Based on successful clinical CAR T cell therapy for B-cell malignancies, Majzner and Mackall reviewed the factors impacting CAR T cell efficacy and safety and the future challenges. Major success factors include good T cell expansion and engraftment with long persistence. Barriers to success result from tumor-intrinsic factors that lead to impaired T cell function due to T cell exhaustion or suppression by the TME, and resistance due to antigen downregulation or loss. In solid tumors, where clinical success has lagged, identifying targets and minimizing toxicity in normal tissue is a critical goal. Multiple new generations of CARs are in clinical development.
Contributed by Katherine Turner
Chimeric antigen receptor (CAR) T cell therapy for B cell malignancies has surpassed expectations, driving an ever-expanding number of clinical trials and the first US Food and Drug Administration approvals of cell therapies for the treatment of cancer. This experience has illuminated some generalizable requirements for CAR T cell efficacy as well as the interplay between disease biology and clinical outcomes. Major CAR intrinsic variables affecting T cell behavior have been defined, and mechanisms of tumor resistance are increasingly understood. Here, we review the clinical experience with CAR T cells amassed to date, including but not limited to B cell malignancies, emphasizing factors associated with efficacy, resistance and major barriers to success. We also discuss how these insights are driving next-generation clinical trials, including those in solid tumors.