Susan F. Slovin, MD, PhD, offers her expert insight on the current state of immunotherapy in prostate cancer.
Susan F. Slovin, MD, PhD
Ever since the FDA approval of sipuleucel-T (Provenge) several years ago, immunotherapy advancements in the field of prostate cancer have been slow.
“It’s an exceptionally challenging area. After the success of sipuleucel-T, there have been combinatorial approaches using radiopharmaceuticals, such as radium-223, the checkpoint inhibitor ipilimumab (Yervoy), as well as some chemotherapy regimens,” says Susan F. Slovin, MD, PhD.
In an interview withTargeted Oncologyat the 2017 Interdisciplinary Prostate Cancer Congress, Slovin, a medical oncologist at Memorial Sloan Kettering Cancer Center, offered her expert insight on the current state of immunotherapy in prostate cancer.
TARGETED ONCOLOGY:Can you give an overview of your talk on immunotherapy in prostate cancer?
Slovin:Prostate cancer was among the first solid tumors to have a positive experience with immunotherapy. Until that time, I don’t believe that any solid tumor malignancywhether it was kidney cancer, prostate cancer, or lung cancer—had any sort of success with an immune approach. For the last 30 years, we’ve seen a variety of different platforms of immunotherapy, including vaccine and viral vectors, none of which showed any impact on prostate cancer.
With the FDA approval of sipuleucel-T, this represented the first successful immunotherapy that showed a survival benefit for a solid tumor, which happened to be prostate cancer. All approaches that have been done subsequently are trying to look at other ways of using the body's immune system to fight the cancer.
TARGETED ONCOLOGY:What agents are being investigated in this space?
It's an exceptionally challenging area. After the success of sipuleucel-T, there have been combinatorial approaches using radiopharmaceuticals, such as radium-223, the checkpoint inhibitor ipilimumab, as well as some chemotherapy regimens.
More recently, the checkpoint inhibitors have been extremely interesting. There have been at least 3 phase I and II trials of the CTLA-4 inhibitor ipilimumab. The original phase I and II trial was done with and without radiation and gave a signal that perhaps there was some long-term durable responses, although not without autoimmune events, such as hypothyroidism and rashes. This is all thought to be an on-target effect of these antibodies.
What’s happened is that 2 phase III trials1 prechemotherapy and 1 post-chemotherapy—have not shown or confirmed an overall survival benefit. While there have been several long-term responses, neither trial confirmed ipilimumab to be a standard of care in patients with castrate-resistant metastatic disease who either have or have not received chemotherapy, particularly docetaxel.
TARGETED ONCOLOGY:Overall, where would you say immunotherapy is at this point in prostate cancer?
We have made tremendous strides looking at different immune-based platforms, which is 1 of the benefits that I'm seeing now. There is a suggestion now that the antiPD-1 agent pembrolizumab (Keytruda) may be generating a signal in patients with much more end-stage disease, particularly those with visceral metastases. It's interesting, because in 1 of the early phase III trials, this metastasis was thought to be an adverse prognostic indicator to the fact that people would not do well. However, using anti–PD-1 surprisingly ended up resulting in some patients having significant declines in PSA and radiographic improvement.
Other approaches being evaluated include the PROSTVAC platform, which is a transgene of PSA in a fowlpox vector given with 3 immune stimulatory molecules. Then you have these new checkpoint inhibitors, as well as a variety of other molecules to which immunotherapies are being developed, including molecules we call VISTA, LAG-3, FoxP3.
There are a lot of new targetsit’s just that we're waiting, because it takes a while for the immunotherapies to kick in. They don’t work immediately, hence the delay in development.
TARGETED ONCOLOGY:What would you want the main takeaways to be from your talk?
The takeaway message is that people go through the various treatments over a time as their disease transforms in a dynamic process. We should be collecting tissues, blood, plasma, and circulating tumor cellsall of this is going to be helpful in looking at our ability to correlate certain changes with the treatments that patients are getting.
One of the major concerns about immunotherapies is that patients have been able to have some signal that the immune system kicked in, either using enzyme-linked immunospot assays suggesting that T cells are being activated, or the development of antibodies suggesting that whatever molecule you're using to introduce into the body, the immune system is recognizing it. However, many of these readouts are not correlating with the change in the biology of the cancer. To know that something works, is going to be a benefit, and should be approved, will depend on whether or not an immune endpoint correlates to a change in the biology of the cancer. Simply generating an antibody does not equal a response. You must show that something has changed in that cancer. That is what we have not been able to observe with a lot of these platforms.
TARGETED ONCOLOGY:Is there anything else you want to highlight?
I think the most important thing is we must continue this work. The one thing that troubles me is that everybody thinks an immunotherapy means checkpoint inhibitors, but it doesn't. Through the last 30 or 40 years, immune-based therapy has encompassed antibodies, chimeric antigen receptor T cells, novel constructs, DNA vaccines, and peptide vaccines. Checkpoint inhibitors have just recently arrived on the scene.