CAR-T immunotherapy is showing promise as a potential treatment for prostate cancer, offering new hope for a disease that has largely resisted other forms of immunotherapy. Our immune system is designed to protect us from pathogens, keeping us healthy and preventing diseases. Immunotherapies take advantage of this system by training the immune cells to detect and destroy cancer cells. Immunotherapy has been highly effective in treating cancers such as melanoma, lung cancer, bladder cancer, kidney cancer, and various blood cancers. However, when it comes to prostate cancer, only one form of immunotherapy, a cancer vaccine, is currently approved.

A New Approach: CAR-T Therapy for Prostate Cancer

Researchers at City of Hope Hospital in Duarte, California, are now exploring a new approach with CAR-T cell therapy (chimeric antigen receptor T-cell therapy). This therapy involves taking immune cells, called T cells, from a patient’s own body and engineering them to fight the cancer. The T cells are modified by adding proteins known as chimeric antigen receptors (CARs). These CARs are designed to bind to specific proteins (antigens) found on cancer cells. Once the engineered cells are reintroduced into the patient’s body, they locate and destroy cancer cells expressing the target antigen.

Currently, CAR-T cell therapies have been approved for treating certain types of blood cancers. They have shown to be highly effective but also come with significant side effects, including cytokine release syndrome, an inflammatory response that can become widespread and severe.

Targeting Prostate Cancer with CAR-T Therapy

The research team focused on a protein called prostate stem cell antigen (PSCA). PSCA is highly expressed in prostate tumors, especially in advanced stages of the disease, and even more so when the cancer has spread to the bones. By engineering the CAR-T cells to bind specifically to PSCA, they aimed to target and kill prostate cancer cells that were no longer responding to other treatments.

The study involved 14 patients, all diagnosed with metastatic prostate cancer that was no longer responding to hormonal therapy. Each patient was treated with 100 million CAR-T cells, with some patients also receiving an additional treatment known as lymphodepletion, which helps to prevent the patient’s remaining T cells from interfering with the CAR-T cells’ attack on cancer cells. Lymphodepletion, however, can increase the risk of infection by weakening the immune system.

Results of the Study

The early clinical trial results are promising:

1. Prostate-Specific Antigen (PSA) Decline: In four patients, PSA levels — which are commonly used to track prostate cancer progression — dropped by 30% or more. One patient experienced an impressive PSA decline of more than 90% during the 28-day monitoring period. This patient also showed signs of shrinking tumors in both the bones and soft tissues, with the positive effects lasting for about eight months.
2. Cytokine Release Syndrome (CRS): Five patients experienced mild cases of CRS, a side effect where the immune system releases too many cytokines too quickly, causing inflammation. However, these cases were treated effectively.
3. Cystitis: Two patients experienced cystitis, which is inflammation of the bladder.

While the responses were encouraging, one of the challenges the researchers encountered was that the CAR-T cells did not persist at high levels beyond the 28-day monitoring period. This could potentially limit the long-term effectiveness of the treatment. The research team plans to investigate ways to extend the lifespan of CAR-T cells in future studies to increase the duration of their anti-cancer effects.

Overcoming Prostate Cancer’s Immunological Defenses

Prostate cancer is known to be immunologically “cold,” meaning it is particularly adept at hiding from the body’s immune system. This has been a significant hurdle for most immunotherapies targeting prostate cancer, which have generally shown limited success. However, CAR-T therapy offers a more potent and focused method to break through these tumor defenses, according to Dr. Tanya Dorff, a medical oncologist at City of Hope and the first author of the study.

Dr. Dorff believes that by specifically targeting PSCA, CAR-T therapy could represent a major breakthrough in prostate cancer treatment, particularly for advanced cases that are resistant to standard therapies like hormonal therapy and chemotherapy.

Expert Perspectives and Future Directions

Although the early results of this study are encouraging, experts caution that CAR-T cell therapy for prostate cancer is still in its early stages and comes with significant risks. Dr. David Einstein, a medical oncologist at Beth Israel Deaconess Medical Center and an assistant professor at Harvard Medical School, highlights the risks of lymphodepletion, which can make patients more vulnerable to infections. Additionally, the risk of cytokine release syndrome can complicate treatment. According to Dr. Einstein, CAR-T cell therapy may only be suitable for a select group of patients, given the intensity of the treatment and the potential for serious side effects.

“This is a different and more intensive treatment experience than hormonal therapy and even chemotherapy,” Dr. Einstein says. Nonetheless, he notes that the results of this early study suggest that CAR-T therapy may offer a promising new option for men with advanced prostate cancer.

Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor-in-chief of the Harvard Medical School Guide to Prostate Diseases, also sees the potential in CAR-T therapy. He describes it as the start of a completely new way of attacking prostate cancer cells that have spread beyond the prostate gland. Unlike traditional methods like hormonal therapy, chemotherapy, and radiation therapy, CAR-T therapy uses a novel approach to eliminating cancer cells. However, Dr. Garnick emphasizes the need for more research to fully understand how this new technology works and to find ways to minimize its side effects.

According to Dr. Garnick, “Because the CAR-T program uses a novel and exciting way of eliminating cancer cells, more work will be needed to help understand both the mechanism by which this occurs and, as Dr. Einstein emphasizes, methods to lessen the side effects associated with this new technology.”

Conclusion

CAR-T immunotherapy for prostate cancer is an exciting and innovative approach that has shown early promise, particularly for patients with advanced disease that no longer responds to traditional treatments like hormonal therapy. The targeting of PSCA by CAR-T cells has led to significant declines in PSA levels and tumor shrinkage in some patients, although the persistence of the engineered cells remains a challenge.

As research continues, the hope is that CAR-T therapy can be refined to improve its effectiveness and manage its side effects. While it is still early days for this treatment in prostate cancer, the results thus far suggest that CAR-T could emerge as an additional immunotherapeutic option for men with prostate cancer, particularly those with few remaining options.