Functional drivers of resistance to anti-CD19 CAR-T cell therapy in diffuse large B cell lymphoma

Abstract

Chimeric antigen receptor T-cell therapy targeting CD19 (CAR-19) promotes impressive durable remissions for relapsed or refractory (rel/ref) large B-cell lymphoma (LBCL) patients with historically poor prognoses. Despite this, over half of patients still fail to respond or eventually progress. Studies to reveal mechanisms of resistance have examined host clinical parameters, CAR-19 product composition, and tumor microenvironment (TME) alterations, while a relative paucity of studies has analyzed contributions by genomic alterations in tumor cells. Factors associated with outcome include increased tumor volume, specific characteristics of infused CAR-T products, infiltration by myeloid cells in tumor microenvironments, and markers of complexity in LBCL genomes. Functional laboratory studies of resistance are largely absent in the current literature, illustrating a need for experiments in genetically accurate immunocompetent systems to confirm candidate alterations' roles in resistance and inform future improvements. In this review, we highlight key studies that have elucidated biomarkers of resistance in hosts, CAR products, TMEs, and comparatively understudied tumor-intrinsic mediators encoded by tumor genomes. We conclude with an experimental framework suitable for CAR-19 resistance biomarker identification and laboratory functional validation.

Keywords: CAR-T; lymphoma; mechanisms; resistance.

Figure 1.

CAR-19 resistance is driven by infusion product, TME, and tumor-intrinsic mechanisms. Whole-genome sequencing (WGS) revealed complex LBCL genomes in association with poor CAR-19 outcomes, and a variety of studies implicate deregulation of specific genes, but functional laboratory studies are lacking. The relationship between tumor genomes and tumor microenvironments (TMEs) also remains undefined.