Table 3.

Challenges facing current clinical use of CAR-modified T cell therapeutics and potential strategies to address each.

Challenge	Potential Strategies to Overcome Challenge
Poor expansion	Optimization of lymphodepleting chemotherapy prior to T cell infusion Optimization of costimulatory domain Further genetic modification of T cells, including expression of additional costimulatory ligands or cytokines (e.g. IL-12)
Suboptimal CAR T cell function	Co-administration of checkpoint blockade agents or ibrutinib Further genetic modification of T cells as above
Loss of expression of target antigen (e.g. CD19-negative relapse)	Targeting of multiple tumor-associated antigens at once
Cytokine release syndrome	Risk-adapted CAR T cell dosing Optimization of prediction models to permit earlier recognition/treatment in select patients Incorporation of “elimination genes” into the CAR construct
Neurologic toxicity	Risk-adapted CAR T cell dosing Improved understanding of pathogenesis Incorporation of “elimination genes” into the CAR construct
B cell aplasia (for CD19-targeted CAR T cells)	IVIG for hypogammaglobulinemia Antigen-specific inhibitory CAR to protect normal B cells73