Second Primary Cancer Risk Informs the Risk-Benefit Profile of CAR T-Cell Therapies

Although the risk of developing second primary cancers (SPCs) following receipt of CAR T-cell therapies for patients with hematologic cancers appears relatively low, mitigation strategies for these toxic effects are warranted, according to findings from a review of the pathobiology and epidemiology of CAR T-cell therapy–associated SPCs published in JAMA Oncology.1

“The recent news of post–CAR T-[cell therapy] SPCs has created distress among the public, as well as among physicians and scientists who readily administer CAR T-[cell] therapies. With this new information, there is also an opportunity for original investigation and risk mitigation,” lead study author Shyam A. Patel, MD, PhD, and coauthors, wrote in the review. Patel is an associate professor in the Department of Medicine at the UMass Chan Medical School, as well as a hematologist/oncologist at UMass Memorial Medical Center in Worcester, Massachusetts.

Post–CAR T-Cell Therapy SPC Pathobiology

CAR T-cell manufacturing involves the viral transduction of a transgene into a T cell, which is not typically associated with impaired T-cell genetic health. However, the genomic integration of lentiviruses is semirandom and may lead to oncogenesis. Insertional mutagenesis has been associated with transgene-positive SPCs, such as in a study showing 2 cases of transgene-positive SPCs due to insertional mutagenesis leading to T-cell lymphoma following treatment with ciltacabtagene autoleucel (Carvykti) for multiple myeloma.

Furthermore, the study authors noted the difference between SPCs that arise from transgene-positive tumors and other insertional mutagenesis events, and SPCs that develop from predisposing conditions or the effects of prior chemotherapy.For example, treatment-related myeloid neoplasms are known to occur in the hematopoietic compartment in patients who have received chemotherapy for the treatment of a primary cancer.

Patients who achieve a prolonged lifespan may have an increased risk of developing SPCs over the course of their lives due to the long lead time for SPCs to develop. However, death from primary cancer may mask the risk of SPC development after chemotherapy exposure. Therefore, the durable responses associated with CAR T-cell therapy may be related to the risk of SPCs seen in recipients of these products, according to the authors.

Moreover, the lymphodepletion that occurs prior to CAR T-cell infusion can alter patients’ immune repertoires and lead to immune dysfunction, including impaired antitumor immune surveillance mechanisms and solid tumor cell growth.

Epidemiology of SPC

In 2023, the FDA issued draft guidance recommendations regarding the oncogenic potential of CAR T-cell therapies following notification that 20 cases of T-cell lymphoma occurred among approximately 30,000 patients who received CAR T-cell therapy. This report was one of several that demonstrated the incidence of SPCs following CAR T-cell therapy administration. In 2024, the Center for International Blood and Marrow Transplant Research reported that at a median follow-up of 13 months, 4.3% of 11,345 CAR T-cell therapy recipients developed SPCs, including T-cell lymphomas, which were reported in 3 cases.

Disease control methods and bridging therapy may also contribute to the epidemiology of SPCs, the authors noted, particularly in cases where several cycles of genotoxic therapy are administered prior to CAR T-cell therapy. However, the relationship between bridging therapy receipt and SPC development may be confounded by the fact that bridging chemotherapy is often administered in patients with more aggressive diseases, who are more likely to have received more prior lines of therapy.

Notably, the authors evaluated SPC risk in population-based registries of patients with non-Hodgkin lymphoma and multiple myeloma who did not receive CAR T-cell therapy. The incidence of SPCs in this population varies by disease subgroup, ranging from 4% to 20%. The authors emphasized that these data show that rates of SPCs are not higher in patients who received CAR T-cell therapy vs those who did not. In comparison, randomized clinical trials that investigated CAR T-cell therapies showed rates of SPCs ranging from 3% to 8%. However, the authors noted that follow-up times varied between studies.

“Longer follow-up of these randomized clinical trials is needed, with a dedicated end point being incidence of SPCs,” they wrote.

SPC Risk-Mitigation Recommendations

“Risk mitigation begins with open-ended conversation involving full disclosure of the small but definitive risk for SPCS post–CAR T-[cell therapy] administration,” the authors explained. They emphasized that oncologists should explain the other factors that may contribute to SPC development to patients, including lymphodepletion, as well as the fact that reduced immune reconstitution following CAR T-cell therapy may be associated with SPC risk.

Primary Prevention Strategies

The authors noted that administering CAR T-cell therapy in earlier lines of therapy and decreasing genotoxic chemotherapy use may lower the risk for SPCs. For instance, findings from the phase 3 CARTITUDE-4 (NCT04181827), TRANSFORM (NCT03575351), KarMMa-3 (NCT03651128), and ZUMA-7 (NCT03391466) trials, which all evaluated CAR T-cell therapy in the second-line setting, demonstrated no increased risk for SPCs among patients who received CAR T-cell therapy vs standard-of-care therapies. Therefore, earlier-line use of CAR T-cell therapy may result in less impaired immune reconstitution after CAR T-cell therapy, and thus a lower risk for SPCs, although longer-term clinical trial follow-up is needed.

The authors explained that since the semirandom and nonspecific integration of viral vectors into unstable loci may cause insertional mutagenesis during CAR T-cell manufacturing, the implementation of risk-mitigation strategies during manufacturing may be considered. Nonviral-based gene therapies that employ novel editing methods may decrease the risk for insertional mutagenesis, as they can more specifically install therapeutic transgenes into T cells.

Furthermore, safe harbor sites may be identified prior to T-cell transduction with the CAR-containing virus. The authors recognize, however, that cost and time may be barriers to procurement and administration of the therapy. Furthermore, the posttransduction sequencing may delay CAR T-cell therapy infusion in the patient, introducing the need for additional cycles of bridging therapy in the meantime.

Secondary Prevention Strategies

Notably, the pre-existing health conditions of some CAR T-cell therapy candidates put them at risk for developing SPCs following CAR T-cell therapy. In these cases, secondary SPC prevention measures can be considered, the authors wrote. For example, post–CAR T-cell therapy SPCs, particularly myeloid neoplasms, have been linked with the presence of baseline clonal hematopoiesis (CH), likely because pre–CAR T-cell therapy lymphodepleting chemotherapy can adversely affect the hematopoietic compartment.

In the stem cell transplant field, experts have debated the need for and feasibility of screening donors for CH before allogeneic stem cell transplant. Prior CH screening depends on individual and systemwide risk-benefit ratios, and research is limited regarding the best practices for autologous CH screening prior to CAR T-cell therapy. The authors explained that conducting a bone marrow biopsy that tests for myeloid variants may be useful. Screening CAR T-cell therapy candidates for baseline CH within the hematopoietic compartment can ensure the mobilization and apheresis of healthy lymphoid cells and relay genomic information about a candidate’s hematopoietic health. Conversely, however, the lack of formalized management recommendations from consensus guidelines is a potential disadvantage of CH screening in CAR T-cell therapy candidates.

At this time, they emphasized that the presence of CH of indeterminate potential or clonal cytopenia of unknown significance should not prevent patients from receiving CAR T-cell therapy since this therapy is likely to help prevent patients from dying of primary disease. In the future, research may investigate CH-associated covariates that may adversely correlate with clinical outcomes in patients who receive CAR T-cell therapy.

The authors continued by acknowledging that hereditary predisposition for SPCs is a minor consideration when assessing a patient’s likelihood of developing an SPC post–CAR T-cell therapy. Genomic integrity may be compromised in patients harboring germline variants at baseline, particularly due to the effects of lymphodepleting chemotherapy or the transduction of a lentivirus into the second copy of a critical gene that has 1 defective allele. For example, one report showed an association between the development of a post–CAR T-cell therapy SPC and a germline TP53 variant in 1 patient.

Accordingly, testing for germline predisposition syndromes at baseline may decrease the risk of post–CAR T-cell therapy SPCs, the authors explained, but it should not necessarily disqualify patients for CAR T-cell therapy. “These decisions are best made on a personalized basis given the limited definitive literature on this topic,” the authors noted.

Other secondary SPC prevention measures may include regularly scheduled screenings conducted in the form of physical examination, laboratory work, or imaging. Although population-based secondary prevention has been useful for the early identification of several cancers, no guidelines currently exist for screening patients during workup for CAR T-cell therapy. Therefore, the role of established cancer screening methods before and after CAR T-cell infusion should be defined.

Furthermore, combatting inflammation, which is a known cause of carcinogenesis, may help prevent the clonal outgrowth of malignant myeloid cells. Many patients have baseline inflammatory comorbidities, and secondary prevention strategies that detect inflammation risk early or decrease inflammatory response may be used for select patients planned to receive CAR T-cell therapy.

Tertiary Prevention Strategies

“Reliable reporting of SPCs is an effective form of tertiary prevention and should be encouraged across all institutions to ensure that the data are adequately presented to the public,” the authors emphasized. They noted that since the current literature has a short median follow-up time for SPC reporting, the true incidence of SPCs may increase with longer follow-up. Moreover, patients with asymptomatic or slowly growing SPCs may not be diagnosed with the SPC. “The range of reported CAR-T–associated T-cell cancers is particularly important, as we are just beginning to understand whether inadvertent transgene insertion is causal,” the authors explained. “It is possible that the spectrum of T-cell cancers may be broader once additional data from reporting become available during the next 2 to 3 years.”

The authors also emphasized that “personalized approaches may be best for patients who are particularly worried about the risk of SPCs, and shared decision-making may be highly valued.” Patients who receive CAR T-cell therapy could consider undergoing active SPC surveillance.

Summary and Next Steps

Overall, the authors explained that despite reported correlations between CAR T-cell therapy and the development of SPCs, causal associations have rarely been published, aside from limited reports of transgene-positive T-cell lymphomas. The authors noted the importance of optimal CAR T-cell therapy engineering going forward and identifying genetic safe harbors within the T-cell genome when developing the next generation of these products.

“The benefits of CAR-T therapy against the primary cancer appear to outweigh the small risk for SPCs, and cautious reassurance is warranted in most cases,” the authors concluded. “We favor proceeding with CAR-T therapy when clinically indicated, given the miniscule risk of SPCs as well as the lack of definitive evidence of causality.”

Reference

1. Patel SA, Spiegel JY, Dahiya S. Second primary cancer after chimeric antigen receptor-T-cell therapy: a review. JAMA Oncol. Published online December 12, 2024. doi:10.1001/jamaoncol.2024.5412