Recent research has shed light on the potential risks of secondary primary cancers (SPCs) in patients who have undergone CAR T-cell therapy for hematologic malignancies. While the overall risk appears to be relatively low, experts are advocating for proactive strategies to mitigate these effects. A comprehensive review published in JAMA Oncology highlights the pathobiological and epidemiological aspects of SPCs associated with CAR T-cell treatments, emphasizing the need for further investigation and risk management. This article delves into the complexities of this issue, exploring the underlying mechanisms, prevalence, and preventive measures.

The process of manufacturing CAR T-cells involves introducing a transgene into T cells using viral vectors, which can lead to genomic integration that may pose oncogenic risks. Specifically, insertional mutagenesis has been linked to cases of transgene-positive SPCs, such as T-cell lymphomas following treatment for multiple myeloma. The authors distinguish between SPCs arising from transgene-positive tumors and those resulting from predisposing conditions or prior chemotherapy. Patients who experience prolonged survival after CAR T-cell therapy may face an increased risk of developing SPCs over time, although this risk might be overshadowed by mortality from the primary cancer. Additionally, lymphodepletion prior to CAR T-cell infusion can compromise immune function, potentially leading to impaired antitumor surveillance and solid tumor growth.

In 2023, the FDA issued draft guidance regarding the oncogenic potential of CAR T-cell therapies following reports of 20 cases of T-cell lymphoma among approximately 30,000 treated patients. Subsequent studies have shown varying incidence rates of SPCs, ranging from 3% to 8%, depending on the study population and follow-up duration. Notably, these rates do not appear to be significantly higher than those observed in patients who did not receive CAR T-cell therapy. However, longer-term clinical trial follow-up is essential to better understand the true incidence of SPCs and establish dedicated endpoints for monitoring.

To address the risk of SPCs, the authors recommend open and transparent discussions with patients about the small but definitive risk associated with CAR T-cell therapy. They suggest that earlier administration of CAR T-cell therapy and reduced use of genotoxic chemotherapy may lower the risk of SPCs. Novel gene-editing methods that allow for more precise integration of therapeutic transgenes into T cells could also minimize the risk of insertional mutagenesis. Furthermore, screening for baseline clonal hematopoiesis and germline predisposition syndromes may help identify patients at higher risk for SPCs. Regular screenings and inflammation management strategies could serve as secondary prevention measures, while reliable reporting of SPCs across institutions is crucial for tertiary prevention.

The authors conclude that despite the reported correlations between CAR T-cell therapy and SPCs, there is limited evidence of causality. The benefits of CAR T-cell therapy in treating primary cancers generally outweigh the small risk of developing SPCs. Therefore, they advocate for cautious reassurance and personalized decision-making when considering CAR T-cell therapy. As research continues, optimizing CAR T-cell engineering and identifying genetic safe harbors within the T-cell genome will be critical for enhancing patient outcomes and minimizing potential risks.