Dr Dahiya on the Pathobiology of Second Primary Cancers After CAR T-Cell Therapy

“In the next few years, [we will] have a lot more data about the incidence of these SPCs as we move CAR T-cell therapy into earlier lines and as we [use and investigate] CAR T-cell therapy for autoimmune [diseases]. A lot of things in terms of the risk of developing these second myeloid neoplasms or myeloid neoplasms will be demystified.”

Saurabh Dahiya, MD, FACP, associate professor, medicine (blood and marrow transplantation and cellular therapy), Stanford University School of Medicine, clinical director, Cancer Cell Therapy, Stanford BMT and Cell Therapy Division, details the pathobiology of second primary cancers (SPCs) following receipt of CAR T-cell therapy and ongoing efforts to better elucidate SPC incidence and risk for patients with hematologic cancers.

In 2023, the FDA issued draft guidance regarding the oncogenic potential of CAR T-cell therapy following reports of 20 cases of T-cell lymphoma among approximately 30,000 treated patients. The report reflected growing concerns about the incidence of SPCs following CAR T-cell administration and the long-term safety profile of this drug class, Dahiya begins.

At the time of the FDA’s warnings in November 2023 and again in January 2024, the primary concern centered on the increased observation of T-cell lymphomas in patients post-CAR T-cell therapy, he says. From the inception of CAR T-cell therapies, insertional mutagenesis has been a theoretical risk, Dahiya states. He explains that insertional mutagenesis is a process by which the CAR transgene integrates into the T-cell genome, potentially activating an oncogene and driving malignant transformation. This risk was initially discussed in the FDA’s perspective article in the New England Journal of Medicine, which reported 3 such cases following CAR T-cell therapy, Dahiya notes.

Additional concerns have emerged regarding T-cell malignancies that are transgene negative, Dahiya continues. These malignancies do not appear to be caused directly by insertional mutagenesis, indicating that CAR T-cell therapy could lead to oncogenic events via other mechanisms, such as immune dysregulation or genomic instability induced by the therapy’s effects on the host immune system, Dahiya suggests.

Further research is needed to clarify the incidence and causality of SPCs associated with CAR T-cell therapy, particularly as its use expands into earlier lines of treatment and autoimmune indications, he emphasizes. As more data become available, the understanding of CAR T-cell–related oncogenic risks will be refined, particularly concerning secondary myeloid neoplasms, Dahiya notes. Future studies comparing CAR T-cell therapy across oncology and autoimmune diseases may help delineate therapy-related risks and inform mitigation strategies, he concludes.