Abstract IA20: Updates on CAR T Cells

Abstract

Abstract The emergence of immune-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with the pillars of chemotherapy, radiation, and targeted small-molecule compounds. Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering provides the field with a broadly expanded set of tools for programming immune cells. In this presentation, I will discuss how these tools could be used to design the next generation of smart T-cell precision therapeutics. We have been exploring in preclinical models and clinical trials methods to synthetically enhance T-cell antitumor efficacy by transfer of genetically engineered T cells. Infusions of chimeric antigen receptor (CAR) T cells can result in remissions in patients with hematologic malignancies, but efficacy is often limited by the extent of expansion and persistence of engineered lymphocytes. In a patient with a delayed clinical response, we show that a complete and durable response to CAR T cell therapy resulted from a clonal expansion of a single CAR T cell. At the peak of the antitumor response, 94 percent of CD8+ CTL019 cells originated from a single clone in which proviral insertion disrupted the gene encoding the methylcytosine dioxygenase TET2. We conclude that loss of function of TET2 secondary to insertional mutagenesis promoted T-cell proliferation, and that the progeny of a single CAR T cell induced durable remission in refractory leukemia. In solid tumors, we have observed antitumor activity in patients with ovarian cancer, pancreatic ductal adenocarcinoma, pleural mesothelioma, and glioblastoma following infusion of CAR T cells expressing scFv specific for mesothelin or EGFRvIII. However, this approach has not yet resulted in complete tumor eradication. Using genome-edited T cells, it may be possible to enhance and prolong the activity of T cells that have disrupted immune and metabolic checkpoints. In preclinical studies, we show that TCR-specific T cells have enhanced antitumor activity following disruption of TCR alpha and beta genes and the PD1 gene using CRISPR/Cas9. This approach is just entering a clinical trial. These findings provide insights into the immunobiology of effector T cells and demonstrate the potential of multiplexed CRISPR/Cas9 genome editing to synthetically enhance the efficacy of immunotherapy.