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.
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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.
Toxicities of Therapy
CRS is one of the most common toxicities associated with CAR-T therapy and is associated with symptoms that can vary from mild infusion reactions and fever to hypotension, capillary leak syndrome, and end-organ dysfunction. The diagnosis of CRS is based on clinical symptoms and can be graded based on the presence of certain symptoms.
The spectrum of neurotoxicity following CAR-T therapy can range from encephalopathy to seizures, obtundation, and even death. The pathophysiology of ICANS is not well understood, and neurotoxicity may be independent of CRS-related adverse events. Physical examination is important for the early detection of ICANS, where careful evaluation for language deficits and inattention is essential.
Toxicity‑Directed Therapies
For the majority of patients, management of adverse events relies upon supportive care, steroids, and tocilizumab. Tocilizumab is an IL-6 receptor antagonist that is commonly used for CRS following CAR-T infusion. Although the level of toxicity required for tocilizumab use varies by center, grade 3 or higher events are usually considered a common threshold for use.
For patients with tocilizumab-refractory CRS, systemic corticosteroids are generally administered. For the treatment of neurotoxicity, tocilizumab is usually not effective. Neurotoxicity is most often treated with systemic corticosteroids and anti-epileptics as needed; dexamethasone is the agent of choice due to its high central nervous system (CNS) penetration. Other agents, normally reserved for refractory CRS, include siltuximab, infliximab, etanercept, and anakinra.
Balancing Efficacy and Toxicity
Overall, a careful risk-benefit balance exists between the efficacy and toxicities associated with CAR-T therapies. Importantly, some degree of toxicity is expected to achieve an optimal response to treatment.
In addition, one of the most important but overlooked facets of toxicity prevention is careful patient selection. In pivotal trials for CAR-T therapies, rigorous safety-related eligibility criteria were included; these criteria should be considered when selecting candidates for treatment in real-world setting. As progress continues to be made in the development of new therapies, further investigation into the mechanisms of both CAR-T efficacy and safety are also needed.
Disclosure: Some guideline authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Reference
- Chohan KL, Siegler EL, Kenderian SS. CAR-T cell therapy: the efficacy and toxicity balance. Curr Hematol Malig Rep. 2023;18(2):9-18. doi:10.1007/s11899-023-00687-7
This article originally appeared on Hematology Advisor
