Advances in Immunotherapy for Prostate Cancer with Dr. Sumit Subudhi

This year an estimated 191,000 men will be diagnosed with prostate cancer in the United States, resulting in over 31,000 related deaths. Recent advances are providing hope that there might soon be better options for these patients, especially those with advanced disease. To that end, for Prostate Cancer Awareness Month, we spoke with Sumit Subudhi, MD, PhD, an assistant professor in the department of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center, to learn how immunotherapy is making an impact in this deadly cancer.

Arthur N. Brodsky, PhD:

Last time we spoke in late 2019, there was some promising early evidence around the cancer treatment combination of nivolumab (Opdivo®) and ipilimumab (Yervoy®), which are checkpoint immunotherapies that target the PD-1 and CTLA-4 pathways, respectively. The preliminary data at the time suggested that this combination immunotherapy might be effective for patients with advanced prostate cancer. Have we learned any more about the potential value of this approach?

Sumit K. Subudhi, MD, PhD:

Yes, there is still excitement about this approach. The original trial was 90 patients and what’s happened now is they’ve expanded the study into a randomized trial with different treatment groups. Initially, we were using an aggressive dosing strategy that’s used for melanoma, but approximately 40 to 50 percent of patients were coming off the study because of treatment-related side effects. Now, we’re using more tolerable dosing and scheduling strategies, which have been successful for kidney cancer and lung cancer.

We believe these can also be effective because different cancers have different thresholds with respect to striking a balance between effectiveness and toxicity. So now that we understand that the melanoma protocol was a little bit too intense, we’re looking at more tolerable regimens, but we still don’t know which is better for prostate cancer. Is it the kidney one or the lung one?

Other patients in this trial are also being treated with either ipilimumab alone or chemotherapy alone. Importantly, if they don’t respond to either of these treatments, they still have the opportunity to receive the nivolumab-ipilimumab combination without all the hassle of having to enroll in a new clinical trial. That’s something I really like about this study.

Arthur N. Brodsky, PhD:

It’s great to hear about efforts that take each patient’s long-term interests into consideration.

Now, I want to move on to the PORTER prostate cancer trial, which is being supported by the Cancer Research Institute (CRI) and sponsored by the Parker Institute for Cancer Immunotherapy (PICI), and specifically two of the newer strategies that are being tested in the study. So far, we’ve been talking about PD-1 and CTLA-4 checkpoint immunotherapies that target T cells, which can directly attack cancer cells. But it’s important to remember that there are other immune cells that are crucial for adaptive immune responses against tumors.

One example is dendritic cells (DCs), which several treatment strategies being explored in the PORTER trial are designed to activate. What makes these dendritic cells important in adaptive immune responses, and how is the PORTER trial working to use them to fight cancer?

Sumit K. Subudhi, MD, PhD:

The importance of dendritic cells in prostate cancer was proven in 2010 by the dendritic cell vaccine sipuleucel-T, also known as Provenge®, which helped improve overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). This dendritic cell vaccine is created with the patient’s own immune cells, more specifically their immature dendritic cells (DCs). These immature DCs are then treated with a drug (PA2024) that consists of two parts: (1) granulocyte-macrophage colony stimulating factor (GM-CSF), which stimulates the DCs to mature, and (2) prostatic acid phosphatase (PAP) that’s expressed on prostate cancer cells. This process activates the dendritic cells and causes them to display the tumor-associated PAP marker on their surface. Three days later, the cells are put back into the patient, where they can present the marker to T cells that are then stimulated to go seek out and destroy cancer cells that express PAP. This process is repeated two more times with two-week intervals.

Since then, Dr. Lawrence Fong showed that patients who received Provenge® had increased infiltration of activated T cells into their prostate tumors, and others have shown that it causes a phenomenon known as antigen spreading. This means that after recognizing the tumor, the immune system launches new and additional attacks against the tumor that are aimed at other cancer-associated markers.

So, why are DCs so important? Because they’re the immune cells that are most effective in initiating T cell responses against tumors. One of the biggest challenges in prostate cancer is the lack of effective T cells within tumors, so if we can get DCs to be more active, then we may have a better chance of promoting anti-tumor immune responses in prostate cancer.

In the PORTER trial, we’re investigating two different ways—one which involves radiation and one which involves a vaccine against two specific prostate cancer markers—to prime and activate these dendritic cells. Both strategies also involve the addition of PD-1 checkpoint immunotherapy to give the T cells a boost after they’re stimulated by the activated dendritic cells.

Arthur N. Brodsky, PhD:

Now I want to zoom out and talk about the strategic concept behind PORTER. How can adaptive platform studies like PORTER help to accelerate our ability to evaluate promising treatments for cancer, including prostate cancer?

Sumit K. Subudhi, MD, PhD:

What’s unique about the PORTER study is that we’re using rational approaches to define what combinations we’re testing. When I took over the trial last year, I sent out an email during a drug selection committee meeting, that basically said, “I want you to think that you’re in a sandbox with all possible tools available, and you can pick the combination that you think is going to cure the most people. But there also must be rationale behind it. There has to be data to support it.”

The first parts of the study involve just fifteen patients in biomarker-rich studies, where we’re collecting blood and tissues at various points in time so that we can understand how the different drugs are modulating the immune response. The reason why that’s important is that we’re trying to better understand what leads to responses and what leads to resistance. If we see a signal of efficacy with a given approach, then we expand the cohort to add more patients. What that allows us to do is find early markers of response or resistance, which can then inform our decisions with respect to finding other drugs and other combinations to add to the trial.

As Dr. James Allison—the director of the CRI Scientific Advisory Council—always says, the immune system is set up to return to a stable homeostasis after it’s triggered. So even after we activate it, there will always be something that then works to shut it back down. It’s so tightly regulated; that’s what’s going to happen. But these studies can help us identify those next “brakes.” And if we can find out what those are and anticipate them, then we can then add drugs to target those brakes and keep the immune response active against cancer.

Arthur N. Brodsky, PhD:

That’s a really insightful way to look at what is such a complex system. My last question deals with the future and how the way we conduct research and clinical trials is changing.

The traditional model has been to look for discoveries in mice, and then test those insights in humans. Then it either works or it doesn’t, and you kind of start from scratch again. But MD Anderson’s Dr. Padmanee Sharma, who is a member of both the CRI Scientific Advisory Council and the CRI Clinical Accelerator Leadership Committee, has been one of the main champions of what’s called reverse translation. In this approach, the research arrow points both ways.

Initial insights can still be found in mice and then tested in patients, but then doctors do really in-depth analysis on samples from those patients that can then allow them to plan better experiments back in the lab, so that the next treatments tested in patients are more scientifically sound and likely to work.

What are some of the exciting avenues that this approach is helping us address?

Sumit K. Subudhi, MD, PhD:

TGF-beta is one exciting avenue. This pathway is known to suppress immune responses involving type 1 “helper” T cells (Th1) that are stimulated by the interferon-gamma pathway. Our group—along with work led by Dr. Antoni Ribas at UCLA, Dr. Thomas Gajewski at the University of Chicago, and Dr. Robert Schreiber at Washington University in St. Louis—have shown that if you don’t get a interferon-gamma response, you are less likely to respond to checkpoint immunotherapies.

Recently, we found that there are high levels of TGF-beta in the bone tumor microenvironment, where prostate cancers often spread to, and that this prevents ipilimumab from promoting Th1-mediated anti-tumor responses. So, then we went into our mouse model of prostate cancer with bone metastases and showed that blocking both CTLA-4 and TGF-beta at the same time shifted the immune response back toward one that attacks and eliminates cancer. Now, we believe that if immunosuppressive TGF-beta activity is disrupted, checkpoint immunotherapy will be more effective. This led us to design a clinical trial to test this potential treatment which we hope will open at the end of this year.

Another promising target is ICOS, which Dr. Sharma identified years ago. Our team here at MD Anderson found that ICOS is very important in the anti-tumor responses stimulated by ipilimumab. In mouse models of prostate cancer, promoting ICOS activity and blocking CTLA-4 was associated with a beneficial immune response against cancer.

This reverse translation approach is not without challenges though. One issue is that some of the important pathways we’re discovering are just not targetable, or, at least, there’s not a drug available to target them yet. You can identify things in patients, you can confirm it in mouse studies, but if there’s not a good and safe drug available to target it, then that’s a major issue that we’ll face.

Another challenge is that sometimes the immune biology in mice is quite different from humans. Take myeloid-derived suppressor cells, or MDSCs, which can help tumors by shutting down immune responses. In mice, these cell populations are well-defined, but in humans they aren’t.

And then there’s the humanization of mouse models. A lot of people use patient-derived cancer xenografts, which means that they take human cancer cells and put them in mice. But since a mouse’s immune system would normally recognize human cells as foreign and eliminate them, for the tumors to grow the mouse’s immune system must be suppressed. This can be a good way to look at how chemotherapy works, but it’s not a great way to look at how immunotherapies work because the immune system can’t behave properly.

These are some of the challenges we are working to address, and I believe that a better understanding of these issues is helping us do so.

Dr. Sumit Subudhi is speaking at the upcoming CRI Virtual Immunotherapy Patient Summit on October 2-3, 2020. Register today for free and ask your questions about new advances in immunotherapy for prostate cancer.