Researchers have found no evidence that chimeric antigen receptor (CAR) T-cell therapy caused secondary cancers in the modified T cells, according to a recent study published by Jadlowsky et al in Nature Medicine.
Background
CAR T-cell therapy is a personalized type of immunotherapy that employs deactivated, engineered viruses that are 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 insertion 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. There have been several documented cases of other therapies causing cancers from insertional mutagenesis. On such trial, involving gene therapy to correct X-linked severe combined immunodeficiency, determined that 25% of the study participants developed leukemia from the therapy.
Since the approval of the first CAR T-cell therapy in 2017, over 30,000 patients with hematologic malignancies have been treated with these therapies. Some of the earliest patients treated in clinical trials have experienced long-lasting remissions of a decade or more.
In late 2023, the U.S. Food and Drug Administration (FDA) announced that the agency was investigating several reported cases of secondary T-cell malignancies in patients who previously received CAR T-cell therapies. Beginning in 2024, the FDA also started requiring drug manufacturers to add a safety label warning to CAR T-cell products.
Currently, CAR T-cell therapy is only approved to treat patients with hematologic malignancies that have relapsed or stopped responding to treatment. Patients who receive CAR T-cell therapies have already received multiple other types of treatment, including radiation and chemotherapy—which are known to have a low risk of secondary cancers.
Study Methods and Results
In the study, the researchers analyzed samples from 783 adult and pediatric patients from who were treated with CAR T-cell therapy in clinical trials. They identified 18 cases of secondary cancers, none of which showed evidence that they were caused by insertional mutagenesis.
The researchers indicated that the rare occurrences of secondary cancers that did occur following CAR T-cell therapy could be attributed to a suppressed immune system from first-line cancer treatments such as radiation and chemotherapy. However, none of the cases among the patients involved in the study were caused by CAR T-cell therapy.
“It typically takes multiples factors causing changes at the cellular level for cancer to develop and grow,” explained co–senior study author Frederic Bushman, PhD, the William Maul Measey Professor and Chair of Microbiology at the University of Pennsylvania. “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,” he highlighted.
Conclusions
“These findings bolster previous … research demonstrating the safety of CAR T-cell therapy,” emphasized co–senior study author Joseph Fraietta, PhD, Assistant Professor of Microbiology at the University of Pennsylvania. “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 [patients] at the cellular level to verify the science of why these cancers occurred,” he added.
The researchers underlined the safety of CAR T-cell therapy and safety measures to monitor each patient both during and following treatment—including follow-up for 15 years postinfusion.
“As we develop new cancer therapies, patient safety is always our top priority,” underscored co–senior study author Carl June, MD, the Richard W. Vague Professor in Immunotherapy at the University of Pennsylvania. “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 life-saving therapy,” he concluded.
Disclosure: For full disclosures of the study authors, visit nature.com.
