New Checkpoint Inhibitor Approach Proposed in Prostate Cancer

Padmanee Sharma, MD, PhD

Although the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) have led to significant breakthroughs in several solid tumors, they have thus far shown minimal clinical benefit in prostate cancers.

Hoping to discover a path forward for checkpoint inhibition in prostate cancer, Padmanee Sharma, MD, PhD, and her fellow researchers at The University of Texas MD Anderson Cancer Center, examined untreated and ipilimumab-treated tumors prostate tumors.

Sharma et al discovered that ipilimumab had led to high levels of active T cells infiltrating the tumors; however, the CTLA-4 inhibitor also increased PD-L1 and VISTA, a third inhibitory immune checkpoint. Based on these findings, the researchers have proposed a combination approach that would target multiple immune-checkpoint pathways.

“We're going to need combination therapy, perhaps an anti-CTLA-4 to drive the T cell infiltration and then an anti—PD-1, anti–PD-L1 or anti-VISTA, we don't know if you'll need all 3 to get through tumor rejection in prostate cancers,” Sharma explains.

OncLive: Please provide an overview of the study and your findings.

In an interview with OncLive, Sharma, a professor of genitourinary medical oncology and immunology at The University of Texas MD Anderson Cancer Center, discussed the significance of the VISTA immune-checkpoint pathway in prostate cancer, and her proposed novel immunotherapy approach for patients with these tumors.Sharma: The current immunotherapy approaches, such as blocking CTLA-4 or PD-1/PD-L1 pathways, have shown promise and we’re seeing FDA approval in multiple tumor types, including melanoma, bladder cancer, and lung cancer. The issue we were facing was they weren't working as well as monotherapies for prostate cancer.

There was a phase III clinical trial with anti—CTLA-4 that did not show statistical significance for prostate cancer. With anti–PD-1, there seemed to be sporadic responses, but nothing seems to reach the level of what we’ve seen in other tumor types.

When we did this study, we wanted to determine what type of immune response we are generating with the anti—CTLA-4 antibody ipilimumab (Yervoy) and if there is a resistance or other mechanism that prevents an antitumor response.

We know that the immune system is a yin-yang. If you push the immune system in 1 direction, it turns on inhibitory pathways, which naturally drives the immune response. The immune response will turn on and do its job for a period of time, but then has its own intrinsic pathways to turn it off. We were trying to understand what some of those potential pathways are that might be at play when we give anti—CTLA-4 to patients with prostate cancer.

We identified that when we gave the anti—CTLA-4 therapy, the tumor microenvironment showed upregulation of multiple inhibitory pathways. PD-1 and PD-L1 expression increased on T cells and PD-L1 also increased on macrophages in tumor cells. But also, another pathway known as VISTA was increased. That is a much newer pathway and one that has not been studied as extensively.

Can you expand further on the impact of these results?

How would checkpoint inhibitors be incorporated within the current sequence of prostate cancer treatments?

What challenges are there in terms of finding biomarkers for these agents?

Do you envision immunotherapy playing a larger role in this field in the next 5 to 10 years?

Are there any other advancements in this field that you are particularly excited about?

This tells us that prostate cancer doesn't have the same immune infiltrates as melanoma, bladder cancer, or lung cancer. For the field of prostate cancer, it tells us that potential immunotherapy strategies exist and can be beneficial to the patient, but we just have to learn what those mechanisms are in order to figure out ways to combine regimens. Most patients go through multiple different therapies, allowing prostate cancer patients to have multiple agents to choose from. Bringing an immunotherapy approach with an immune checkpoint agent would be important, but I don't think it's going to be a monotherapy approach that way. I think it will be a combination therapy approach. We learned a lesson of biomarkers from the genomic medicine field. If you have a particular mutation in the tumor cell, then you can target that particular mutation. However, the immune response is so dynamic and always evolving. This makes the immune response more complicated, because it is specific for an individual. If I took a biopsy today, tomorrow it could be different. I can't base my decisions on a single time point, which is the importance of getting these longitudinal biopsies and watching over time what happens in our patients when we give 1 agent and then attempt to decide the most beneficial combination strategy.Absolutely, I think that immunotherapy in prostate cancer is going to be evolving so that it plays a bigger role. We’re going to get better strategies with immunotherapy combinations so we can see clinical efficacy that will lead to FDA approval. A lot of the immune checkpoint agents that we have right now are targeting T cell pathways. I think what we're learning now is there are going to be a lot of agents targeting macrophages and myeloid cell pathways, which are also going to be important.

Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer [published online March 27, 2017]. Nat Med. doi:10.1038/nm.4308.

We believe that PD-1, PD-L1, and VISTA are now the inhibitory pathways that are upregulating in prostate tumors to suppress the antitumor immune response. We’re going to need combination therapy, perhaps an anti—CTLA-4, to drive the T-cell infiltration and then an anti–PD-1, anti–PD-L1, or anti-VISTA, we don’t know if you'll need all 3 to get through tumor rejection in prostate cancers. We used this data to base our next clinical trial, which is now an anti–CTLA-4 plus anti–PD-1 combination in patients with prostate cancer. It’s important because the immune response should be able to recognize prostate cancer as well as it recognizes melanoma or bladder cancer; the immune response is there to protect you against foreign cells that have these mutations. Prostate cancer has fewer mutations; however, again, it’s not the amount of mutations, but it does need to see one good antigen.