Physicians Take on CAR-T Therapy Secondary Cancer Risks

Myeloma patients all around the world seek different ways to control their disease into a complete response, including immunotherapy clinical trials. However, clinical trials and newly developed pharmaceuticals are not without risk. 

On November 28th, 2023, the Food and Drug Administration (FDA) released a statement claiming previously FDA-approved CAR-T immunotherapies are associated with secondary cancer development. 

What does this mean for patients who have received CAR-T immunotherapy? Should CAR-T therapies be removed from the hematological cancer treatment list? 

Let’s examine how CAR-T immunotherapy works, FDA findings on the subject, and what clinic physicians say about this potential risk of secondary cancers. 

Understanding CAR-T Immunotherapy 

Since 2017, six CAR-T pharmacologic therapies have been approved by the FDA for the treatment of blood cancers: Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta. 

The two CAR T-cell products specifically approved for multiple myeloma treatment are Abecma and CARVYKTI, though many on the horizon are currently in clinical trials. 

CAR-T therapy is an individualized treatment; the patient’s T-cells are collected and sent to a laboratory to be re-engineered, where a gene is inserted to create surface proteins known as chimeric antigen receptors (CARs). These surface proteins are trained to target and attack specific proteins on cancer cells. 

In the case of Abecma and CARVYKTI, both products are “trained” to look for BCMA on the surface of multiple myeloma cells. 

After being replicated thousands of times, the patient’s re-engineered T-cells are infused back into the patient; the newly created receptors on the T-cells enable them to bind to and kill cancer cells. 

While revolutionary, what implications for secondary cancers have arisen for CAR-T immunotherapy? 

Understanding the FDA Findings 

As a participatory patient of CAR-T therapy, it would be understandable to ask why the FDA would approve CAR-T therapies that can cause secondary cancers. 

To understand this question, let’s delve into the recent discoveries and statements made by the FDA on this subject. 

Statements made by professors and physicians make it clear that it is more likely that myeloma patients are to die from myeloma versus the secondary cancers posed by CAR-T therapy. 

These statements are not made lightly; the number of secondary cancer cases associated with CAR-T therapy is low: “Per media reports, the FDA is aware of 20 cases of T-cell malignancies in CAR-T recipients of an estimated denominator exceeding 30,000 patients.” 

What Are Physicians Advising? 

Although it is terrifying to think that a pharmacological agent, like CAR-T therapy, may cause secondary cancers, it is essential to note that all pharmacological agents have risks of side effects.  

There are also other important points to consider on this subject: the benefits of CAR-T therapy, the reality of other factors contributing to secondary cancers, and the fact that active cancer remains a greater threat to the patient’s life than the possibility of a secondary malignancy. 

The benefits of CAR-T therapy outweigh the risk of secondary primary malignancies (SPMs). Many randomized studies utilizing CAR-T therapy have evidenced improved progression-free survival/overall survival. Additionally, CAR-T therapy is a “one-and-done” infusion associated with rapid and durable remissions, outperforming standard therapies. 

Other factors could contribute to secondary cancers. Other treatments associated with large B-cell lymphoma (LBCL), myeloma, and other lymphoid malignancies have been associated with secondary cancers (pretransplant conditioning, bendamustine, and lenalidomide). 

It has also been identified that individuals with lymphoid malignancies have developed secondary T-cell malignancies prior to the development of CAR-T therapies. Therefore, secondary cancers have several factors contributing to their development, versus CAR-T therapy being the sole contributor. 

An important point to consider is that patients can only develop secondary cancers if they do not first die of their primary cancers. Patients who receive effective cancer therapies will have higher rates of secondary cancers than patients who do not. In other words, a person who survives their primary malignancy via malignancy treatment may have a higher chance of developing secondary cancers due to increased longevity.

Lastly, the active/primary malignancy remains the main threat to an affected patient’s life. A patient with myeloma who develops secondary cancer from CAR-T therapy is more likely to die of their underlying myeloma than they are from the secondary cancer. In fact, some of the associated secondary cancers have excellent prognoses. 

Therefore, seeking treatments like that of CAR-T therapy to treat the underlying myeloma is more critical than dreading a hypothetical secondary cancer. 

Conclusion 

Hearing about a newly developed and promising pharmaceutical possibly being related to secondary cancers can be heartbreaking and nerve-wracking! However, learning about the whole picture is paramount before jumping to conclusions. 

We know that CAR-T therapy utilizes the patient’s T-cells to attack cancer cells, the FDA released a statement that the previously approved CAR-T therapies may be causing secondary cancers, and physicians still see benefit in CAR-T therapy implementation. 

It is still undetermined precisely what leads to secondary cancers, so more research and follow-up need to be conducted to determine the risks associated with CAR-T immunotherapy. If you are a myeloma patient who has received CAR-T therapy or are interested in receiving CAR-T therapy and have questions, schedule an appointment with your oncologist or utilize HealthTree resources for more information. 

References 

Banerjee, R., Poh, C., Hirayama, A.V., Gauthier, J., Cassaday, R.D., Shadman, M., Cowan, A.J., Till, B.G., Green, D.J., Kiem, H.P., Gopal, A.K., & Maloney, D.G. (2024, February 15). Answering the “doctor, can CAR-T therapy cause cancer?” question in clinic. Blood Advances. 

Burton-Bethke, A. (2022, December 08). ASH 2023: The risk of secondary cancers with CAR-T therapy. HealthTree. 

Food & Drug Administration. (2023, November 28). FDA investigating serious risk of T-cell malignancy following BCMA-Directed or CD19-Directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. 

National Cancer Institute. (2022, March 10). CAR T cells: Engineering patients’ immune cells to treat their cancers.