Dr. James Gulley is the Head of the Immunotherapy Section and the Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research in Bethesda, MD.
There is a vaccine that was under investigation called ProstVac. Can you tell us a little about that vaccine and whether or not it has been effective?
Dr. Gulley: ProstVac is a pox viral-based therapeutic vaccine that has the genes for PSA, as well as three different human T-cell co-stimulatory molecules. What that means is that the vaccine is something that we can give that can train the patient’s immune system to recognize and attack cells that make PSA. Normal prostate cells or prostate cancer cells can make PSA. There are cancer patients who have had their prostates removed. The only cells left behind that would express PSA are the cancer cells.
There are two basic viruses that are used. One is vaccinia for the initial vaccine. It’s a really good jolt to the immune system. All the subsequent boosting vaccines are given with fowlpox that again contain the same genes for PSA and co-stimulatory molecules. That can continue to boost an immune response.
There were initial studies done with this agent that showed that it was safe to give in patients with advanced cancer and that when given it could generate immune responses to PSA in those patients. If you took cancer cells with the immune cells from those patients, those immune cells could recognize and kill those cancer cells that make PSA.
We then did additional studies looking at this activity, including one randomized Phase II study that was double-blinded. 125 men received vaccine versus placebo. In that study, we found that there was no difference in progression-free survival, but there was an improvement in overall survival, which was our secondary endpoint.
This is very similar to what was seen with Provenge (sipuleucel-T). So we followed this up with a larger study to confirm whether or not these findings are correct. We embarked on a 1,200-patient study that over enrolled. There were 1,297 patients enrolled on that study. We presented the results at the conference of the American Society of Clinical Oncology in 2018: there was no improvement in overall survival with the vaccine.
I should mention a little bit about the trial design. There were three arms in the study: one group received the vaccine plus GM-CSF. This was used in the Phase II trial and showed an improvement in survival. GM-CSF, or Granulocyte-macrophage colony-stimulating factor, can further boost immune response. We don’t know if it is required for the vaccine or not. Interestingly, because of the difficulty in getting this outside of the United States and because we didn’t know if it was needed or not, we did one arm with GM-CSF and another with no GM-CSF. The third arm got a placebo. The placebo vaccine was just comprised fowlpox vector.
What we saw in that study, which showed no improvement in survival, is that we don’t really have a clear explanation of what happened or why we saw a difference in the Phase II study. It could be that the Phase II study was just under-powered and the results we saw were based on chance. (I’m just going to lay everything out here.) It could be that the vaccine was effective and that it did generate immune responses, but that those immune responses did not translate into improved survival for a variety of different reasons.
First, multiple agents have been approved since the initiation of the drug; Zytiga (abiraterone), Xtandi (enzalutamide), Jevtana (cabazitaxel), Xofigo (radium-223), and Provenge (sipuleucel-T) were all approved after that study was designed. It’s possible that when these agents are used afterwards they delete out any treatment effect.
If you look at the overall survival data from Xtandi (enzalutamide) and Zytiga (abiraterone), you’ll see huge improvement in survival in the post chemotherapy setting. In the pre-chemotherapy setting it’s very difficult to see an improvement in survival. In fact, there was no statistically significant improvement in survival with Zytiga (abiraterone) in the pre-chemotherapy setting, suggesting that that could be another explanation for why an improvement in survival just wasn’t seen. The lines are really overlapping. Finally, it could be that the vaccine was generating an immune response. That immune response went to the tumor, but those cells were held in check because of regulation of PD-L1 or something like that. It turns out that when you have activated T-cells that recognize a tumor, they make gamma interferon and cause the other T-cells there to recruit other cells, but that gamma interferon will cause up-regulation of PD-L1. (PD-L1 is a stop sign to T-cells.)
As soon as the T-cells see that stop sign, then they stop everything and they can’t do anything while that’s there. If you come in with an immune checkpoint inhibitor and block either the PD-1 or the PD-L1, you basically cover that stop sign and those T-cells go back to work.
Perhaps that is what’s going on. We did a study in the neo-adjuvant setting where we gave a ProstVac vaccine to patients undergoing surgery. We did see immune cells getting into the prostate, but often not into the tumor, so it may not just be the PD-L1. There are other things excluding the T-cells from the tumor, for example there may be no HLA-A2 expression. Maybe there is up-regulation of TGF-beta. These are still things we’re grappling with, things we’re trying to understand. We’re also trying to come in with other clinical studies to address these different aspects of what might be going on in the tumor microenvironment to lead to a better outcome.
You’re still looking for explanations?
Dr. Gulley: Correct. There are ongoing studies looking at ProstVac in men with a biochemical recurrence. There are ongoing studies in active surveillance—with patients who don’t need treatment.
There are ongoing studies in combination with other agents, like ProstVac and Opdivo (nivolumab). We’ve looked at that combination in men with metastatic disease. I mentioned earlier two of the twelve patients had good responses. Ten of them didn’t. We’re trying to understand that better, so we’re taking it into the neoadjuvant setting. We’ve enrolled one out of the seventeen patients we need to understand a combination of a vaccine plus Opdivo (nivolumab). We’re getting biopsies and comparing that with the prostatectomy specimen to see if there is an increase in immune cells. Do we get more of an increase in immune cells from that combination than we get from the vaccine alone? How do we improve upon that?
If a man reading this is interested in joining a trial, there are multiple options for him to consider?
Dr. Gulley: Absolutely.