The PennZone

LOS ANGELES, June 12, 2024 ~ A team of investigators at City of Hope, funded by the Prostate Cancer Foundation (PCF), has made a groundbreaking discovery in the treatment of advanced prostate cancer. Their first-in-human phase 1 clinical trial, published today in Nature Medicine, shows that patients with advanced prostate cancer can be safely treated with chimeric antigen receptor (CAR) T cell therapy.

According to Howard R. Soule, PhD, Executive Vice President, Chief Science Officer and Lori and Michael Milken Chair of the Prostate Cancer Foundation, this is a significant advancement in the fight against metastatic castration-resistant prostate cancer (mCRPC), which claims over 30,000 lives each year. He stated that PCF is proud to have invested in this crucial work and looks forward to seeing further progress with PSCA-directed CAR T cell therapy.

The team at City of Hope, led by associate professor Saul Priceman, PhD, developed CAR T cells that target prostate stem cell antigen (PSCA), a protein highly expressed in prostate cancer. The phase 1 trial treated 14 patients with mCRPC using PSCA-directed CAR T-cell therapy. These patients had advanced prostate cancer that had spread beyond the prostate and was no longer responding to hormone treatment.

The CAR T cells were created by reprogramming the patients' own immune system T cells in a laboratory to recognize and attack the PSCA protein on the surface of cancer cells. The reprogrammed cells were then infused back into the patients and monitored for a 28-day study period.

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Priceman stated that their major finding was that PSCA-directed CAR T cells are safe and effective against mCRPC. This opens up new possibilities for developing cellular immunotherapy for these patients who currently have limited treatment options.

The goal of the phase 1 study was to assess the safety and dose-limiting toxicities of this approach and gather preliminary data on its efficacy. To test the safety of CAR T cells alone, patients received a single infusion of 100 million CAR T cells without prior lymphodepletion chemotherapy, which is commonly used in blood cancers to improve the effectiveness of CAR T cell treatment.

However, when lymphodepletion was incorporated at the same dose of CAR T cells, researchers found that some patients experienced cystitis, or inflammation of the bladder. This is likely due to the fact that PSCA is also found in the bladder and the CAR T cells may have attacked bladder cells. The team also noted that cyclophosphamide, a component of the lymphodepletion regimen, can also cause cystitis. When they reduced the dose of cyclophosphamide, this side effect was largely mitigated.

The results showed that four out of 14 patients had declines in their PSA levels, a biomarker for disease progression in prostate cancer. One patient had a significant decline and imaging showed therapeutic responses in some treated patients. One patient's PSA level decreased by 95% and their cancer that had spread to bones and soft tissue also declined for approximately eight months.

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Five out of 14 patients experienced mild or moderate cytokine release syndrome, a common and treatable side effect of CAR T cell therapy characterized by fever, nausea, fatigue, and other symptoms.

One limitation of this therapy's effectiveness is that CAR T cells did not persist at high levels beyond the 28-day monitoring period. This is a common challenge in solid tumor CAR T cell therapy and will be addressed in a phase 1B trial using PSCA-CAR T cell therapy with repeat dosing and in combination with radiation to enhance anti-tumor activity. The City of Hope trial is currently enrolling patients.

This groundbreaking work has been recognized by PCF with a 2022 PCF TACTICAL (Therapy ACceleration To Intercept Cancer Lethality) Award. This award supports large-scale, pioneering, multi-institutional team research projects addressing metastatic, lethal prostate cancer. The team, consisting of principal and co-investigators from the University of Pennsylvania, City of Hope, Children's Hospital of Philadelphia, the National Cancer Institute, the National Institute on Aging, the University of Southern California, and The Corporal Michael J. Crescenz VA Medical Center, has been awarded $10 million over three years to fund their project Developing Engineered Cell Therapies for Metastatic Castrate-Resistant Prostate Cancer to Increase Efficacy and Decrease Toxicity.

This groundbreaking research offers hope for patients with advanced prostate cancer and brings us one step closer to ending death and suffering from this disease. The City of Hope team will continue their work in developing effective treatments for mCRPC and improving the lives of those affected by this devastating disease.

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