test for immunogenicity, sensitivity, efficacy and allergic reactions of biologics that are equivalent to in vivo animal testing. Here we describe a novel test named SkimuneT, a non-artificial (non-3D) human in vitro test which can predict allergic responses to monoclonal antibodies. SkimuneT gives a predictive readout of skin damage which also correlates with inflammatory cytokine release and T cell proliferation responses. This test allows for the improved development of therapeutic drugs and compounds by the early detection of allergic reactions and immune responses and therefore aid in the safety profiling and a reduction in the cost of potentially adverse reactions being picked up before Phase I clinical trials.
12:35 A Novel T-Cell Engaging Bispecific Antibody Platform: Maximizing Tumor Cell Cytotoxicity While Minimizing Cytokine Release
Nathan Trinklein, Ph.D., Vice President, TeneoBio
We have created a large collection of fully human anti-CD3 antibodies with diverse T-cell agonist activities. These novel T-cell agonist antibodies were identified using our unique discovery platform that screens large numbers of antibodies by combining antibody repertoire deep sequencing, high-throughput gene assembly, and recombinant expression. The CD3 antibodies we identified show diverse in vitro T-cell activation profiles measured by CD69 upregulation, and cytokine production. Using our discovery platform, we have also generated human antibodies targeting tumor antigens that may be combined with our unique CD3 antibodies to create bispecific molecules that mediate T-cell killing of tumor cells. Using multiple myeloma tumor cells along with primary human PBMCs, our panel of aCD3 bispecific antibodies show a spectrum of in vitro tumor cell killing activity with varied levels of cytokine release.
12:50 Luncheon Presentation I: Identifying Critical Receptor Targets and Off-Target Profiling Using Plasma Membrane Protein Array Technology
Jim Freeth, Managing Director, Retrogenix Limited
Human cell microarray screening enables rapid discovery of the primary cell surface receptors and off-targets of antibodies, proteins, viruses and small molecules. Case studies from pharmaceutical partners will demonstrate how this unrivalled platform has been used for: 1) Uncovering novel targets from antibody phenotypic screening approaches; 2) Identifying receptors for protein ligands in normal and disease processes, such as immune checkpoint interactions; 3) Off-target profiling of biotherapeutics including CAR T cell lines.
1:20 Luncheon Presentation II (Sponsorship Opportunity Available)
1:50 Session Break
2:20 Problem-Solving Breakout Discussions
These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion. Pre-registration to sign up for one of the topics will occur a week or two prior to the Event via the App.
Multispecific Antibodies for Immuno-oncology – Considerations in Efficacy and Safety
Jijie Gu, Ph.D. Research Fellow, Immunology & Oncology Biologics at Global Biologics, AbbVie
- Why do T cell bispecifics only work for hematological tumors? What is the key hurdle for efficacy in solid Tumors?
- What are the key safety risks of redirected T cell killing of tumors?
- How to profile the mechanism of tumor/stroma escaping immune surveillance
- What are the pros and cons of targeting two co-stimulatory or co-inhibitory molecules using bispecifics versus combination?
- Can T cell multispecifics achieve similar efficacy of CAR-T therapy?
- How to decide choice of Fc engineering for multispecifics for immune-oncology
Predicting and Mediating CAR, TCR, and TIL Toxicities
Saad Kenderian, M.D., Assistant Professor of Medicine and Oncology, Hematology, Mayo Clinic College of Medicine
- Recognize expected toxicities after CART cell therapy
- Preclinical modeling of cytokine release syndrome after CART cell therapy
- Management of toxicities after CART cell therapy
- Strategies to develop novel approaches and prevent cytokine release syndrome after CART cell therapy
3:20 Refreshment Break in the Exhibit Hall with Poster Viewing
4:00 Chairperson’s Remarks
4:10 Bicycles and Bicycle Drug Conjugates: Next-Generation Therapeutics
Sir Gregory Winter, Ph.D., FRS, Master, Trinity College and Co-Founder and Director, Bicycle Therapeutics
Bicycles® are a novel therapeutic class of constrained bicyclic peptides that combine antibody-like affinity and selectivity with small molecule-like tissue penetration, tunable exposure and chemical synthesis. They have potential in many indications, including oncology, where Bicycles’ unique properties have been used to develop Bicycle Drug Conjugates™ (BDCs); a novel toxin delivery platform which greatly improves toxin loading into tumour tissues. This presentation will describe both the Bicycle® and BDC platforms.
4:55 Young Scientist Keynote: Programming Proteins by Deep Sequencing and Design
Tim Whitehead, Ph.D., Assistant Professor, Chemical Engineering and Materials Science, Michigan State University
Next-generation sequencing has presented protein scientists with the ability to observe entire populations of molecules before, during, and after a high-throughput screen or selection for function. My group leverages this unprecedented wealth of sequence-function information to design and engineer protein affinity, specificity, and function and to infer structural complexes of proteins. My talk will present an overview of the above and detail methodological improvements that enable the engineering work.
5:40 Welcome Reception in the Exhibit Hall with Poster Viewing
6:55 End of Day
TUESDAY, MAY 2
8:00 am Registration and Morning Coffee
8:25 Chairperson’s Remarks
Saad Kenderian, M.D., Assistant Professor of Medicine and Oncology, Hematology, Mayo Clinic College of Medicine
8:30 Toxicities after Chimeric Antigen Receptor T Cell Therapy: Management, Prevention and Preclinical Modeling
Saad Kenderian, M.D., Assistant Professor of Medicine and Oncology, Hematology, Mayo Clinic College of Medicine
Despite the impressive responses after chimeric antigen receptor T (CART) cells in hematological malignancies, their application is limited by the development of cytokine release syndrome (CRS). While steroids and the IL-6 receptor blocker tocilizumab can generally reverse the syndrome, there is a concern that early introduction of immunosuppression can impair CART cell activity and therefore are reserved for severe CRS. The lack of relevant preclinical models for CRS after CART cell therapy is a significant limitation for the development interventions to treat or prevent CRS. In this presentation, we will review relevant preclinical models of human CRS after CART cell therapy and efforts to develop and optimize preventative strategies.
9:00 Biomarker Correlates and Potential Mechanisms of CAR T Cell Toxicities
Adrian Bot, M.D., Ph.D., Vice President, Translational Medicine, Kite Pharma
Treatment with CD19-directed CAR T cells can lead to durable clinical responses in lymphoma patients, but they may be associated with reversible toxicities. Biomarker analysis implicated several immune programs in the cytokine release syndrome and neurotoxicities associated with this therapeutic modality. Elucidation of mechanisms differentially involved with toxicities but dispensable for clinical activity, may allow rationale management of such toxicities, and development of next generation T cell products.
9:30 Controlling Specificity and Activity of Adoptive Cellular Therapies
Peter Emtage, Ph.D., CSO, Cell Design Labs
Cell Design Labs’ THROTTLE Switch™ and synNotch™ technologies allow for the ability to control the intrinsic activity of CAR-Ts. THROTTLE-Switch™ achieves this using a small molecule definable mechanism while synNotch™ incorporates a logic gated decision paradigm. The application of these systems in the clinic will provide physicians with the ability to modulate safety issues like CRS and on/off target toxicities while maximizing efficacy.
10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:50 Switch Mediated Control of CAR-T Cell Therapy
Travis S. Young, Ph.D., Principal Investigator, Biology, California Institute for Biomedical Research
Given the promising results for CAR-T cells in early clinical trials, along with the need for a solution to adverse effects and long-term T cell aplasia associated with its use, we have established an antibody-based control “switch” which affords tunable CAR-T cell activity. The universal design allows the same CAR to be retargeted to multiple tumor antigens to combat antigen-loss relapse mutations and to expand into multiple indications.
11:20 Harnessing T Cells to Fight Cancer with Novel Multispecific Antibodies
Jijie Gu, Ph.D., Research Fellow in Foundational Immunology & Head of Oncology Biologics Discovery at Global Biologics, AbbVie Bioresearch Center
Modulating T cells to kill tumor cells requires the better understanding of T cell biology for both efficacy and safety. In this presentation, we will discuss the development of multispecific antibody technology and how this technology could be used to design molecules to fine tune T cell functions for tumor killing.
11:50 ProTIA – A Novel Format of Bispecific T Cell Engagers Designed for Activation by Tumor-Associated Proteases
Volker Schellenberger, Ph.D., President and CEO, Amunix
Amunix is developing bispecific T cell activators based on our proprietary ProTIA (Protease Triggered Immune Activator) platform. ProTIA therapeutics have been engineered for activation at the tumor site by tumor-associated proteases. ProTIA molecules release their highly selective payload in the tumor microenvironment, which maximizes anti-tumor effects while minimizing systemic toxicity (compared to other bispecific molecules such as BiTEs). ProTIA molecules are based on Amunix’ proprietary XTEN™ polymer technology which has been validated in hundreds of patients and through partnerships with partners such as Biogen, Lilly, Roche, Janssen, and Versartis.
12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing
2:00 Chairperson’s Remarks
David Teachey, M.D., Associate Professor, Pediatrics, Children’s Hospital of Philadelphia
2:05 Is This Really Just "Fatigue"? - Case Series of Immune Related Hypophysitis Secondary to Immune Checkpoint Inhibitors
Misako Nagasaka, M.D., Hematology and Oncology Fellow, Oncology, Karmanos Cancer Institute
While immunotherapy targeting the PD1/L1 pathway has shown promising activity in many tumor types, immune related (IR) adverse events from these agents present a serious concern. Autoimmune hypophysitis are rare but serious IR events known to occur with PD1/PDL-1 inhibitors. The most typical presentation of autoimmune hypophysitis is "fatigue", a very common everyday complaint in the oncology clinic. Although autoimmune hypophysitis itself is rare, it will likely become more prevalent as the usage of checkpoint inhibitors increase. Early recognition and treatment of autoimmune hypophysitis is imperative in providing quality care.
2:35 Cytokine Release Syndrome after CAR T Therapy for Acute Lymphoblastic Leukemia
David Teachey, M.D., Associate Professor, Pediatrics, Children’s Hospital of Philadelphia
Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory hematologic malignancies. Dramatic responses have been reported in patients with relapsed/refractory ALL. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. The clinical presentation, management, and biology of CRS, as well as, the ability to predict which patients may develop severe CRS will be discussed.
3:05 Extended Q&A With Session Speakers
3:35 Refreshment Break in the Exhibit Hall with Poster Viewing
4:25 Efficacy and Toxicity of Targeting Shared Tissue Differentiation Antigens versus Neoepitopes
Smita Chandran, Ph.D., Senior Research Scientist, Memorial Sloan Kettering Cancer Center
Immunological targeting of neoepitopes and shared tissue-differentiation antigens can mediate complete and durable tumor regression in patients with metastatic melanoma. The expression of nonmutated self-antigens on normal tissue- a pattern that is distinct from the tumor specific expression of mutated neoantigens- can lead to undesirable on-target, off-tumor toxicity. However, directing T cells toward neoantigens that would result in tumor elimination, and not tumor escape, is critical to the efficacy of targeting mutations. Understanding the balance between efficacy and toxicity will be critical to the widespread success of cellular immunotherapies against these two classes of antigens.
4:55 Cancer Immunotherapy and Immune Related Adverse Events Oncologists’ New Frontier
Ammar Sukari, M.D., Assistant Professor, Head and Neck Multi-Disciplinary Team Leader, Department of Oncology, School of Medicine , Wayne State University/Karmanos Cancer Institute
Many researchers believe that anti-cancer immunotherapy has the potential to eventually cure many types of cancer. Despite mounting data, there are still many un-answered questions that require more research and clinical trials to answer. This presentation will address immune related toxicities and side effects of checkpoint inhibitors and the best way to manage these side effects.
5:30 Registration for Dinner Short Courses
Recommended Dinner Short Course*
SC13: Phenotypic Screening Applications and Technologies - Detailed Agenda
*Separate registration required