A Solid Foundation for Immunotherapy: The importance of T cell subsets in CAR-T cell therapy for B-cell acute lymphoblastic leukemia

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of childhood cancer worldwide. Chimeric antigen receptor T cell (CAR-T) immunotherapy is a promising new therapy for B-ALL, however achieving long term remission is still a challenge. One important aspect to the efficacy of CAR-T cell therapy is the quality of the patient derived T cells used to make CAR-T cells. By nature T cells are a highly variable cell type containing many different subsets and differentiation statuses. Consequently the T cells that are used to produce CAR-T cells can vary significantly from patient to patient. The presence of less differentiated memory T cell subsets, T memory stem cells and central memory T cells, in the final CAR-T product are associated with a more durable antitumor response than their further differentiated counterparts. Furthermore, while both CD4+ and CD8+ CAR-T cells are capable of antitumor activity separately, they have a synergistic effect when combined into a 1:1 ratio. Preliminary clinical studies using a defined 1:1 ratio of CD4+ and CD8+ CAR-T cells have produced promising results but still lack in long term efficacy. Both a T helper cell type 1 and type 2 CAR-T cell response is needed for effective B-ALL clearance and patients who relapse often lack a type 2 response. Lastly, regulatory T cells in the CAR-T product have been shown to be associated with a worse prognosis for B-ALL patients but also lower levels of cytokine release syndrome. A large variety of methods for promoting beneficial T cell subsets during CAR-T production for B-ALL are being explored, many of which have produced promising results. Optimization of T cell subsets in CAR-T cell therapy for B-ALL is a promising avenue for future research to help improve treatment of patients.