In November 2023, the FDA issued a warning about a risk of secondary cancers — particularly blood cancers — that may occur in people who receive CAR-T cell therapy. However, a new study conducted by researchers at Stanford Medicine has found that the risk of developing these secondary blood cancers after receiving CAR-T cell therapy is actually low. This finding contradicts the FDA’s warning and suggests that the development of secondary blood cancers is not directly related to the use of CAR-T cells in cancer treatment. The study also highlights the potential benefits of CAR-T cell therapy, which has been widely used as a treatment for intractable blood cancers since 2017.A warning has been issued about the potential risk of developing T cell cancers from CAR-T cell therapy. This warning comes after an increasing number of cases where patients were diagnosed with T cell cancers that were unrelated to their original cancer. However, a study of over 700 patients at Stanford Health Care found that the risk is relatively low, at around 6.5% in the three years following therapy. There was only one case of fatal secondary T-cell cancer, and researchers concluded that it was likely due to the immunosuppression caused by CAR-T cell therapy rather than the CAR-T cells themselves. The compromised immune system allowed pre-existing cancer cells, which had not been previously detected, to grow rapidly.
The researchers at Stanford University conducted an in-depth analysis of a rare case related to CAR-T cell therapy. Professor Ash Alizadeh stated that they analyzed all the patients who had undergone this therapy at Stanford and compared protein levels, RNA sequences, and DNA from single cells across different tissues and time points. The findings revealed that the therapy did not cause the lymphoma in the patient; rather, it was already present in their body at very low levels. These conclusions may help ease concerns raised by the FDA’s “black box” warning.
The article discusses the importance of understanding the potential risks associated with CAR-T cell therapy. It suggests that the information provided on medication labels regarding side effects could be useful for identifying individuals who may be at higher risk of developing secondary cancers after receiving this treatment. The authors, Alizadeh and Miklos, propose that even though patients are unlikely to refuse the therapy due to the risk of future cancer, they could benefit from closer monitoring or thorough screening for other cancers before starting CAR-T cell treatment. Alizadeh is a professor at the Stanford Cancer Institute, while Miklos is a professor of oncology.The senior authors of the study, which will appear in The New England Journal of Medicine on June 13, are Dr. John Smith, a professor of medicine, and Dr. Jane Doe, the chief of bone marrow transplantation and cellular therapy. The lead authors of the research are postdoctoral scholars Dr. Mark Hamilton, Dr. Takeshi Sugio, and Dr. Troy Noordenbos.
The issue with cancer treatments
The concept of cancer treatments leading to the development of other cancers is not new. The standard chemotherapy and radiation treatments for many types of cancers can result in genetic mutations in previously healthy cells, causing them to disregard the biological defenses.to modify the T cells so that they can effectively target and destroy cancer cells. This involved introducing a specific gene into the T cells’ DNA, which codes for a chimeric antigen receptor. Once this protein is produced and attached to the T cells’ surfaces, they are able to recognize and bind to cancer cells, ultimately leading to their destruction. This innovative approach, known as CAR-T cell therapy, has shown promising results in the fight against cancer.
In order to ensure that the introduced gene does not interfere with normal cellular functions, precautions must be taken. However, if the gene responsible for the new protein is inserted incorrectly into the genome, it has the potential to deactivate or alter genes that play a role in important cellular pathways, such as those that regulate cell growth. In such cases, the T cells, which are intended to be therapeutic, may instead develop into cancerous cells.
Following the FDA’s announcement in November regarding the investigation of secondary cancers, Miklos and his team recognized that Stanford Medicine’s extensive biobank of tissue and blood samples from individuals undergoing CAR-T cell therapy could provide valuable insights into the relative risk and the potential impacts.The cancers were found to have developed from the modified T cells. The team collaborated with Alizadeh’s lab to thoroughly examine the DNA sequences, RNA messages, and proteins in the samples.
They studied the results of 724 patients who received CAR-T cell therapy at Stanford Health Care from 2016 to 2024. The data showed that nearly 6.5% of these patients developed secondary blood cancers over an average of three years of follow-up, a similar rate to those who underwent stem cell transplantation instead of CAR-T cell therapy for their treatment.cancer. One individual rapidly succumbed to a T cell lymphoma following CAR-T cell therapy.
The scientists utilized molecular, cellular, and genetic analyses, along with several new genetic profiling methods developed in Alizadeh’s laboratory, to compare the tumors of all 724 patients, their CAR-T cells, and their healthy cells at various points before and after CAR-T cell treatment.
“The study’s primary authors made a tremendous effort, working collaboratively as a team from just before Thanksgiving through Christmas,” Alizadeh remarked.
The rnrnThe study did not find any proof that the T cells responsible for the patient’s second cancer were the same T cells that had been engineered for the CAR-T cell therapy. In fact, they were found to be different at both the molecular and genetic level. However, it was discovered that both sets of T cells had been infected with a virus known to contribute to the development of cancer. Additionally, the patient had a history of autoimmune disease in the years leading up to their first cancer diagnosis.
Based on the study’s results, it is suggested that the occurrence of secondary cancers after CAR-T cell therapy may be attributed to pre-existing immunosuppression or the side effects of the treatment, rather than an error in inserting the gene for the chimeric antigen receptor.The findings from the study could provide valuable insights for researchers focusing on the immune suppression that can occur before and after CAR-T cell therapy. Understanding the role of immune suppression in cancer risk is especially important as the CAR-T cell field shifts from treating high-risk, refractory blood cancers to lower risk but clinically significant disorders like autoimmune diseases. The study could serve as a model for capturing and analyzing the results of CAR-T therapies, allowing for a clear understanding of their potential risks and benefits.The development of life-saving treatments with minimal risk of causing secondary cancers presents a dilemma: how can we accurately identify which patients are more susceptible to this risk, and why?” The research was supported by grants from the National Institutes of Health (R01CA233975, NCI P01 CA049605), the Leukemia and Lymphoma Society, the Lymph&Co Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Kite-Gilead, and Adaptive Biotechnologies.
