Review of therapeutic approaches for B-cell malignancies with immune checkpoint blockade and chimeric antigen receptor t-cell therapies: Development, benefits, and limitations.

Abstract

e14069 Background: Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapies have emerged as approaches to treat B-cell malignancies. Methods: PubMed/NCBI/MEDLINE databases were accessed with keywords "immune checkpoint inhibitors and B-cell malignancies" "CAR T-cell and B-cell malignancies", and various permutations including "clinical data" "toxicities", "reviews", "quality of life", and "adverse effects". Results: The first-in-class approved immune checkpoint inhibitor was ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen. Thereafter, nivolumab was also approved for use in the treatment of Hodgkin's lymphoma in 2016. In phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma received the anti-PD-1 monoclonal antibody nivolumab. Eighty-one patients were treated and drug-related adverse events occurred in 51 (63%) patients. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma and other hematologic malignancies. Clinical trial results describing CD19-targeted CAR T-cell therapy of patients with relapsed B-ALL were published in 2015. In this study, all five patients treated with CAR T cells achieved minimal residual disease negative complete remission. Updated results describing the treatment of 16 patients with relapsed or refractory B-ALL treated with CAR T cells were published: the overall CR rate in this trial was 88% and 12 of 14 patients were classified as minimal residual disease negative. 44% of these patients went on to standard-of- care allogeneic hematopoietic stem cell transplant. Initial studies also reported potent anti-leukemic effects of CD19 CAR T cell therapy in three patients with refractory chronic lymphocytic leukemia where two of the three patients achieved MRD-CR. Infused CAR T cells proliferated up to 10,000-fold and persisted in recipients for at least 6 months and shown to retain antitumor activity after six months. Costs for CAR T-cell therapies remain exorbitant, reaching over $1M (USD) per patient. Conclusions: Clinical data reveal safety and efficacy, and also associated toxicities for both approaches.