Table 3.

Problems to be solved in anti‐CD19 CAR T‐cell therapy

Problems	Possible way to overcome
1) Disease control during the CAR‐T cell production	Bridging therapy with new agents; e.g. ibrutinib, lenalidomide Improved production method to shorten the period of CAR‐T cell production35 “Off‐the‐shelf” CAR‐T40
2) Production failure	Improved production method35 “Off‐the‐shelf” CAR‐T40
3) Healthy B‐cell depletion; on‐target off‐tumor effect	Anti‐FcμR CAR‐T (in patients with CLL)41
4) Poor expansion and early elimination of CAR‐T cells	Further improvement of lymphodepletion‐chemotherapy Fully‐human antigen recognition domain of CAR42
5) Insufficient activity of CAR‐T cells	Further genomic modification of CAR, such as armored CAR‐T cell13, 14 Combination use of immune checkpoint inhibitors45
6) CD19 negative conversion	Targeting multiple agents at once; e.g. CD2049, CD22, CD123 (in patients with B‐ALL)48
7) Optimal management of CRS	Early intervention based on cytokine parameters34, 39 Risk adapted cell dose modification Incorporation of “suicide gene” or “elimination gene” into CAR‐T cell54, 55 Combination use of ibrutinib50
8) Optimal management of neurologic toxicity	Further research to understand its pathophysiology

CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CRS, cytokine release syndrome.