Chimeric antigen receptor T cells for mature B-cell lymphoma and Burkitt lymphoma

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has changed the landscape of immunotherapy for B-cell malignancies, including mature B-cell lymphomas. Although two CD19 CAR T-cell products have been commercially approved to treat relapsed/refractory B-cell lymphomas, outcomes in these patients remain inferior to those of patients with B-cell leukemia, regardless of therapy. Recent clinical studies and preclinical reports suggest that certain characteristics, such as the suppressive lymphoma tumor microenvironment and inferior endogenous T-cell fitness, may contribute to discrepant responses in these patients. In addition, these studies revealed that limited CAR T-cell persistence and tumor antigen escape, which also impact B-cell acute lymphoblastic leukemia, may play a more prominent role in lymphoma. Multiple promising strategies to overcome these barriers have advanced to clinical trials. In this review, we assess CAR T-cell therapies for pediatric relapsed/refractory mature B-cell lymphomas, potential obstacles diminishing antitumor activity and limiting CAR T-cell persistence, and current strategies to overcome these obstacles.

Graphical abstract

Figure 1.

Schematic diagram of the lymphoma tumor microenvironment and treatment modalities currently being evaluated to target aspects of the tumor microenvironment. D, dendritic cell; IDO, indoleamine 2,3-dioxygenase; M2 TAM, M2 tumor-associated macrophage; T4, intratumoral CD4⁺ cell; T8, intratumoral CD8⁺ cell; Treg, regulatory T cell.

Figure 2.

Preclinical and early clinical strategies to optimize CAR T-cell therapy in B-NHL. (A) Modification of CAR T-cell design. (B) Identification of novel tumor antigen targets. ROR1, receptor tyrosine kinase-like orphan receptor 1; scFv, single-chain variable fragment.