Although the anti-CTLA-4 agent Yervoy (ipilimumab) opens the door to more anti-tumor T-cells entering a prostate-cancer tumor, the treatment produces little patient benefit, a clinical trial indicates.
Yerboy activates the immune system by going after the CTLA-4 protein receptor that slows immune-system activity. But prostate cancer responds to Yerboy by increasing the expression of two other immune checkpoint molecules, PD-L1 and VISTA. And both send a don’t-eat-me signal to immune cells. That reaction is why Yerboy, by itself, offers little patient benefit.
The study suggests that combining Yervoy with PD-1 and VISTA inhibitors could be a way to treat prostate cancer patients, however. The research, “VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer,” was published in Nature Medicine.
“This paper highlights the importance of studying immune response longitudinally,” lead author Padmanee Sharma, MD, PhD, said in a press release.
“Observing immune response at one point in time doesn’t reflect what’s going on because the immune system is so dynamic,” said Sharma, a professor of genitourinary medical oncology and immunology at the University of Texas MD Anderson Cancer Center. “So baseline sampling in prostate tumors shows minimal immune infiltrate. You can change that with ipilimumab, but what else changes becomes incredibly important.”
Prostate cancers have low numbers of T-cells, a kind of white blood cell that can recognize and kill cancer cells.
“We’ve known that prostate cancer is immunologically cold, or quiet, with very little penetration of the tumors or their surrounding microenvironment by immune cells,” Sharma said.
Yervoy blocks signals that prevent T-cells from recognizing cancer cells. Sharma and her team decided to see if Yervoy could increase the number of T-cells in tumors before patients had surgery. Their Phase 1 clinical trial (NCT02113657) included 16 patients with locally advanced prostate cancer.
“Our study explored whether we could increase immune cell infiltration by combining the anti-hormonal drug Lupron with two rounds of the checkpoint inhibitor ipilimumab before surgery in patients with locally advanced prostate cancer,” Sharma said.
Analysis of the surgically removed tumors revealed that Yervoy increased the numbers of T-cells in tumors, as well as another kind of immune cell, macrophages. But researchers also discovered that the tumor cell tissue had two proteins on their surfaces, PD-L1 and VISTA, that were not there before treatment.
The proteins are called immune checkpoints because they can stop the chain of events that lead to an immune reaction. Basically they signal the shutdown of T-cells in the tumor environment.
“Understanding these changes using post-treatment or on-treatment biopsies is important to develop rational combination strategies for these immune-modulating drugs,” Sharma said. “The presurgical clinical trials, also called window of opportunity trials, allow researchers to learn a lot from a small number of patients to guide the design of larger trials.”
The findings suggest that Yervoy could work in synergy with molecules that block the PD-1 and VISTA immune checkpoints. While it brings T-cells toward the tumors, the other drugs could remove the brakes that prevent immune cells from attacking the tumors.
Sharma is now planning a clinical trial testing a combination of Yervoy and the anti-PD-1 Opdivo (nivolumab) in 90 prostate cancer patients. It will take place at nine U.S. cancer centers.