Overcoming Intrinsic Resistance of Cancer Cells to CAR T-Cell Killing

Abstract

In the past few years, chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for cancers that failed standard treatments. Such therapies have already been approved in several blood cancers, such as B-cell leukemia and lymphoma. Despite this progress, a significant proportion of patients experience primary or secondary resistance to CAR T-cell therapy. Here, we review the mechanisms by which CAR T cells eliminate their target and how cancer cells may be insensitive to such killing (here referred to as intrinsic resistance). Recent studies suggest that the activation of apoptosis through death receptor signaling is responsible for a major part of CAR T-cell cytotoxicity in vivo Indeed, cancer cells harboring aberrant apoptotic machinery may be insensitive to CAR T-cell killing. This intrinsic resistance of cancer cells to CAR T-cell killing could be responsible for a significant portion of treatment failure. Finally, we discuss strategies that may be envisioned to overcome such resistance to enhance CAR T-cell efficacy.

Figure 1.

Mechanisms of resistance to CAR T-cell therapy.

Figure 2.

CAR-dependent and CAR-independent killing mechanisms of CAR T cells. Three pathways may be used by CAR T cells to kill their target. A–C, The perforin/granzyme pathway (granzyme/perforin; A), the death receptor pathway (FasL/Fas, TRAIL/TRAIL-R1/2, and TNFα/TNFR1; B), and the cytokine pathway (IFNγ; C). The perforin/granzyme pathway is dependent on target antigen recognition by CAR, whereas the death receptor and the cytokine pathways could mediate cytotoxicity independently of this specific recognition (dashed arrow). Indeed, CAR T cells may be activated by antigen-positive tumor cells and then induce bystander killing of antigen-negative tumor cells through the death receptor and the cytokine pathways.

Figure 3.

Killing mechanisms of CAR T cells and therapeutic strategies to overcome intrinsic resistance and/or enhance sensitivity to CAR T-cell killing. Three pathways may be used by CAR T cells to kill their target: (i) the perforin/granzyme pathway (granzyme/perforin); (ii) the death receptor pathway (FasL/Fas, TRAIL/TRAIL-R1/2, and TNFα/TNFR1); and (iii) the cytokine pathway (IFNγ). The perforin/granzyme pathway target cytochrome C releases from the mitochondrial intermembrane space through activation of Bax and Bak by tBid. Once released, cytochrome C organizes the apoptosome platform and targets the terminal effector pathway of apoptosis. The death receptor and cytokine pathways target tumor cell apoptosis independently from the mitochondria. Using therapeutic agents affecting different steps of the apoptosis cascade, tumor cell sensitivity to apoptosis can be enhanced, leading to CAR T-cell–mediated killing improvement. Proapoptotic molecules (red), antiapoptotic molecules (green), therapeutic agents to modulate apoptosis sensitivity (blue).