Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma

Abstract

Although chimeric antigen receptor (CAR) T cell therapy (CAR-T) has altered the treatment landscape for relapsed/refractory B cell malignancies and multiple myeloma, only a minority of patients attain long-term disease remission. The underlying reasons for CAR-T resistance are multifaceted and can be broadly divided into host-related, tumor-intrinsic, microenvironmental and macroenvironmental, and CAR-T-related factors. Emerging host-related determinants of response to CAR-T relate to gut microbiome composition, intact hematopoietic function, body composition, and physical reserve. Emerging tumor-intrinsic resistance mechanisms include complex genomic alterations and mutations to immunomodulatory genes. Furthermore, the extent of systemic inflammation prior to CAR-T is a potent biomarker of response and reflects a proinflammatory tumor micromilieu characterized by infiltration of myeloid-derived suppressor cells and regulatory T cell populations. The tumor and its surrounding micromilieu also can shape the response of the host to CAR-T infusion and the subsequent expansion and persistence of CAR T cells, a prerequisite for efficient eradication of tumor cells. Here, focusing on both large B cell lymphoma and multiple myeloma, we review resistance mechanisms, explore therapeutic avenues to overcome resistance to CAR-T, and discuss the management of patients who relapse after CAR-T.

Keywords: CAR-T; Chimeric Antigen Receptor T-cell Therapy; Lymphoma; Multiple myeloma; Relapse; Resistance.

Fig. 1. Mechanism of resistance

Overview of the multi-facetted reasons for resistance to CAR T-cell therapies ranging from the underlying tumor and surrounding tumor microenvironment (TME) to CAR product attributes and subsequent CAR T-cell expansion kinetics, to host factors such as gut microbiome composition, physical fitness and body composition as well as bone marrow reserve.

Fig. 2. Strategies to prevent resistance to CAR-T cell therapy

A Avoid deterioration of the host. B Avoid tumor-intrinsic resistance and target loss. C Avoid high tumor burden. D Personalize CAR T-cell product selection, matching CAR T-cell product characteristics to tumor target abundance and other tumor- and patient-specific features. E Arm the physician “cell-therapist” with improved monitoring and intervention capabilities.