Foundation-Funded Research Shows Promising Results Against Lethal Prostate Cancer

In a groundbreaking development, City of Hope researchers, funded by the Prostate Cancer Foundation (PCF), have successfully demonstrated that chimeric antigen receptor (CAR) T cell therapy is a safe and potentially effective treatment for advanced prostate cancer. The findings of their first-in-human phase 1 clinical trial were published in Nature Medicine. This trial marks a significant step forward in combating metastatic castration-resistant prostate cancer (mCRPC), which claims the lives of over 30,000 men annually.

Dr. Howard R. Soule, PCF's Executive Vice President and Chief Science Officer, emphasized the importance of this advancement. "PCF is proud to invest in this crucial work which advances our mission to end death and suffering from prostate cancer, and we look forward to seeing their future progress with PSCA-directed CAR T cell therapy," said Soule.

The research team, led by Dr. Saul Priceman, developed CAR T cells targeting prostate stem cell antigen (PSCA), a protein highly expressed in prostate cancer. The phase 1 trial involved 14 patients with PSCA-positive mCRPC, whose cancer had spread beyond the prostate and was unresponsive to hormone treatments. The patients' immune system T cells were engineered in the lab to recognize and attack PSCA-expressing cancer cells. These modified CAR T cells were then infused back into the patients, who were monitored over a 28-day period.

"Our trial's major finding is that PSCA-directed CAR T cells are safe and effective against mCRPC," said Dr. Priceman. This discovery opens new doors for developing cellular immunotherapy for patients with limited treatment options.

The primary objective of the phase 1 study was to evaluate the safety of the therapy and identify dose-limiting toxicities while also gathering initial data on its efficacy. To test the therapy's safety, patients received a single infusion of 100 million CAR T cells without prior lymphodepletion chemotherapy, which is typically used in blood cancers to enhance CAR T cell treatment efficacy. Subsequently, lymphodepletion was incorporated at the same CAR T cell dose. Researchers observed that lymphodepletion caused cystitis, or bladder irritation, likely because PSCA is also present in bladder cells. The toxic effect was mitigated by reducing the dose of cyclophosphamide, a component of the lymphodepletion regimen known to cause cystitis.

Four of the 14 patients experienced a decline in PSA levels, a biomarker for prostate cancer progression, with one patient showing a significant reduction. Imaging also revealed therapeutic responses in some patients. One patient saw a 95% decrease in PSA levels and a reduction in cancer spread to bones and soft tissue, maintaining this positive response for about eight months.

Five patients experienced mild to moderate cytokine release syndrome, a common and manageable side effect of CAR T cell therapy characterized by fever, nausea, and fatigue. A notable limitation observed was that the CAR T cells did not persist at high levels beyond the 28-day monitoring period, a common challenge in solid tumor CAR T cell therapy. To address this, researchers plan a phase 1B trial using a repeat dosing strategy and combining the therapy with radiation to boost anti-tumor activity. This trial is currently enrolling patients.

This study was further supported by a 2022 PCF TACTICAL Award, aimed at accelerating large-scale, pioneering research projects targeting metastatic, lethal prostate cancer. The collaborative effort includes investigators from the University of Pennsylvania, City of Hope, Children's Hospital of Philadelphia, the National Cancer Institute, and other esteemed institutions. The team received $10 million over three years to develop engineered cell therapies for metastatic castrate-resistant prostate cancer, aiming to increase efficacy while reducing toxicity.