Cambridge Healthtech Institute’s Inaugural
Target Discovery for T Cell Therapy
Next Step to Advance Immunotherapies
August 14, 2014
T cell target discovery remains one of the biggest challenges facing the immunotherapy field. With treatments becoming ready for prime-time, researchers will need to increase their discovery efforts to meet patient need and continue advancing the field. Cambridge Healthtech Institute's Inaugural Target Discovery for T Cell Therapy gathers leaders from academia and industry actively engaged in discovery and translation of novel targets for T cell immunotherapy. Experts will share strategies for chimeric antigen receptors (CARs), T cell receptors (TCRs), tumor infiltrating lymphocytes (TILs), and novel methods for novel targets. Clinical data will be showcased as well as in depth examinations of where the field is headed.
THURSDAY, AUGUST 14
8:00 am Symposium Registration & Morning Coffee
8:25 Chairperson’s Opening Remarks
Adrian Bot, M.D., Ph.D., Vice President, Translational Medicine, Kite Pharma, Inc.
8:30 Keynote Presentation
CAR T Cells from the Mouse Cage to the Patients’ Health
Zelig Eshhar, Ph.D., Professor, Immunology, The Weizmann Institute of Science
This presentation will be a brief chronicle description of the pioneering of the CAR strategy and its emergence and evolution for adoptive cell treatment of cancer. It will focus on experimental models for cancer in experimental settings and summarize the lessons learned from such models. The potential and challenges for cancer therapy in patients will also be discussed. Finally, the pioneering of the CAR strategy and its emergence and evolution for adoptive cell treatment of cancer will be outlined.
9:00 CAR T Cell Therapy: Target Antigen Discovery and Clinical Translation
Richard Morgan, Ph.D., Vice President, Immunotherapy, Bluebird Bio
This talk will emphasize the importance of tumor antigen discovery in the selection of targets in CAR T cell therapy. As examples, I will compare and contrast Her2/neu and EGFRvIII as solid tumor targets. I will also discuss the clinical translation of these two CAR-based therapies.
9:30 Clinical Responses in Patients Infused with T Lymphocytes Redirected to Target Κ-Light Immunoglobulin Chain
Carlos A. Ramos, M.D., Assistant Professor, Medicine, Section of
Hematology-Oncology, Baylor College of Medicine
T cells expressing chimeric antigen receptors (CARs) targeting B-cell¬ malignancies show remarkable clinical efficacy but their long term persistence causes depletion of normal B cells and hypogammaglobulinemia because the antigens targeted do not discriminate tumor from normal B cells. Since B-cell malignancies express either a κ or a λ-light immunoglobulin we generated a CAR (κ.CAR) specific for κ-light chain to selectively target κ+ lymphoma/leukemia cells, while sparing the normal B cells expressing the non-targeted λ-light chain. We present results of a phase I clinical of T cells express
10:00 Coffee Break
10:30 Overview of the Protein Expression of CT Antigens
Achim A. Jungbluth, M.D., Ph.D., Director, Immunohistochemistry, Pathology, Memorial Sloan-Kettering Cancer Center
Cancer Testis (CT) antigens were identified by their ability to elicit cellular and/or humoral autologous immuneresponses in tumor patients. They are named after their typical pattern of expression since they are present in various types of malignant tumors while their expression in normal adult tissues is mainly restricted to testicular germ cells. Due to this tumor-associated expression pattern, they are considered ideal targets for vaccine-based immunotherapy of cancer. In spite of their identification almost 15 years ago and numerous studies, there is debate about the proper serological typing reagents to CT antigens a well as their expression on a protein level. This presentation will address issues of immunohistochemical typing for CT antigens and give an overview of their presence on a protein level.
11:00 Target Discovery for TCR-Mediated Immunotherapy of Cancer with ImmTACs
Emma Hickman, Ph.D., Head, Target Validation, Immunocore
ImmTACs are bi-specific, pico-Molar affinity T cell Receptors fused to an anti-CD3 specific scFv that re-directs a potent T cell response towards its target. The most advanced ImmTAC reagent to-date, IMCgp100, is well tolerated in melanoma patients and induces T cell mobilisation and tumour shrinkage in clinical trials. Here we discuss our approach to target identification and target profiling for the ImmTAC platform.
11:30 Fine-Tuning TCR-Antigen Specificity and Predicting Potential Off-Target Reactivity
Joanna E. Brewer, Ph.D., Group Leader, Cellular Biology, Adaptimmune Ltd.
Adoptive T cell therapy (ACT) with gene-modified T cells isemerging as a highly promising strategy forthe treatment of many types of cancer. Mutating T cell receptors, to improve their affinity for tumour specific epitopes,provides the needed potency for efficacy but may present safety concerns for off-target recognition as TCRs effectively bypass thymic selection. A combination of peptide bioinformatics and primary cell screening offers a robust delineation of any possible peptide epitopes that can be recognised by an individual TCR.
12:00 pm Enjoy Lunch on Your Own
1:30 Developing Potent Cancer Therapies Targeting Cancer Germline and Mutated Antigens
Paul F. Robbins, Ph.D., Head, DNA Sequencing and FACS Cores, Surgery Branch; Staff Scientist, Center for Cancer Research, National Cancer Institute
Current cancer gene therapy trials have focused on transducing autologous T cells with T cell receptors (TCRs) that recognize tumor antigens with limited or no normal tissues expression, as severe toxicities were observed in clinical trials targeting differentiation antigens. In a recent trial utilizing a TCR directed against the cancer germline antigen NY-ESO-1, whose expression is limited to the normal testis, objective clinical response rates of 58 and 56% were observed in patients with melanoma and synovial cell sarcoma, respectively, but no normal tissue toxicities attributed to the transferred T cells were observed. Additional strategies are also being developed to target mutated epitopes that are generally limited in their expression to a single patient but that may represent particularly potent targets for therapy.
2:00 In vivo Discovery of Targets for Cancer Immunotherapy
Kai W. Wucherpfennig, M.D., Ph.D., Cancer Immunology & AIDS, Dana-Farber Cancer Institute; Professor of Neurology at Harvard Medical School
A novel pooled shRNA screen has been developed to discover genes that represent key negative regulators of cytotoxic T cell function in tumors. shRNAs that target such negative regulators greatly enhance T cell accumulation in tumors and improve T cell function. This approach enables systematic target discovery in relevant tissue microenvironments.
2:30 Bridging T Cells to Tumors: Clinical Progress with BiTE Antibodies
Stanley R. Frankel, M.D., Medical Sciences Executive Medical Director, Oncology Early Development, Therapeutic Area Head, Amgen
3:00 Refreshment Break
3:30 Immune Profiling during Pre-Clinical Development and in Phase I/II Clinical Trials
Yoav Peretz, Ph.D., Scientific Director, Immunology, ImmuneCarta, Caprion
Immune monitoring of patients enrolled in clinical trials has become crucial to help guide the development of immunotherapies and reveal potential relationships between the clinical and immunological response. The lack of protective signatures is partly explained by the realization that monoparametric evaluations fail to capture the phenotypic and functional heterogeneity of the immune response.Therefore, multiparametric flow cytometry has become the tool of choice given its ability to simultaneously analyze the relative distribution of cellular phenotypes and functions in complex mixtures of cells such as in peripheral blood and tissues. In the case-reports presented, we will describe the tools used to comprehensively monitor cellular responses and evaluate the immunostimulatory and suppressive compartments. Use of these analytical tools to evaluate changes in the phenotype and function of cellular subsets during disease and after treatment enables the identification of correlates and predictive biomarkers of immune protection.
3:45 Emerging Biomarker Approaches to Predict Response in Melanoma T Cell Therapy
Laszlo Radvanyi, Ph.D., Chief Scientific Officer, Lion Biotechnologies
The high clinical response rates (up to 50%) in melanoma patients receiving autologous tumor-infiltrating lymphocyte (TIL) therapy offers us an unprecedented opportunity to identify both on-treatment and predictive immunotherapy biomarkers. This talk will present our work on a comprehensive systems biology platform identifying biomarkers of response and resistance in a diverse array of specimen types from patients receiving TIL therapy. A number of TIL phenotypic markers and genomic markers in tumors predictive of response and improved survival after therapy have been identified; these markers also beginning to shed light on the mechanisms underlying therapy resistance.
4:15 Chairperson’s Closing Remarks
Adrian Bot, M.D., Ph.D., Vice President, Translational Medicine, Kite Pharma, Inc.
4:30 Close of Symposium