Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

Abstract

CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments. CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments.

Keywords: T cells; cancer immunotherapy; chimeric antigen receptor; persistence; tumor microenvironment.

Figure 1

Novel modifications in cytokine recipe and their receptors to enhance CAR T cell persistence.

Figure 2

Novel molecular signaling targets to improve CAR T cell persistence.

Figure 3

Novel strategies to enhance the persistence of CAR T cells. The overall aim of these approaches is to improve intrinsic CAR T cell fitness and allow to elicit optimal CAR T cell persistence in the setting of many intrinsic and/or extrinsic barriers operative within a harsh tumor microenvironment.