A Study Investigates If CAR T Therapy Directly Causes Secondary Malignancies

Despite the Food and Drug Administration (FDA) requesting that approved BCMA- or CD-19-targeted CAR T-cell therapies come with a warning following reports of T-cell malignancies, including CAR-positive lymphoma, among patients who received the treatment, researchers have announced that they have found no evidence that the therapy caused secondary cancer in modified T cells.

That’s according to research published in Nature Medicine from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center.

CAR T-cell therapy, as defined by the National Cancer Institute, utilizes a patient’s T cells, part of the immune system, which are extracted, changed in a laboratory to attack cancer cells, grown in the laboratory and infused back into the patient. The treatment, according to a news release from Penn Medicine, involves the use of engineered viruses to deliver genetic instructions that enable a patient’s T cells to target and eliminate cancer cells. There is, according to the release, a risk of a cancer-associated gene mistakenly being turned on and causing unregulated growth, which is known as insertional mutagenesis.

Researchers drew on data from 783 adult and pediatric patients who received treatment with CAR T-cell therapy at Penn Medicine and Children’s Hospital of Philadelphia in clinical trials, and found 18 cases of secondary cancers, noting that there was no evidence that these cancers were caused by intentional mutagenesis. Instead, researchers cited suppression of the immune system from prior cancer treatments as the cause of the secondary cancers.

The FDA began investigating secondary malignancies associated with CAR T-cell therapy in Nov. 2023, and issued letters in Jan. 2024 to pharmaceutical companies behind CAR T-cell therapies asking that their labeling contain a warning of secondary malignancies and that patient counseling information and medication guide also mention the risk for cancers.

CURE® spoke with the Nature Medicine study’s co-senior author, Dr. Joseph Fraietta, about the findings and what they mean for patients. Fraietta is an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

Transcript:

After looking at over 38 clinical trials of cell therapies and engineered T cell therapies — not only CAR T-cell therapies — with over 2,200 years of total patient follow-up, the frequency of secondary malignancies is very low, actually. Across our trials, none of them were directly attributed to the engineered cell product. In other words, the cell product really didn't grow out and cause any issues.

I hope [the study] puts CAR T-cell therapies more into context in terms of the relative risk with other sorts of therapies as well. And notably, this is our experience at the University of Pennsylvania, although similar studies by other groups, these large safety data sets, they're coming out. But with that, there are also isolated instances of some of these products causing secondary malignancies, but they're very few and far between. I'm not sure how the FDA will look at it, because there's still a risk. However, these secondary malignancies that are directly attributed to the CAR T-cell products are infrequent.

Transcript has been edited for clarity and conciseness.

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