Cerebral spinal fluid impairs peripheral blood T cell response to stimulation with bispecific T cell engagers against leukemia 4526

Abstract Description Leptomeningeal metastasis, called leptomeningeal disease (LMD), occurs in multiple different cancer types and rarely curable as treatment options are typically ineffective and come with significant morbidity. Novel therapies, specifically immunotherapy based approaches such as chimeric antigen T-cells (CAR-T) and bispecific T cell engagers (BiTEs), are urgently needed. Given that immune cell biology within the LMD microenvironment is unique, we hypothesized that cerebral spinal fluid (CSF) impacts the function and efficacy of immunotherapies in this niche. To understand the differences between T cell function in CSF compared to more conventional T cell conditions, we utilized a T cell stimulation assay combining peripheral blood T cells, a B-cell acute lymphoblastic leukemia (B-ALL) cell line called Nalm6, and an antiCD3-antiC19 BiTE in either human CSF or RPMI. Surface receptor expression for activation markers, exhaustion markers, and differentiation state was obtained along with intracellular cytokine production and cytotoxicity during the height of the T cell activation. We found that the T cells activated in CSF were less proliferative, exhibited higher apoptosis, had altered stimulation and exhaustion phenotypes, and cleared the leukemia less effectively with the BiTE than in RPMI. These results demonstrate a need to define mechanisms which will enhance T cell function and survival in CSF to optimize anti-tumor activity by immunotherapy against LMD are urgently needed. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)