New study confirms CAR T cell therapy does not cause secondary cancers

Within a large group of more than 700 patients treated with CAR T cell therapy, researchers found no evidence that the therapy itself caused any type of secondary cancer in the modified T cells, according to new analysis reported today in Nature Medicine from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine's Abramson Cancer Center. The rare occurrences of secondary cancers that did occur following CAR T cell therapy could be attributed to a damaged immune system from first-line cancer treatments like radiation and chemotherapy, but none of the cases in this group were caused by the treatment that alters cancer-associated genes in the patients' T cells.

These findings bolster previous Penn research demonstrating the safety of CAR T cell therapy. Penn's robust patient samples and follow-up protocols allowed us to analyze not only whether patients who received CAR T cell therapy developed cancer after treatment, but to examine the cancer in those individuals at the cellular level to verify the science of why these cancers occurred." 

Joseph Fraietta, PhD, co-senior author, assistant professor of Microbiology

Pioneered at Penn Medicine, CAR T cell therapy is a personalized form of immunotherapy that uses a deactivated virus to program an individual's own T cells to target and kill their cancer cells. Since the approval of the first CAR T cell therapy in 2017, more than 30,000 patients with blood cancers have been treated. Some of the earliest patients treated in clinical trials have gone on to experience long-lasting remissions of a decade or more. 

Investigating concerns about CAR T therapy 

In late 2023, the FDA announced that they were investigating several reported cases of secondary T cell malignancies in patients who previously received CAR T cell therapy products. Starting in 2024, the FDA also began requiring drugmakers to add a safety label warning to CAR T cell products. 

CAR T cell therapy is currently only approved to treat blood cancers that have relapsed or stopped responding to treatment. Patients who receive CAR T cell therapies have already tried multiple other types of treatment, like radiation or chemotherapy, which are known to have a low risk of causing secondary cancers.

CAR T cell therapy employs engineered viruses-naturally adept at entering cells-to deliver genetic instructions that enable a patient's T cells to target and eliminate cancer cells. Because the delivery of the information involves being inserted into an existing cell and sharing new genetic information, there is a risk of mistakenly turning on a cancer-associated gene and causing unregulated growth, a process known as insertional mutagenesis. This process was of particular interest to researchers as there have been several documented cases of other therapies causing cancers from insertional mutagenesis, such as in a French trial of gene therapy to correct X-linked severe combined immunodeficiency, where 25 percent of study participants developed leukemia from the therapy.

Reaffirming the safety profile of CAR T cell therapy 

For this study, researchers analyzed samples from 783 adult and pediatric patients from Penn Medicine and Children's Hospital of Philadelphia who were treated with CAR T cell therapy in clinical trials and found 18 cases of secondary cancers. None of the 18 cases showed evidence that they were caused by insertional mutagenesis. 

The researchers attributed the rare occurrence of secondary cancers to the suppression of the immune system from prior cancer treatments. 

"It typically takes multiples factors causing changes at the cellular level for cancer to develop and grow," said co-senior author, Frederic Bushman, PhD, the William Maul Measey Professor and Chair of Microbiology at Penn. "As we continue to evaluate larger cohorts of individuals treated with CAR T cell therapy, there is a chance we find an exception. However, the evidence continues to reassure us that the benefits of CAR T cell therapy far outweigh the risks." 

Overall, study authors emphasize the safety of CAR T cell therapy, and the strength of Penn Medicine's built-in safety measures to monitor each patient both during and after treatment – including follow-up for 15 years after infusion. 

"As we develop new cancer therapies, patient safety is always our top priority," said co-senior author, Carl June, MD, the Richard W. Vague Professor in Immunotherapy. "We know that all cancer treatments come with some form of risk, and we aim to continue to make CAR T cell therapy even safer and more effective, so that more patients and their families can benefit from this lifesaving therapy."