Development of T-cell lymphoma 'very serious' but 'very rare' after CAR T-cell therapy
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Key takeaways:
- T-cell lymphoma following CAR-T is rare.
- Tissue collection imperative to continue research into CAR-T toxicities.
More evidence has emerged that T-cell lymphoma following chimeric antigen receptor T-cell therapy is both rare and not necessarily caused by the treatment.
The FDA published a safety advisory on the risks of second primary malignancies in November, but findings presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR showed no vector integration in a patient who developed T-cell lymphoma after being treated with CAR T cells.
“At the RNA, DNA and protein level, we do not see the CAR T-cell vector inserting and causing this tumor,” Mark P. Hamilton, MD, PhD, hematology fellow at Stanford, told Healio. “We can’t exclude that the CAR T cell caused this immune suppression that allowed that separate mechanism of causing the tumor to take off.”
Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research, said in January just 22 cases of T-cell malignancies out of more than 27,000 treated individuals had been reported by the end of 2023, Healio previously reported.
The FDA has identified three cases of post-infusion T-cell lymphoma thus far, Hamilton said.
Researchers examined 724 patients treated with cell therapy at Stanford from 2016 to 2023 and found one patient — a 59-year-old woman — who developed a secondary malignancy (Epstein-Barr virus diffuse large B-cell lymphoma) different from the original B-cell lymphoma.
The rarity backs up a recent study published in Nature Medicine by lead author Guido Ghilardi, MD, postdoctoral researcher at University of Pennsylvania School of Medicine, where researchers found one case in 449 patients, Hamilton said.
“I think part of the purpose was to understand if there were more of these [cases] that we were missing,” Hamilton explained. “It does show that this is something that’s very rare after CAR T-cell therapy, though very serious, too. We have to balance the rarity as well as how serious the problem is.”
Hamilton and colleagues conducted five different assays on the Stanford patient’s tissue to determine vector integration. They did one using RNA at single-cell resolution, one with a protein analysis and three DNA assays.
They did not find CAR T-cell expression in the tumor tissue.
“We’ve got a framework for understanding how to look for the vector inside of the tumor in order to really determine what is causing these tumors, because it can be something outside of the CAR T cell itself,” Hamilton said.
He noted the patient had underlying mutations in the T-cell lymphoma.
“This means she likely had a preexisting susceptibility to this tumor,” Hamilton said. “In the absence of the CAR vector integrating, it is still important to try to understand what may have led to the tumor forming.”
Researchers also examined bone marrow of post-CAR-T patients who did not develop subsequent cancer and found CAR T cells present.
“We do think it’s important that, as we are vigilant about finding these additional tumors and really understanding what’s causing them, we understand it may be normal to find small amounts of the CAR T cell, and it doesn’t necessarily mean the CAR T cell is causing a cancer.”
Limited data on secondary malignancies highlight the importance of collecting viable tissue that can be used in future, larger studies, Hamilton said, especially as CAR-T use expands to other areas such as autoimmune diseases “where the patient doesn’t have cancer at all.”
“We feel like these are raising the need for vigilance after therapy but wouldn’t be a good reason to deny somebody a life-saving therapy while we’re still understanding what’s causing these second primary malignancies,” Hamilton said. “I think this is a warning that we should be vigilant in our post-CAR-T patients.”
References:
- Ghilardi G, et al. Nat Med. 2024;doi:10.1038/s41591-024-02826-w.
- Hamilton MP, et al. Abstract LBA-2. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; Feb. 21-24, 2024; San Antonio.
For more information:
Mark P. Hamilton, MD, PhD, can be reached at mphamilt@stanford.edu.
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Hamilton MP, et al. Abstract LBA-2. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; Feb. 21-24, 2024; San Antonio.
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