Dr Freeman on Factors Influencing Response to CAR T-Cell Therapy in Hematology

Ciara Freeman, MD, PhD, Medical Oncology, Blood and Marrow Transplant and Cellular Immunotherapy Program, Moffitt Cancer Center, discusses findings from a longitudinal single-cell analysis that was conducted to pinpoint factors linked to either a positive response or therapeutic failure with FDA-approved, BCMA-directed CAR T-cell therapy in patients with hematologic malignancies.

Examining tumor cells, investigators observed a correlation between patients categorized as having durable or non-durable responses to CAR T-cell therapy and the presence or absence of extramedullary disease (EMD), Freeman begins. Notably, patients with less durable responses or primary refractory disease tended to exhibit EMD or high tumor burden, she states. Additionally, this patient population had a lower rate of expression of key immunotherapy targets, such as BCMA, a critical target for BCMA-directed CAR T-cell therapy, Freeman notes. Reduced expression of these tumor antigens predisposes patients to early treatment failure, she adds.

Other antigens essential to CAR T-cell therapy response were also downregulated, particularly in patients with EMD, Freeman expands. Analyzing the tumor microenvironment and cell composition surrounding plasma cells, the investigators found that patients with durable responses displayed a favorable T-cell phenotype, she states. Conversely, patients with non-durable responses exhibited an exhausted T-cell phenotype, showing reduced T-cell fitness and engagement, especially when comparing pretreatment and post-treatment tumor samples, Freeman elucidates.

These findings offer valuable insights and a platform for further investigation into optimizing therapies for patients with hematologic malignancies, she continues. They also prompt exploration into upfront identification of patients most likely to respond to CAR T-cell therapy and potential strategies to enhance CAR T-cell efficacy, such as modifying CAR T-cell manufacturing processes or utilizing different CAR constructs to boost T-cell vitality, Freeman says. Screening patients for tumor expression of specific targets may also aid in predicting patients’ responsiveness to current CAR T-cell therapies, she adds. The collaborative efforts at Moffitt Cancer Institution have contributed significantly to this informative work, and these results were shared at the at the 2023 ASH Annual Meeting, Freeman concludes.