Sitero Summarizes Recent FDA Investigation into Risk of T-Cell Malignancy Following CAR T-cell Immunotherapy

By: Ryan Bartlett, Biosafety Officer

The Food and Drug Administration (FDA) is investigating the potential for patients to develop T-cell malignancy after receiving Chimeric Antigen Receptor (CAR) T-cell Immunotherapies. The FDA has received reports of T-cell malignancies, including CAR-positive lymphoma, in patients treated with BCMA- or CD19-directed autologous CAR T-cell immunotherapies.

These reports come from clinical trials and postmarketing adverse event data. The FDA states that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T-cell immunotherapies. Products in this class include Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta.

While the agency has not stopped the use of these therapies at this time, the agency is considering regulatory action based on this evaluation. Although the overall benefits of these products likely outweigh their potential risks, the FDA is investigating the risk of T-cell malignancy with serious outcomes. The reported serious outcomes have included hospitalization and death.

What are CAR T-cells?

CAR T-cells are a type of immunotherapy used in the treatment of certain cancers. These are a specialized form of a type of white blood cell (T-cell) that plays a crucial role in the immune system. The uniqueness of CAR T-cells lies in the addition of a synthetic receptor called a chimeric antigen receptor (CAR) on their surface.

Breaking down the terms:

Chimeric Antigen Receptor (CAR): This is a laboratory-engineered receptor designed to recognize specific proteins on the surface of cancer cells. It combines components from different sources, hence the term “chimeric.” The CAR is added to the T-cells to enhance their ability to target and destroy cancer cells.

T Cells: These are white blood cells that are a key part of the immune system. T-cells play a vital role in recognizing and attacking infected or abnormal cells, including cancer cells. They do this by identifying specific proteins, called antigens, on the surface of these cells.

CAR T-cell Therapy & Potential Malignancies

CAR T-cell therapy involves extracting a patient’s own T-cells, genetically modifying them (often using lentiviral or retroviral vectors) to express the CAR on their surface, and then infusing these modified T-cells back into the patient. The CAR enables the T-cells to recognize and bind to specific antigens present on the surface of cancer cells, destroying those cancer cells. This targeted approach has shown promising results, particularly in the treatment of certain blood cancers, such as leukemia and lymphoma.

Even though this can be a promising and effective treatment for certain cancers, CAR T-cell therapy has been associated with the risk of causing malignancies, particularly T-cell malignancies. This is why the initial FDA approval of these therapies required postmarketing 15-year-long follow-up observational safety studies.

Contributing Factors

The mechanism behind this risk is not entirely clear, but several factors may contribute:

  1. Insertional Mutagenesis: Genetically modifying T-cells for CAR T-cell therapy involves inserting a chimeric antigen receptor (CAR) gene into the T-cells using viral vectors (often lentiviral or retroviral vectors). In some cases, this process of gene insertion can lead to changes in the host cell’s DNA, a phenomenon known as insertional mutagenesis. If these genetic alterations occur in critical genes that regulate cell growth and division, it could lead to the development of malignancies.
  2. Proliferation and Survival Signals: The introduction of CARs into T-cells provides them with signals that promote their proliferation and survival. While this is crucial for the effectiveness of the therapy against cancer cells, it also carries the risk of uncontrolled growth of these modified T-cells, potentially leading to the development of malignancies.
  3. Immunosurveillance and Suppression: T-cells play a vital role in the body’s immune surveillance, identifying and eliminating abnormal or cancerous cells. However, in the context of CAR T-cell therapy, the modified T-cells may not be as effective in recognizing and eliminating their own abnormal or transformed counterparts, allowing for the potential development of malignancies.

Key Takeaways

As gene therapy products with integrating vectors pose a potential risk of developing secondary malignancies, this risk is labeled as a class warning in the U.S. prescribing information. CAR T-cell therapy is relatively new, and the long-term effects are still being studied. Postmarketing surveillance and long-term follow-up studies are essential to understand the potential risks associated with this treatment over time, including the development of secondary malignancies.

It is important to note that while the risk of T-cell malignancies is a concern, CAR T-cell therapy has shown significant success in treating certain cancers, often providing durable responses. The overall benefits of CAR T-cell therapy may still outweigh the risks for many patients with specific types of cancer. Ongoing research and monitoring will continue to refine our understanding of the safety profile of CAR T-cell therapies.

The FDA has recommended that patients and clinical trial participants receiving these therapies should be monitored lifelong for new malignancies. If a new malignancy occurs, contacting the manufacturer for reporting and obtaining instructions on collecting patient samples for testing is recommended. Any suspected adverse events, including T-cell malignancies, should be reported to the FDA.

Additional Resources

  • To report suspected adverse events, including T-cell malignancies, contact the FDA at 1-800-FDA-1088 or
  • Healthcare providers, clinical investigators, patients, and caregivers with questions can contact the FDA’s Center for Biologics Evaluation and Research (CBER) at