Table 1.
Challenges for chimeric antigen receptor (CAR) T cell therapy in solid tumors.
| Challenge(s) | Overcoming strategy(s) | Reference | |
|---|---|---|---|
| Tumor microenvironment | Soluble molecules | Use of gene edited CAR T cells that disrupt sensitivity to inhibitory pathways such as adenosine and prostaglandin E2 signaling, PD-1, IDO, and TIM-3 inhibitory molecules | (8–13) |
| Immunosuppressive immune cells | The concomitant application of CAR T cells with blockage and depletion of various immunosuppressive molecules and cells such as Tregs and myeloid-derived suppressor cells | (10, 14–16) | |
| Use of armored-CAR T cells | |||
| Physical and metabolic barriers | Generation of CAR T cells which degrade the extracellular matrix and target tumor-associated stromal cells to facilitate infiltration of T cells into solid tumor masses | (17, 18) | |
| Trafficking | Use of CAR T cells overexpressing chemokine receptors or combined application of CAR T cells with an oncolytic virus armed with the chemokines that match the chemokines receptors expressed by T cells | (19–22) | |
| Genetic addition of molecules which improve CAR T localization | |||
| Local delivery of CAR T cells | |||
| Target antigen heterogeneity | Use of CARs targeting multiple antigens | (18, 23, 24) | |
| Use of dual-specific T cells | |||
| Monitoring of patients for expression of tumor antigen | |||
| Intrinsic regulatory mechanisms of T cells | Use of PD-1 switch receptors to blunt inhibitory effect of PD-1 signaling | (25–34) | |
| Blocking inhibitory immune receptors to augment adoptive T cell transfer | |||
| Gene-editing of CAR T cells to disrupt expression of inhibitory receptors | |||
| Use of CAR T cells overexpressing antiapoptotic proteins | |||
| Use of CAR T cells downregulating apoptotic proteins | |||
| Use of dominant negative TGF-β receptor | |||
| Use of drug/radio resistant CAR T cells | |||
| Use of more persistent T cells | |||
| Use of gene edited T cells | |||