In the past 20 years, the development of chimeric antigen receptor (CAR) T-cell therapy has made a significant improvement in treatment of hematological cancers. Compared to first generation CAR therapies, next-generation CAR structures have incorporated costimulation domains, which increase the persistence of T-cells and enhance antitumor activity.
Currently in the United States, 6 CAR-T therapies have been approved by the Food and Drug Administration (FDA) and several clinical trials are still ongoing. Although currently approved therapies have resulted in excellent clinical outcomes, the potential for side effects must also be considered, which can include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
When evaluating the potential benefits of CAR-T therapy, clinicians must consider the risk-benefit balance of the treatment. In a review published in Current Hematologic Malignancy Reports, Karan L. Chohan, MD, of the department of medicine at the Mayo Clinic in Rochester, Minnesota, summarized current literature surrounding the efficacy and safety of current CAR-T therapies. Dr Chohan and her colleagues also reviewed treatment barriers and toxicity-directed therapies.
Treatment Efficacy and Barriers
Currently, there are several limitations to the efficacy of CAR-T therapy, including on-target/off-tumor targeting, CAR T-cell dysfunction, and antigen escape.
Firstly, as CARs are designed to detect a specific antigen, depending on the extent of target antigen expression on normal cells, this can result in off-tumor targeting of the correct antigen on healthy tissue.
As a result, there is ongoing research into modulating CAR affinity to recognize tumor cells with high antigen density but not normal cells with lower antigen density. Secondly, inhibitory immune cells and cytokines in the tumor microenvironment (TME) can lead to T cell exhaustion and death, particularly in solid tumor malignancies.
Lastly, antigen escape, where antigen expression on tumors cells is either reduced or nullified through downregulation or mutation, may limit treatment efficacy and can lead to disease resistance and relapse following CAR-T therapy.