Low risk of secondary cancers post CAR-T cell therapy, study finds

A recent study conducted by Stanford Medicine researchers has found that the risk of developing secondary blood cancers following CAR-T cell therapy is relatively low. This finding comes in the wake of an FDA warning issued in November 2023, which highlighted potential risks associated with the therapy, particularly concerning secondary cancers. The study, involving over 700 patients treated at Stanford Health Care, suggests that the incidence of secondary blood cancers is around 6.5% within three years post-therapy.

CAR-T cell therapy emerged in 2017 as a revolutionary treatment for resistant blood cancers. The treatment involves extracting T cells from a patient, genetically engineering them to better target and destroy cancer cells, and then reintroducing them into the patient's body. The FDA's warning had raised concerns, following reports of patients developing T cell cancers unrelated to their original diagnosis.

In the comprehensive study led by Professors Ash Alizadeh and David Miklos, the researchers found that the solitary case of fatal secondary T-cell lymphoma was likely due to immunosuppression induced by the therapy, rather than the therapy itself. This immunosuppression allowed pre-existing, undetected cancer cells to proliferate uncontrollably. Alizadeh explained that the team's deep dive into this case — analyzing protein levels, RNA sequences, and DNA across various tissues and time points — demonstrated that CAR-T cells did not introduce the lymphoma. Instead, it had been present at minimal levels before therapy.

The study's findings might provide some relief in light of the FDA's "black box" warning, known for highlighting severe side effects on medication labels. More importantly, the results could help medical professionals identify patients who are at higher risk of secondary cancers before they receive CAR-T cell therapy. These patients, although unlikely to avoid the treatment due to its potential for saving lives, could be monitored more closely or screened more rigorously before treatment begins.

The senior authors of the study, Alizadeh and Miklos, collaborated with postdoctoral scholars Mark Hamilton, Takeshi Sugio, and Troy Noordenbos. Their extensive research is set to be published in The New England Journal of Medicine on June 13. The study's findings indicate that secondary cancers related to CAR-T cell therapy are likely due to the underlying immunosuppression or its side effects, rather than the genetic engineering process itself.

The researchers conducted molecular, cellular, and genetic analyses of the 724 patients treated with CAR-T cell therapy between 2016 and 2024. They found that the incidence of secondary blood cancers within three years was comparable to that of patients who underwent stem cell transplantation. The study identified one patient who quickly developed and succumbed to T cell lymphoma post-therapy. However, genetic profiling techniques revealed that the T cells causing the secondary cancer were not the same as the engineered CAR-T cells.

The study suggests that focusing on immune suppression, which can precede and follow CAR-T cell therapy, might be crucial for understanding the associated cancer risks. As the field of CAR-T cell therapy expands to treat not just high-risk blood cancers but also other significant disorders like autoimmune diseases, understanding these risks becomes increasingly important.

In conclusion, while CAR-T cell therapy presents a low risk of secondary cancers, the challenge remains in predicting which patients are at higher risk and understanding the reasons behind it. This study provides a framework for evaluating the outcomes of CAR-T therapies, aiming to clarify their risks and benefits, and ultimately improve patient monitoring and care.