PracticeUpdate: Haematology & Oncology

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EXPERT OPINION Future of immunotherapy and biomarkers in prostate cancer Interview with Gautam Jha, MD Dr Jha, Assistant Professor, University of Minnesota Medical Health in the US speaks with PracticeUpdate’s Farzanna Haffizulla, MD, FACP, FAMWA, on enhancing the immunotherapy response.

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Medical Advisor Dr Barry M Dale Consultant Haematologist, Medical Oncologist

Dr Haffizulla : What about the future for immunotherapy? What’s on the horizon? What biomarkers might we be looking at, or other prognostic or predictive markers in immunotherapy? Dr Jha : One of the biggest drawbacks with immunotherapy, in general, is that there have not been good biomarkers. For example, at least with the PD-1 line of therapy, we look for PD-1 expression and, again, we know that it is dynamic, and it does not always correlate with response. Unfortunately, PD-1 hasn’t worked as well in prostate cancer as it has in many other cancer types. However, I think there is a big promise with immunotherapy; we have sipuleucel-T, which is already approved, and PROSTVAC, which is in later stages of development. Combining this with our checkpoint inhibitors like either ipilimumab or PD-1 inhibitors or, in fact, a new inhibitor. I have my own investigator-initiated trial with indoximod, which is an IDO inhibitor, which suppresses the inhibitory Tregs and would allow a much more enhanced response to sipuleucel-T. Those combined with other cytokines like IL-7 or IL-15 would be quite promising. So, this would make this modest response from sipuleucel-T or PROSTVAC into a much more enhanced response, which might last for a long period of benefit. Dr Haffizulla : Let’s talk about the role of immunotherapy in prostate cancer. Where we were, where we are, and where we’re going. We mentioned sipuleucel-T. Let’s talk some more about that particular vaccine and where we’ve come from that point. Dr Jha : Sipuleucel-T was the first landmark vaccine in that it was the first to get approved and was the first step in the right direction. Consistently, trial after trial, it was shown that it could improve survival, offering us a survival advantage of over 4 months, which was unheard of at that time. The important thing is that it is such a well-tolerated therapy. The only drug that worked before sipuleucel-T was docetaxel, which has substantial toxicity, as you know, and the survival advantage gained with that was barely 3 months or so. Dr Haffizulla : You want to minimise the toxicity and maxim- ise the efficacy, and, of course, you’re looking at cost, and you’re looking at the individual patient, and if this suits his particular clinical scenario. Dr Jha : Yes; there has to be an individualised approach, and it’s clear that vaccine therapy, especially sipuleucel-T, is not for everyone. It has been approved and tested in only a very spe- cific set of patients, patients who were castration-resistant

but had either minimal symptomatic disease or were com- pletely asymptomatic. We’re talking about patients who were in extremely good health, had no visible disease, and were not taking an opiate for pain; so, essentially, these were the guys who had an anticipated survival of least a year or more. This is not a therapy that you would do at the end of the road, or in patients who have progressed on lines and lines and lines of therapy or someone who has a huge disease burden; you would not be benefiting the patient. In fact, you might be harming him by delaying more effective therapy. Dr Haffizulla : It makes me think about using these vaccines in prevention for patients who may have a very strong fam- ily history or may have other risk factors. What are your thoughts on using it in prevention? Dr Jha : It is quite interesting that you bring it up. Some call it a vaccine. Essentially, a vaccine is something that would enhance our immune response to fight the disease, but this one does not prevent the occurrence of disease. It would be great if we had something which could do that, and if it would be effective. The cost of this thing is so prohibitive that we have to select the right patients; the population who is going to benefit from this therapy. And this is a tremendous thing because it works and it is very well tolerated. Dr Haffizulla : Yes, because the way these vaccines are cre- ated, as you mentioned, are from the actual tumour itself, from the patients themselves, or from their peripheral blood mononuclear cells. Dr Jha : Yes. This is essentially using the antigen-presenting cells of the patient, and the dendritic cells, which are col- lected and are sensitised outside the patient’s body to es- sentially one of the proteins expressed on the cancer cells, prostatic acid phosphatase. This is not a tumour-based vaccine. There are some tumour- based vaccines, but none of them are far enough in develop- ment for prostate cancer. There are some being tested, but that arena is much more advanced in, say, kidney cancer melanoma. So, some tumour-based vaccines are in develop- ment, but not as much for the prostate. Dr Haffizulla : Let’s talk some more about the future of im- munotherapy. We just discussed sipuleucel-T and it being an effective adjunct to the therapeutic landscape already. What are your thoughts on what might be happening in the future? Dr Jha : With our improved understanding of immunotherapy, I feel things are changing, and we will start seeing more and more results. I feel that we could combine one of those checkpoint inhibitors, and all of the cytokines to enhance or augment the current immunotherapy. Things like sipuleucel-T or PROSTVAC, and checkpoint inhibitors like CTLA-4 or like PD-1. As I mentioned, I am working on a trial using an IDO inhibitor, which is an enzyme but inhibits or is quite immunosuppressive. In other words, an inhibition that will enhance or augment the response to immunotherapy. This would be quite compelling. Dr Haffizulla : So, really stepping back from the picture and looking at ways that we can have a vertical blockade and a horizontal blockade, more synergism really in the therapeutic paradigm. Dr Jha : Synergism, yes. Exactly.

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VOL. 1 • No. 4 • 2016

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