Challenges and solutions to superior chimeric antigen receptor‐T design and deployment for B‐cell lymphomas

Abstract

SummaryChimeric antigen receptor‐T (CAR‐T) therapies represent a major breakthrough in cancer medicine, given the ex vivo‐based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B‐cell lymphomas. Although more than a decade has passed since the initial introduction of CAR‐T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR‐T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time‐honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR‐T products in early lines of therapy. Such barriers include antigen escape, “cold” tumour microenvironments, host inflammation and CAR‐T cell exhaustion. We highlight solutions including point‐of‐care CAR‐T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR‐T deployment for B‐cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first‐in‐class anti‐CD3/CD20 bispecific antibodies—mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024.