CAR-T therapy successfully targets advanced prostate cancer

CAR-T therapy

A team of investigators at City of Hope in the US funded by the Prostate Cancer Foundation (PCF) reports that patients with advanced prostate cancer can be safely treated with chimeric antigen receptor (CAR)-T cell therapy.

The results of their first-in-human Phase I clinical trial, which also showed promising therapeutic activity, were published in Nature Medicine.

Saul Priceman, City of Hope Associate Professor, Department of Hematology & Hematopoietic Cell Transplantation, and team developed CAR-T cells that target prostate stem cell antigen (PSCA), which is highly expressed in prostate cancer.

The Phase I trial treated 14 PSCA-positive patients with mCRPC, which had spread beyond the prostate and no longer responded to hormone treatment, using the PSCA-directed CAR T-cell therapy.

Patients’ own immune system T cells were reprogrammed in a laboratory with a CAR to recognise and attack the PSCA protein on the surface of cancer cells. The CAR-T cells were then infused back into the patients who were monitored for a 28-day study period.

Four of the 14 patients had declines in their PSA levels, which is a biomarker of disease progression in prostate cancer, including one patient with significant decline. Furthermore, imaging showed therapeutic responses in some of the treated patients.

One patient’s PSA level decreased by 95% and the cancer that had spread to his bones and soft tissue also declined. He experienced this positive response for approximately eight months.

“Our trial’s major finding is that PSCA-directed CAR-T cells are safe and do work against mCRPC,” said Priceman. “This opens up the opportunity to continue to develop this type of cellular immunotherapy for these patients, who currently have no other effective treatment options.”

Side-effects of the CAR-T therapy

The goal of the Phase I study was to examine the therapy’s safety and dose-limiting toxicities and gather preliminary data on efficacy of the approach.

To assess the safety of CAR-T cells alone, patients received a single infusion of 100 million CAR-T cells without having prior lymphodepletion chemotherapy. This was followed by incorporation of lymphodepletion at the same CAR-T cell dose.

Researchers found that with lymphodepletion, there was a side effect of cystitis, or irritation of the bladder. Since PSCA is also found in the bladder, it is likely the CAR-T cells attacked the bladder cells, causing inflammation, they concluded.

Historically, cyclophosphamide, which is part of the lymphodepletion regimen, can also cause cystitis. When the team reduced the dose of cyclophosphamide, the toxicity was largely mitigated in patients.

Five of the 14 patients had mild or moderate cytokine release syndrome.

One limiting factor of the therapy’s effectiveness is that CAR-T cells did not persist in patients at high levels beyond the 28-day monitoring period. This is a common challenge in solid tumour CAR-T cell therapy that the researchers hope to address in a Phase Ib trial using the PSCA-CAR T cell therapy in a repeat dosing strategy and in combination with radiation to enhance anti-tumour activity.

“This represents an important advance against metastatic castration-resistant prostate cancer (mCRPC) which continues to claim more than 30,000 men’s lives each year,” said Howard Soule, Executive Vice President, Chief Science Officer and Lori and Michael Milken Chair of the Prostate Cancer Foundation. “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.”

Diana Spencer, Senior Digital Content Editor, DDW

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