Study uncovers key insights into rare secondary cancers from CAR-T therapy

A recent comprehensive study has shed light on a rare but significant case of a secondary cancer in a patient who had undergone CAR-T therapy for an initial cancer. This analysis offers valuable insights that could guide oncologists and pathologists in understanding the clinical presentation and pathological characteristics of CAR-T related secondary cancers.

The findings were published on June 13, 2024, in the New England Journal of Medicine. CAR-T therapy, a promising new treatment for blood cancers, involves re-engineering a patient’s T cells in a laboratory to produce chimeric antigen receptors (CARs) on their surface. These CARs can identify and bind to specific proteins on cancer cells, making this therapy particularly effective for treating blood cancers like multiple myeloma.

According to Dr. Metin Ozdemirli, professor of pathology at Georgetown University School of Medicine and the study's first author, CAR-T therapy has demonstrated substantial benefits for cancer patients. However, this case study highlights a rare event where a patient developed a secondary cancer after receiving CAR-T therapy. Dr. Ozdemirli emphasized that the insights gained from this study could help physicians detect and manage similar conditions more effectively.

Despite the estimated 30,000 patients who have undergone CAR-T therapy, second cancers are infrequent, with the U.S. FDA tracking around 25 cases. These secondary cancers are typically lymphomas, as was the case with the patient discussed in this study.

The exact mechanism through which CAR-T cells become lymphomas remains unclear. Possible explanations include the presence of lymphoma-causing mutations in the cells when initially collected, mutations occurring during the preparation of CAR-T cells outside the patient’s body, or the acquisition of mutations after re-infusion into the patient. It could also be a combination of these factors.

Four months post-CAR-T therapy, the patient experienced progressively worsening non-bloody diarrhea and significant weight loss. Blood tests led to an endoscopic examination, revealing ulcerations in the duodenum. Despite treatment, the symptoms persisted, resembling an autoimmune disorder. Further tests and biopsies ultimately identified the issue as indolent T-cell lymphoma of the gastrointestinal tract, with molecular analysis confirming it as a CAR-T positive case.

Dr. Ozdemirli suggests that physicians should consider CAR-T therapy a potential source of new cancers and autoimmune issues. Early detection becomes more feasible when physicians know what to look for. He also noted the unexpected finding that a type of helper T cell, crucial for fighting infections, had survived the initial treatment and became cancerous. This highlights the heterogeneity of immune cells collected for CAR-T therapy, which are not a single-cell type but a mixture of various cells.

Though secondary cancers are uncommon following chemotherapy or radiation therapy, they can occur. Similar to any tissue in the body, CAR-T cells can also develop cancer over a lifespan. However, there is no current evidence suggesting that the preparation of CAR-T cells outside the body increases this risk.

For future diagnostic and treatment purposes, the researchers highlighted the potential of switchable cell therapies. These therapies could enable patients to adjust CAR-T cell activity with medication, potentially minimizing toxic side effects. Advancing research and understanding in this area is a crucial next step for the investigators.