How Immunotherapy Is Making an Impact in Prostate Cancer

Prostate cancer is the second most commonly occurring cancer among men, and fourth overall. In 2018, there were more than one million new cases of prostate cancer worldwide. In the United States alone, there were almost 165,000 new cases and roughly 30,000 deaths due to prostate cancer last year.

Prostate cancer comes in several forms, with a type called acinar adenocarcinoma being by far the most common. In all subtypes, once the cancer has metastasized, or spread from the prostate to other organs, the odds are survival are significantly lower. These advanced prostate cancers will often respond to traditional treatments such as chemotherapy and hormone therapy, but eventually become resistant to these treatments in most cases.

As a result, new strategies are urgently needed to improve prostate cancer care and increase patient survival. To that end, immunotherapy—a new class of treatments that help patients’ immune systems fight cancer—is one avenue that appears especially promising for patients. The U.S. Food and Drug Administration (FDA) has already approved one immunotherapy for patients with metastatic, castration-resistant (hormone refractory) prostate cancer, whereas another has been approved for a small subset of prostate cancer patients with a specific biomarker. In addition, there are currently 340 active clinical trials that are evaluating a number of immunotherapies for patients with nearly all types of prostate cancer.

To better understand the current immunotherapy landscape in prostate cancer and how these immune-based approaches are starting to improve care for some patients, we spoke with Sumit K. Subudhi, MD, PhD, an assistant professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, TX.

Arthur N. Brodsky, PhD:

Right now, there’s one widely approved immunotherapy for prostate cancer: a vaccine called sipuleucel-T that is made up of patients’ own immune cells. How does this vaccine work?

Sumit K. Subudhi, MD, PhD:

The way I describe it to my patients is that this is a vaccine that helps boost the patient’s own immune system to fight the cancer. They first undergo a procedure called apheresis or leukapheresis, where their immune cells—also called peripheral blood mononuclear cells (PBMCs)—are collected.  These PBMCs are cultured for a few days with a protein consisting of GM-CSF and prostatic acid phosphatase (PAP), which is expressed frequently in prostate cancers. This process results in the activation of dendritic cells (DCs) that now also express PAP.

These activated DCs infused into the patient three days later, and the hope is these activated dendritic cells will now get the patient’s cancer-fighting T cells going. In a full course of treatment, they undergo the same extraction and re-infusion process three times. The good part is that it only takes one month to complete and the toxicities are usually limited mostly to flu-like symptoms that most patients encounter while they’re getting the infusion in the hospital with nurses and doctors around. So it’s very safe.

Arthur N. Brodsky, PhD:

This vaccine was approved in 2010, and since then there have been a lot of advancements in immunotherapy. Especially with a type called immune checkpoint blockade or therapies. These target—and block—“brakes” that could otherwise shut down cancer-targeting T cells. These treatments have helped in a number of other cancers, but they haven’t been that successful for prostate cancer patients, except for a small proportion of patients whose tumors have a property called MSI-high. What does a patient being MSI-high mean, and why are patients with this biomarker more likely to benefit from immunotherapy?

Sumit K. Subudhi, MD, PhD:

It might be best to start with understanding why immune checkpoint therapies don’t work well overall in prostate cancer. Compared to other cancers, prostate cancer has usually very few T cells found within the tumor microenvironment. This might be linked to prostate cancers having relatively low tumor mutational burdens compared to cancers such as melanoma and non-small cell lung cancer where immune checkpoint therapies have been quite successful.

This tumor mutational burden is just the number of mutations a tumor has, and it is linked to the number of neoantigens a tumor has. These neoantigens are mutated tumor markers that can be recognized and targeted by the patient’s immune system to help fight the cancer. So prostate cancer has few T cells and few mutations, and possibly few targets for the immune system.

However, in patients with MSI-high cancer, their tumors can’t repair their DNA and thus they usually have a lot of mutations. They have a lot of T cells and they have a high tumor mutational burden, and potentially many neoantigen targets. And that’s why in those MSI-high patients you see the immune checkpoint therapies being much more successful. There’s already FDA approval of a PD-1-blocking checkpoint immunotherapy in this setting.

Arthur N. Brodsky, PhD:

It’s great that immunotherapy works so well for these patients, but I know you and your colleagues remain focused on developing ways to help the majority of prostate cancer patients, those who don’t have MSI-high tumors and don’t respond to immunotherapy. In that regard, one way to improve immune checkpoint therapies is to combine them. Earlier this year at a conference your team revealed promising results involving the combination of immune checkpoint therapies targeting the PD-1 and CTLA-4 pathways. Could you talk about the rationale behind this strategy and what these results might mean for patients?

Sumit K. Subudhi, MD, PhD:

We initially did a study at MD Anderson with patients with metastatic castration-resistant prostate cancer being treated with ipilimumab, an immune checkpoint therapy that blocks the CTLA-4 “brake.” There, we saw a subset of patients that were responding, so we designed a clinical trial to better understand what happens when patients get ipilimumab. In this trial, we found that after two doses of ipilimumab, you get a lot of T cells coming into the prostate. So ipilimumab is taking that tumor microenvironment, which has very few T cells, and it’s driving a lot of activated T cells into the tumor.

But despite having these important T cells inside the tumor microenvironment, the prostate cancer wasn’t being eliminated. So then we compared patient tissue before and after treatment to see what was preventing patients from responding. And we found that following treatment of ipilimumab there is some adaptive resistance response by the tumor where it upregulates other “brakes”—like PD-1, PD-L1, and VISTA—within the tumor microenvironment to prevent those activated T cells doing their job of killing cancer cells.

In our mouse models of prostate cancer, targeting PD-1 and CTLA-4 together improved the cure rate. So then we launched a multi-center international trial testing this approach in humans, and we’ve witnessed dramatic responses in a subset of patients thus far. To this day, some of these patients treated with the immune checkpoint combination are still experiencing durable responses, with undetectable levels of PSA (prostate-specific antigen), suggesting that they may have possibly been cured of their cancer.

Because of this exciting result, this trial is being expanded into a phase II study with more than 300 patients to better confirm our findings as well as to better understand which patients are responding the best and why. Currently, we believe that patients with a relatively high tumor mutational burden are the ones who responded best to the combination of nivolumab (anti-PD-1) plus ipilimumab.

The major issue in this trial though was that there was a significant toxicity rate that prevented most patients from receiving all four doses of nivolumab plus ipilimumab. So in this expanded cohort, we are going to be trying two different dosing schedules to try to improve on the safety profile.

Arthur N. Brodsky, PhD:

Hopefully that approach will provide a foundation moving forward for the development of even more refined strategies for prostate cancer. Moving on, I want to turn to personalized immunotherapies, including neoantigen-based vaccines as well as cell-based treatments that can be designed for a specific patient’s tumor based on the unique neoantigens it expresses. Are any of these promising therapeutic approaches currently being evaluated for prostate cancer patients?

Sumit K. Subudhi, MD, PhD:

I agree with you that cellular immunotherapies and these other vaccines look promising because as we mentioned earlier, the prostate tumor microenvironment has very few T cells in general and both cellular and vaccine strategies should help drive T cells into the microenvironment just like ipilimumab does.

However, we know that even these treatments will likely not be sufficient for most of our patients because our immune system is set up to always be in balance and the cancer takes advantage of this by engaging the immune system’s brakes. Those brakes can include other immune checkpoints such as PD-1, PD-L1, VISTA, LAG-3, et cetera, or they can include immune-suppressing populations like myeloid-derived suppressor cells (MDSCs) or macrophages and regulatory T cells to name a few.

So many of our studies will require combinations that can be given either concurrently or sequentially, and I think most likely sequentially will be the most important to avoid the toxicities that can occur when you give too many drugs at once.

Arthur N. Brodsky, PhD:

Looking to the future, in your opinion, what are the biggest challenges and unanswered questions in the field of prostate cancer immunotherapy that could help advance the field and improve treatment for patients?

Sumit K. Subudhi, MD, PhD:

A better understanding of the bone tumor microenvironment is going to be the key because what separates prostate cancer from most other solid tumor cancers is that 70-80% of the time, it spreads to the bone. That’s very different from any other cancer, and what our recent preliminary study suggests is that bone metastatic tumor microenvironment is much more immune-suppressing than the primary site. And so a better understanding of what makes it more immune-suppressing could help guide our therapeutic approaches. Our group has found that a molecule called TGF beta is highly expressed in the tumor microenvironment and is considered an immunosuppressive molecule that shuts down the anti-tumor T cell responses, so we will be looking to confirm this in future clinical trials.

Arthur N. Brodsky, PhD:

Throughout this conversation we’ve been discussing a number of promising immunotherapies. At points we’ve mentioned this explicitly, but I just wanted to point out that all of the strategies we’ve discussed are being tested in clinical trials. And sometimes these clinical trials get a bad rep because of some misconceptions that are out there. Could just share a little bit about the importance of these clinical trials and how they help to advance the field and improve the options available for patients?

Sumit K. Subudhi, MD, PhD:

The way I describe it to my patients is just that just about every drug they’ve received thus far has gone through a clinical trial and the reason why it’s a standard of care is that there are brave and courageous patients that agreed to enroll in clinical trials. And at the time when those patients were in a clinical trial, there was no great other option. Since 2010, there have been several new drugs that have been FDA approved for prostate cancer, but none of them are curative. And so the point of clinical trials is we hope that we are finding rational combinations that will improve the patient’s outcome and especially with immunotherapies, we’re hoping to lead to a cure.

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Dr. Subudhi will be speaking at the CRI Immunotherapy Patient Summit in Houston on October 26, 2019. Register today.  

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