The development of any type of secondary cancer following chimeric antigen receptor (CAR) T-cell therapy may be rare, according to a recent study published by Ghilardi et al in Nature Medicine.
Background
Secondary cancers, including T-cell lymphomas, are known risks of cancer treatments such as chemotherapy, radiation, and stem cell transplant. CAR T-cell therapy—a personalized immunotherapy approach in which patients’ T cells are modified to target and kill their cancer cells—is currently only approved to treat hematologic malignancies that have relapsed or stopped responding to treatment. Therefore, patients who receive this type of therapy have already received multiple other types of treatments, have few remaining therapeutic options, and are facing dire prognoses.
Since its approval in 2017, CAR T-cell therapy has been used to treat more than 30,000 U.S. patients with hematologic malignancies. Some of the earliest patients treated in clinical trials have experienced remission for longer than a decade.
In November 2023, the U.S. Food and Drug Administration (FDA) launched an investigation into several reported cases of secondary T-cell malignancies, including CAR-positive lymphoma, in patients who received CAR T-cell therapy. In January 2024, the FDA stated that drug manufacturers will be required to add a safety label warning to CAR T-cell therapy products. Although the FDA review is ongoing, it remains unclear whether the secondary T-cell malignancies were caused by CAR T-cell therapy.
Researchers at the University of Pennsylvania have already established protocols to monitor patients during and 15 years following treatment with CAR T-cell therapy. The university also participates in national reporting requirements and databases that track outcomes data from all cell therapies and bone marrow transplants.
Study Methods and Results
In the recent study, researchers analyzed the outcomes of 449 patients who underwent treatment with commercially available CAR T-cell therapies at Penn Medicine between January 2018 and November 2023. The researchers found that 3.6% (n = 16) of the patients were diagnosed with a secondary cancer following receipt of CAR T-cell therapy. A majority of the secondary cancers (n = 12) were solid tumors such as skin cancer, prostate cancer, and lung cancer.
The researchers also discovered that one of the patients who developed a secondary lung tumor following CAR T-cell therapy also had incidental T-cell lymphoma in their lymph node—which was removed during surgery for the lung tumor. Molecular analyses demonstrated that the T-cell lymphoma didn’t harbor the CAR transgene, meaning that it was not a CAR-positive lymphoma and there was no clear connection to the CAR T-cell therapy.
Conclusions
“When this case was identified, we did a detailed analysis and concluded the T-cell lymphoma was not related to the CAR T-cell therapy. As the news of other cases came to light, we knew we should go deeper, to comb through our own data to better understand and help define the risk of any type of secondary cancer in patients who have received CAR T-cell products,” stressed senior study author Marco Ruella, MD, Assistant Professor of Hematology-Oncology and Scientific Director of the Lymphoma Program at the University of Pennsylvania. “What we found was very encouraging and reinforces the overall safety profile for this type of personalized cell therapy,” he highlighted.
“It’s important to have long-term follow-up and reporting systems in place for any new cancer treatment to understand the risks and benefits over time, so that we can—together with patients and their families—evaluate the best possible treatment options for each individual,” underscored co–study author David Porter, MD, the Jodi Fisher Horowitz Professor of Leukemia Care Excellence and Director of Cell Therapy and Transplantation at the Abramson Cancer Center at the University of Pennsylvania. “Just as Penn Medicine researchers … are continually working on finding new ways to make CAR T-cell therapy more effective for more patients, our team also has robust systems in place to study future cases like this so that we can contribute to a comprehensive understanding of secondary cancers in this patient population,” he concluded.
Disclosure: The research in this study was made possible by the Penn Medicine Cellular Therapy and Transplant BioBank. For full disclosures of the study authors, visit nature.com.
