Are there any immunotherapy approaches currently available to advanced prostate cancer patients? Patient Power Founder and Host, Andrew Schorr, leads a discussion with prostate cancer experts Dr. William Catalona of Lurie Cancer Center and Dr. Russell Szmulewitz on immunotherapy research. Dr. Szmulewitz gives a short account of immunology and cancer biology, explaining the difficulty of targeting prostate cancer’s immune system. Together, Drs. Catalona and Szmulewitz explain adoptive cell therapy and how current research is working to answer safety and efficacy questions.
Sponsored by the Patient Empowerment Network through educational grants from Astellas, Medivation, Inc. and Sanofi. Produced by Patient Power in partnership with the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Us TOO International.
Transcript
Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.
Andrew Schorr:
Let’s go on to the next slide where we talk about immunotherapy. Dr. Catalona has mentioned this. Now, it came up with sipuleucel-T, Provenge.
But some of you have been doing your research and hearing in other cancers, they’ve been talking a lot about what are called checkpoint inhibitors, immune modulators. And we’re going to get to adoptive cell therapy. So Dr. Szmulewitz, demystify this for us. What’s the buzz, and how does it apply to prostate cancer?
Dr. Szmulewitz:
Okay. I’ll do my very best. But it really requires a really deep understanding of immunology, as well as cancer biology.
Andrew Schorr:
Give us a little class.
Dr. Szmulewitz:
So I’ll do my best. So in order for the immune system to work, to kill anything, it needs to be there. So it needs to be in the environment of what it needs to kill. And it needs to recognize what it needs to kill and recognize it as either foreign or different in order to kill it. And so cancers, what they often do is have mechanisms to either deter the immune system from coming in or to deter the immune system from recognizing it as foreign, because the challenge is it is derived from the body.
So it isn’t entirely foreign. But we know that, in some way, it is. And so one of the things that you alluded to are these checkpoint blockades. And so the cancers, many cancers, they make more signals on their surface that say don’t eat me, don’t attack me. I’m just like you, I’m your friend. And what has been developed are therapies that slap them down, that block those signals so that the immune system will go, wait a second. You aren’t friendly. We should try to get rid of you. And so these checkpoint blockades therapy have been utilized effectively in a subset of other cancers, melanoma and kidney cancer and lung cancer and, pretty soon, bladder or urethral cancer.
So prostate cancer has not been on the leading edge of checkpoint blockade use. And the question is why, and what do we need in order to best harness our immune system? So the why is complicated, and the what should we do is complicated. The why has an advantage, because the earliest studies with these checkpoint blockades didn’t show a lot of efficacy in prostate cancer. We now realize that prostate cancer, the environment, is not that immune. So it’s something about the environment that deters the immune system or keeps the immune system out.
And one of them is what Dr. Catalona mentioned is that prostate cancer doesn’t express a lot of the target for the immune system. And so can we use radiation to increase the amount of targets for the immune system? Can we suppress some of the signaling that stops the environment from being receptive to the immune system?
I think that, for prostate cancer, there is a lot of research and a lot of hope that, now that we understand this biology better, we can, through a combination of therapies is what it’s going to take, better utilize these checkpoint blockades.
Andrew Schorr:
What do you think?
Dr. Catalona:
I agree. And, first of all, prostate cancer hasn’t been studied that much with the checkpoint inhibitors. But the other thing is when you get into the complexities of the immune system, it’s very unlikely that one immunotherapy by itself has a chance. But either by combining say the immunotherapy with either hormonal therapy, radiation, chemotherapy, or bringing in two immunotherapies that work by different mechanisms is going to have really a better chance than just simple therapy with a checkpoint inhibitor.
Dr. Szmulewitz:
And I’d like to add that there is in patients’ promise. And so there was a very large study of a drug called ipilimumab in prostate cancer, which is an immunotherapy. And it is a blockade of sorts. And in this study with prostate cancer, it was very nearly FDA approved for prostate cancer. The problem with ipilimumab, and this was a first-generation immune therapy, is that it was quite toxic. It had a lot of side effects, which dampened its clinical benefit. So if we can refine our immune therapy, especially in our patient population, which is tired and has other already burden of illness, I think that there’s a window where we can really have magnitude.
So adoptive cell therapy, I have no clue what that is, Dr. Szmulewitz. What is adoptive cell therapy?
Dr. Szmulewitz:
Well, I can’t pretend to be an expert. What I will say is it’s a way of using a person’s specific immune system and modulating it and then giving it back. And so sipuleucel-T is actually, in some ways, an adoptive immune therapy. I think the next generation of immune therapies are going to take T cells, the cells within the immune system that can eat up the cancer, and modify them in the laboratory to specifically fight prostate cancer. They’re doing it in leukemias and lymphomas, because we have a good sense of what those targets are. And they’re very uniform.
And I think the challenge with prostate cancer is that, outside of the hormone receptor, it is very diverse and heterogeneous in what’s driving it and in what is made at the surface of the cancer to be targeted. And I think that adoptive T-cell therapy will have a role but still needs a fair amount of research to harness its benefit.
Andrew Schorr:
But the idea is in sipuleucel-T, I’m going to get that right, I’ll say Provenge, maybe that’s easier, was kind of that idea a little bit of making a drug for you.
Dr. Szmulewitz:
Yeah. So in sipuleucel-T, your own cells are taken out. And they are then primed outside of the body. What they’re primed with is a prostate protein. And so it’s a bit of a combination between an adaptive therapy and a vaccine. What it doesn’t do is take the T cells and engineer them to fight the cancer.
And so the challenge with immunotherapy and prostate cancer is if the T cells aren’t there in the environment, then all of the stimulation with vaccines isn’t going to be as effective as it could be if the T cells both aren’t there and aren’t recognizing the target. And I think that’s really what the next generation will be.
Andrew Schorr:
Dr. Catalona, you’re the professor. Let me see if I get this right. When someone develops a cancer, any cancer, your immune system let you down, in a way, because you are developing aberrant cells, and they were able to fool your immune system and continue to develop. So is the future, do you think, if this can continue to develop where your immune system gets revved up safely somehow with few or, wouldn’t it be great, no side effects to do its job that it hadn’t done earlier?
Dr. Catalona:
Well, basically, one of the problems is that if your immune system is too reactive, then you can get autoimmune disease like colitis or arthritis oror, you know all of these terrible, lupus, all of these terrible autoimmune diseases. So the reason the immune system incorporates these properties of being able to dampen down an immune response is really to protect the patient from autoimmune disease. So what you need to do is you need to alter the immune system in a way that it’s not going to dampen the specific response against the tumor.
And you want to make the response against the tumor be more specific for those antigens that are only expressed on the tumor cells but are not expressed on normal cells. And that’s why I think, to have successful immunotherapy, you really have to focus on specific antigen recognition and knock down the immune system in appropriate but not in an excessive manner. And I think when that occurs, it’s more likely to be successful.
Andrew Schorr:
It’s all about safety. These are powerful weapons you’re working on, right, Dr. Szmulewitz. But it’s how to use them, when to use them, who to use them for, and use it safely.
Dr. Szmulewitz:
Yes. That’s right. And I think that to get to those three questions in reverse order, how to use them safely. So to use them safely, you have to make them not blanket immune dysregulators, because that we know is not safe, especially in our patient population who is already ill. And whom to use them and when to use them, I think in whom, we have to know each specific patient’s—the Holy Grail, if you will —will be to know, okay, your tumor has this mutation.
Therefore, it will make this aberrant protein that will be foreign to the immune environment. Therefore, we’ll give you a vaccine to boost or modify the T cells to fight that specific protein. And I think the when is perhaps just as challenging. In my opinion, and based on the sipuleucel-T literature, would be early. The earlier, the less the volume of the disease, the perhaps bigger the magnitude of benefit. Now, I would encourage the community to say we need drug development early on in the process, not necessarily late in the process.
We need end points that the FDA can act on that are early in the process, so we can get potent and useful drugs to patients earlier on.
Published By :
Patient Power
Date :
Jun 30, 2016
