Stanford Study Finds Low Risk of Secondary Cancer with CAR T Therapy

In November 2023, the FDA first warned about the risk of T cell malignancies after treatment with CAR T cell therapies, which are used to treat patients with lymphoma and leukemia. In April 2024, regulators concluded that T cell malignancies may present soon after treatment and may be fatal. The FDA began requiring approved CAR T therapies to have a boxed warning about this risk.

Now a new study, published last month in The New England Journal of Medicine, highlights work from researchers at Stanford Medicine. They analyzed patients at Stanford Health Care who were treated with a CAR T-cell therapy between 2016 and 2024.

They found that the risk of secondary blood cancers after treatment with a CAR-T cell therapy is low and may not be related to the CAR T-cells. In their study of 724 patients just 6.5% patients had a secondary malignancy in the three years after therapy. One patient died.

Stanford researchers said this was likely due to the immunosuppression caused by CAR-T cell therapy, rather than the CAR-T cells themselves. They theorize that the compromised immune system allowed preexisting, but not previously detected, cancer cells to grow.

Ash Alizadeh, M.D., Ph.D.

“We compared protein levels, RNA sequences and DNA from single cells across multiple tissues and time points to determine that the therapy didn’t introduce the lymphoma into this patient; instead it was already brewing in their body at very low levels,” professor of medicine Ash Alizadeh, M.D., Ph.D., a member of the Stanford Cancer Institute, said in a news release.

Currently, there are six approved CAR T-cell therapies:

• Abecma (idecabtagene vicleucel) to treat multiple myeloma
• Breyanzi (lisocabtagene maraleucel) to treat large B cell lymphoma, follicular lymphoma and mantle cell lymphoma
• Carvykti (ciltacabtagene autoleucel) to treat multiple myeloma
• Kymriah (tisagenlecleucel) to treat large B cell lymphoma, follicular lymphoma and acute lymphoblastic leukemia
• Tecartus (brexucabtagene autoleucel) to treat mantle cell lymphoma or acute lymphoblastic leukemia.
• Yescarta (axicabtagene ciloleucel) to treat large B-cell lymphoma

For these therapies, a patient’s own immune T cells are engineered to seek out cancer cells. These T cells encode for the protein chimeric antigen receptor, which binds to cancer cells.

In the Stanford study, the person who died was treated with Yescarta for diffuse large B-cell lymphoma. Researchers profiled both the original and the secondary lymphoma and found that each were molecularly and genetically distinct. Both lymphomas, however, were positive for Epstein–Barr virus, a virus known to cause cancer. The patient also had a history of autoimmune disease.

“These results may help researchers focus on the immune suppression that can precede and often follows CAR-T cell therapy,” David Miklos, M.D., Ph.D., professor of medicine and chief of bone marrow transplantation and cellular therapy at Stanford, said in the news release. “Understanding how it contributes to cancer risk is particularly important as the CAR-T cell field pivots from treating high-risk, refractory blood cancers to lower risk, but clinically important, disorders including autoimmune diseases.”