Born to survive: how cancer cells resist CAR T cell therapy

Abstract

Although chimeric antigen receptor T cells demonstrated remarkable efficacy in patients with chemo-resistant hematologic malignancies, a significant portion still resist or relapse. This immune evasion may be due to CAR T cells dysfunction, a hostile tumor microenvironment, or resistant cancer cells. Here, we review the intrinsic resistance mechanisms of cancer cells to CAR T cell therapy and potential strategies to circumvent them.

Keywords: Immunotherapy; Leukemia; Lymphoma; Myeloma; Therapy.

Fig. 1

Mechanisms responsible for loss of target antigen, conferring resistance to CAR T cell therapy. A Due to tumor heterogeneity before any treatment, pre-existing antigen-negative tumor cells may be responsible for resistance to CAR T cell therapy. B Point mutations or altered alternative splicing may lead to a truncated target antigen that can no longer be recognized by CAR T cells. C Defect in target antigen maturation and trafficking due to lack of appropriate chaperon proteins may be responsible for target antigen membrane expression loss. D Exceptionally, a tumor cell may be transfected with the CAR vector leading to an epitope masking by the CAR itself and hiding the target antigen from the CAR T cells. E Lineage switch may be responsible for a complete phenotypic markers remodeling including loss of the target antigen

Fig. 2

Resistance mechanisms to CAR T cell therapy independent of target antigen loss. A Expression of inhibitory ligands (such as PD-L1) by tumor cells inhibit CAR T cell cytotoxicity despite target antigen recognition by CAR. B Lack of CD58 expression by tumor cells prevent CD2 to deliver a costimulatory to CAR T cell resulting in an impaired cytotoxicity despite target antigen recognition by CAR. C Impaired apoptotic machinery in tumor cells confer intrinsic tumor cell resistance to CAR T cell mediated immune killing despite target antigen recognition by CAR