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Study provides path for new immunotherapy approaches to prostate cancer

The University of Texas MD Anderson Cancer Center Apr 01, 2017

Results underpin clinical trial of anti–CTLA4 and anti–PD1 combination; expose VISTA role.
Prostate cancer, notoriously resistant to immunotherapy due to its immunologically cool nature, triggers two pathways to chill an immune attack after one immunotherapy drug fires up the immune system, researchers at The University of Texas MD Anderson Cancer Center report in the journal Nature Medicine.

Based on their findings, the researchers launched a clinical trial for stage IV prostate cancer in March combining two drugs that target separate brakes on the immune system. The checkpoint inhibitors largely failed individually against the disease. Their results also implicate for the first time on a human tumor a third brake called VISTA in potentially inhibiting immune response.

Immune checkpoint inhibitors treat T cells, white blood cells that are the immune system’s targeted weapons, freeing them to attack tumors by blocking proteins on the T cells’ surface that shut them down. Ipilimumab blocks CTLA4 on T cells, the first known immune checkpoint, unleashing them to attack. “Untreated prostate cancer is largely a desert for T cells,” said co–author Jim Allison, PhD, chair of Immunology.

Immune analysis of the surgically removed tumors showed high levels of penetration of the tumors by activated T cells. “But we didn’t see any complete responses among 16 prostate cancer patients, so we suspected other immune–inhibiting mechanisms had come into play,” Sharma said.

Genomic and immune analysis of the tumors found increased levels of immune–suppressing PD–L1 and VISTA. T cells and other immune cells found in the tumors also had both proteins elevated.

PD–L1 connects with the immune checkpoint PD1 on T cells, activating PD1 to shut down the T cell. A number of drugs blocking PD1 are approved for advanced melanoma, Hodgkin lymphoma, lung, kidney, bladder and head and neck cancers. PD1 inhibitors don’t work where there is no pre–existing T cell penetration of tumors.

“We concluded that driving T cells into the tumors would be step one, but then the next step would be to block PD–L1 and VISTA,” Sharma said.

These results underpin the immunotherapy combination clinical trial: ipilimumab to bring T cells into the tumor, and the PD1 inhibitor nivolumab to defeat the PD–L1/PD1 response that follows. The trial, led by Sharma, will enroll 90 patients at nine centers nationally.
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