‘Reassuring’ study shows no link between CAR T-cell therapy and secondary cancers
Key takeaways:
- Researchers did not observe insertional mutagenesis of CAR-T products among patients who developed secondary malignancies.
- CAR-T integration in some cells did occur.
A new retrospective analysis has added to building evidence that suggests chimeric antigen receptor T-cell therapy does not directly cause secondary malignancies.
Rare subsequent cancers develop due to previous treatments such as radiation and chemotherapy. Also, CAR-T integration occurred in some cells, which led to nonmalignant expansion.
The findings are “reassuring,” Joseph A. Fraietta, PhD, assistant professor of microbiology and director of the translational and correlative sciences laboratory in the Center for Cellular Immunotherapies at University of Pennsylvania, told Healio.
“Our study really provides comprehensive long-term safety data that supports the continued clinical use of gene modified T-cell therapies, including CAR T-cell therapies,” Fraietta added. “By ruling out insertional mutagenesis as a significant risk, our findings help address concerns from regulatory agencies and clinicians [and], I believe, reinforce the viability of CAR-T and other gene-modified T-cell therapies as a standard treatment approach.”
Background and methods
The FDA has approved six CAR-T products for the treatment of hematologic malignancies — idecabtagene vicleucel (Abecma, Bristol Myers Squibb, 2seventy bio), lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb), ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech), tisagenlecleucel (Kymriah, Novartis), brexucabtagene autoleucel (Tecartus, Kite Pharma/Gilead Sciences) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences).
More than 30,000 individuals have received CAR-T treatment since 2017, according to a press release.
Adverse events such as cytokine release syndrome and neurotoxicity are common, but the FDA issued a safety advisory for secondary malignancies in November 2023 and required a boxed warning for CAR-T products in January 2024.
“I think the field at that time sort of held its breath,” Fraietta said.
Incidence, however, has proven rare, and data on the CAR-T product becoming cancerous is scarce.
Still, Fraietta and colleagues wanted to further the research on insertional mutagenesis.
They evaluated 783 patients (426 adults; 357 children) with HIV-1 or cancer who received lentiviral or gammaretroviral-transduced autologous T cells during a phase 1 or phase 1/phase 2 trial at University of Pennsylvania or Children’s Hospital of Philadelphia between October 2001 and May 2023.
Researchers included 38 trials in the analysis, with data based on 2,205 patient years.
The role of insertional mutagenesis in secondary malignancies served as the primary endpoint.
Results and next steps
Median follow-up was 1.56 years (range, 3 days to 15.85 years).
Secondary malignancies occurred in 2.3% of the study population, at a rate of 0.0082 events per patient year.
Secondary malignancies developed at a median 1.94 years (range, 52 days to 14 years) following treatment administration.
Researchers estimated the risk for a secondary malignancy 5 years after treatment to be 2.8% (95% CI, 1.7%-4.5%).
However, they did not observe evidence of insertional mutagenesis in any of the secondary malignancies.
“The secondary malignancies that we saw were most common in patients with more of these late-in-life, B-cell cancers,” Fraietta said. “A lot of the susceptibility was probably due to advanced age and the fact that many of these patients, prior to receiving CAR T-cell therapy, received a number of lines of chemotherapies.”
Fraietta and colleagues evaluated vector integration sites for 176 patients, eight of whom had secondary malignancies. They found integration and clonal expansion to be rare. One case showed integration in a tumor suppression gene.
“The fact that we had insertions in tumor suppressor genes wasn’t totally unexpected,” Fraietta said. “I’ve been looking closely at some of these other studies that have been coming out, and I think when you see those very rare instances of product transformation, it’s not only where that CAR gene lands — maybe that’s the first hit — but I think when you see transformation like that and cancer, it’s because the person probably has a sensitized genetic background. They have other hits, and then maybe that CAR landing somewhere is the hit that you need to sort of drive transformation.
“In our patients this was a beneficial thing, but I think that it shows that there is the possibility for insertional mutagenesis to occur,” Fraietta added. “Sometimes that’s a good thing, and sometimes that’s a bad thing.”
These results show long-term monitoring and follow-up are “essential,” Fraietta said.
Researchers acknowledged study limitations, including lack of gene-edited therapies in the trials and the fact most patients in the analysis had advanced cancers.
“Future research needs to work on refining some of these designs for these viral vectors, which are the tools that we use to insert those CARs into cells,” Fraietta said. “The goal would be to reduce any theoretical risks.”
Moving CAR-T earlier into disease treatment could mitigate risks, too.
“That’s so very important,” Fraietta said. “We haven’t scaled CAR T cell therapy out to the extent that we would like. But in addition to some of these prior lines of therapies like chemotherapy maybe being associated more with the incidence of these secondary malignancies, when patients are treated with all of these prior lines of therapy before CAR T cell therapy, you beat up the T cells. When we get T cells from a patient on a trial, sometimes they’ve been treated with six to eight lines of prior therapy, and then it becomes very hard to engineer and expand T cells for that patient. For that reason, I hope that in certain indications they do move up, and that maybe it would be appropriate for them to be used as like first- or second-line therapy.”
References:
- Jadlowsky JK, et al. Nat Med. 2025;doi:10.1038/s41591-024-03478-6.
- No evidence that CAR T cell therapy causes secondary cancers, Penn study finds (press release). Available at: https://www.pennmedicine.org/news/news-releases/2025/february/no-evidence-that-car-t-cell-therapy-causes-secondary-cancers. Published Feb. 3, 2025. Accessed Feb. 18, 2025.
For more information:
Joseph A. Fraietta, PhD, can be reached at joseph.fraietta@pennmedicine.upenn.edu.
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