Study Confirms Safety of Genetically Modified T Cells

Genetically engineered T cells have substantially improved outcomes for many patients with refractory blood cancers, demonstrating relatively high overall response rates and providing patients with months or years of remission. However, in 2023, the Food and Drug Administration reported that 22 cases of T cell malignancies had been identified in patients previously treated with engineered T cells, prompting concerns about whether this rare occurrence might be caused by the treatment itself.¹

To create cancer-fighting T cell therapies, scientists use viral vectors to insert a sequence of DNA into a patient’s own T cells, enabling them to target tumor proteins. Because the viral vectors do not target a predetermined region of the genome, there is a theoretical risk that this insertion could disrupt key tumor suppressor genes and lead to a secondary malignancy.

To evaluate these risks, Carl June, an immunotherapy researcher at the University of Pennsylvania, and a team of scientists collated data on safety outcomes from 783 patients collected during 38 different T cell therapy clinical trials that took place between 2001 and 2023. Their study, published in Nature Medicine, found that T cell malignancies were very rare: Over a median follow-up time of 1.56 years (ranging from three days to nearly 16 years), they identified just one instance of this disease.² Importantly, when researchers analyzed DNA sequences from this T cell lymphoma, they did not contain the therapeutic gene modification used in the T cell therapy, providing further support that this treatment does not contribute to secondary malignancies.

“Each new publication that comes out is another piece of proof that it's not a major concern,” said Adam Snook, who studies T cell therapies at Thomas Jefferson University and was not involved in the present study.

Instead, said June, “The most common cause, it turns out, is, [something] epidemiologists call immortal time bias. It used to be that these people would have a lot of chemotherapy that’s cytotoxic, DNA damaging—usually four or five [different regimens]—and then they used to die.” If these patients are successfully treated with T cell therapy after the unsuccessful lines of chemotherapy, they will live longer. However, the DNA damage done by the chemotherapy isn’t erased, leaving these patients more vulnerable to new malignancies in the following years.

The researchers were able to access stored blood samples from 176 of the patients involved in these trials, enabling them to pinpoint the transgene integration sites. They noted that in some of the cells, especially those that persisted in the blood for several months after treatment, some of the integration sites were in or near cancer-associated genes. Even in these cases however, the cells did not show signs of malignancy. “It takes more than one event to create cancer,” noted Snook. “It would be really hard for a single lentiviral insertion event to take a normal T cell and turn it into a cancer T cell. That would be nearly impossible.”

These types of long-term safety assessments are especially important as researchers begin to explore whether genetically modified T cell therapy could also be used to treat serious but less immediately deadly diseases, like lupus and multiple sclerosis. To decrease the already very slight risk of insertional mutagenesis even further, June said, “You could knock [the transgene] into a safe harbor site instead of the semi-random way that many viruses go in… People are working on that now, and I think the field probably will go to that.”

Disclosure of conflicts of interest: Carl June is a scientific co-founder of Capstan Therapeutics, Dispatch Biotherapeutics and BlueWhale Bio; he has a scientific advisory role at several other biotechnology companies.