This session will discuss 1) genetically engineered myeloid cells (GEMys) that may target and modulate the tumor microenvironment, suggesting how the myeloid compartment contributes to the functions of CAR-T cells; 2) engineering-based approaches such as the expression of memory-associated genes to counteract exhaustion, and enhance persistence and antitumor activity of current CAR T-cell based approaches and 3) the development and clinical evaluation of TCR based therapeutics. Covering the spectrum from pre-clinical to clinical, this unique session will provide critical insights into core immunotherapeutic principles and delineate the iterative changes that have been made over the years to make these once theoretical concepts a reality. This proposal is supported by the Subcommittee on Emerging Gene & Cell Therapies. 

Dr. James Cronk will present genetically engineered myeloid cells (GEMys), an immunotherapy platform recently developed in the Kaplan lab to target and modulate the tumor microenvironment. He will discuss the core immunosuppressive gene signature found in the premetastatic niche, and the ability of GEMys producing interleukin 12 (IL-12) to reverse the immunosuppressive signature and induce an effective anti-tumor immune response via activation of T cell-mediated immunity. Dr. Cronk will show clinical trial evidence that the myeloid compartment plays an important role in modulating CAR-T cell therapy for solid tumors, and finally will discuss plans for an upcoming clinical trial which will evaluate IL-12 GEMy therapy in solid tumor patients.

Dr. Evan Weber will discuss CAR T cell therapy has revolutionized cancer treatment for patients with hematologic malignancies. However, poor CAR T persistence and exhaustion limit clinical responses. The expression of memory-associated genes, such as TCF7, is linked to response and long-term persistence in patients, thereby implicating T cell memory programs in therapeutic efficacy. We performed mechanistic studies to identify the master transcription factor(s) responsible for promoting memory in human CAR T cells and hypothesized that enforcing their activity would enhance CAR T potency. Indeed, overexpression of memory-associated transcription factors promotes a memory-like gene expression program, counteracts exhaustion, and enhances persistence and antitumor activity in multiple xenograft models. In summary, my talk will address core mechanisms that mediate poor CAR T persistence and exhaustion in preclinical models and patients and put forth novel and broadly applicable engineering-based approaches to overcome them.  

Dr. Marie Bleakley will discuss the development and clinical evaluation of TCR based therapeutics (TCR-T) focusing on hematologic malignancies. She will provide an overview of the field including concepts, clinical trials, challenges, and new advances. Examples will be provided from a clinical trial of TCR-T targeting the leukemia-associated minor histocompatibility antigen, HA-1.