Mechanisms of Resistance to CAR T-Cells and How to Overcome Them

Abstract

In the last few decades, chimeric antigen receptor (CAR) T-cell therapy has led to a paradigm shift in the treatment of hematological malignancies, including various subtypes of B-cell non-Hodgkin's lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, most patients experience refractoriness to CAR T-cells or relapse after treatment. Many efforts are underway to understand the mechanisms behind CAR T-cell failure, which are mainly related to CAR T-cell dysfunction, tumor-intrinsic resistance, an immunosuppressive tumor microenvironment, manufacturing issues, or patient-related factors. Several strategies are being developed to overcome these resistance mechanisms, including the engineering of more functional allogeneic CAR T-cell products, the targeting of alternative tumor antigens, and combination therapies with other drugs such as checkpoint inhibitors or small molecules to enhance CAR T-cell efficacy. In this review, we will provide an updated overview of the mechanisms of CAR T-cell failure and the therapeutic advances currently under development to address them.

Keywords: B-cell acute lymphoblastic leukemia; B-cell lymphoma; CAR NK; CAR T-cell resistance; CAR T-cells; allogeneic CAR T-cells; dual targeting; multiple myeloma.

Figure 1

Key mechanisms of resistance to CAR T-cell therapy. Resistance to CAR T-cell therapy arises from multiple, often overlapping, mechanisms. These include CAR T-cell dysfunction, characterized by progressive loss of proliferative capacity, cytotoxic function, and persistence due to senescence or exhaustion (top left); intrinsic tumor resistance, involving antigen escape (e.g., loss or downregulation of CD19), trogocytosis-mediated fratricidal killing, and tumor-intrinsic genetic alterations enhancing immune evasion (top right); and an immunosuppressive tumor microenvironment, which impairs CAR T-cell trafficking, expansion, and activity through hypoxia, nutrient deprivation, suppressive cytokines (e.g., IL-10, TGF-β), regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) (bottom). Together, these factors contribute to limited tumor infiltration, reduced cytotoxic capacity, and diminished therapeutic efficacy.

Figure 2

Structure and signaling pathways of second-generation CAR T-cells. Upon antigen recognition, CAR engagement triggers CD3z phosphorylation and recruitment of ZAP-70, leading to downstream LAT signaling and activation of NFAT, NF-κB, and AP-1 transcription factors. Distinct costimulatory domains promote divergent signaling and metabolic programs. CD28 costimulation recruits Lck and PI3K, driving PDK1/AKT/mTOR activation, robust clonal expansion, T_EM differentiation, and glycolytic reprogramming. In contrast, 4-1BB costimulation recruits TRAF1/2, leading to TRAF3 degradation, NIK stabilization, and activation of the non-canonical NF-κB pathway (p52/RelB), which supports T_CM differentiation, enhanced fatty acid oxidation, and long-term persistence. Abbreviations: H/T (hinge/transmembrane), scFv (single-chain variable fragment), T_CM (central memory T-cells), T_EM (effector memory T-cells).