Dr. Charles G. Drake Video (Text Version)
Immunotherapy for Prostate Cancer: The Basic Science of CTLA-4 Blockade
Dr. Howard Soule
Now we’ll begin the first of two scientific/clinical discussions. The first on immunotherapy; it’s a pleasure to introduce Dr. Charles Drake, who is an Associate Professor of Urology, Oncology and Medicine at the Sidney Kimmel Cancer Center at Johns Hopkins University. Chuck is a physician scientist with a strong interest in immunology and it’s a real pleasure to have him speak today on checkpoint biology; Chuck.
Charles G. Drake, M.D., Ph.D.; Associate Professor of Urology, Oncology and Medicine, Sidney Kimmel Cancer Center at Johns Hopkins University
Well I’d like to start by thanking the CDMRP for all it’s done for prostate cancer research and also thank you for your attendance here and for your interest in this subject. What I’m going to talk about today is the idea of using the immune system against prostate cancer and you’ve already heard a little bit about this—this morning from Dr. Kwon. What I’m going to do is take a tiny step back and really carefully step through the basic science that led to the development of anti-CTLA-4 as a clinical modality for—for men with prostate cancer. And at the end you’re going—by doing that in a mechanistic way what’s going to happen is you’re going to be able to anticipate the best way to use this kind of agent and also perhaps get a feeling for what the side effects might—might be. These are my financial relationships. I can tell you that I’ve consulted—most relevant—I’ve consulted in the past for Bristol-Myers Squibb which has generally been somewhat frustrating because what we want to do is bring these agents earlier into the disease process and to be used in combination and we continue to work hard towards that goal.
On your right, you see the ultimate goal of immunotherapy actually. These are the activated CDAT cells. These are—these T-cells are like Dr. Soule’s son; they’re the Marines. When they’re properly activated they can traffic widely throughout the body and they can lyse tumor cells; they can kill tumor cells that are resistant to chemotherapy. Activated T-cells can even traffic to the brain by the way, to the bone marrow—any place in the body. The trick is to get them activated, so although they’re powerful killers, trained killers in fact, one of the problems is that they require at least two and maybe even more signals to get activated. In that sense, they’re a little bit more like teenagers. Your teenagers never listen when you tell them to do something, right. So they need two signals; the first one is a specific signal when you call out their—their name. Could you please get off the couch, Joe? So—so the first signal is—is transmitted by a molecule called the T-cell receptor. This is a specific signal. The goal of immunotherapy is to activate specific T-cells that will—will be specific for prostate cancer antigens.
The antigens that have been targeted in current trials and continue to be targeted include prostatic acid phosphatase, the subject of Provenge or sipuleucel-T, PSMA which is being targeted by antibodies, PSCA, and PSA. But that’s not enough. Again a second signal, a second shout out is required to get T-cells activated. We call that—immunologists are sometimes not so imaginative; that’s called signal two. Signal two is mediated by a set of molecules called B7 molecules and a set of molecules on T-cells called CD28. Now in 1987, a really interesting thing happened actually; so a group in France led by a gentleman named Dr. Goldstein was cloning out molecules from T-cells and he found the molecule that looked like CD28. It came from a cytotoxic, a CT, a cytotoxic lymphocyte so he named it CTLA-4.
CTLA-4 was looked—it has about 80% homology to CD28, right, so everybody expected that this would be something that would lead to T-cells being activated. In fact, there was a series of experiments over the next 5 to 7 years that were incredibly controversial. Does it activate T-cells; does it turn them off? But I think any controversy was laid to rest when mice were created that lacked CTLA-4. This is a picture of a normal heart. This is the myocardial muscle; your heart probably looks just like this hopefully. When CTLA-4 was knocked out what happens is this—so all those little dots are lymphocytes. So CTLA-4 from this study clearly is a negative regulator; it stops lymphocytes from trafficking widely throughout the body.
So this is one of the effects; these mice turned out to die early on. They died between 2 and 4 weeks of age of massive lymphocytic infiltration of their heart, pancreas, and other organs—liver as well. The other thing that’s CTLA-4 does for lymphocytes is it affects their ability to divide, to proliferate. So here’s a picture of a division, proliferation down here and here we’re looking at a wild-type mouse. And see this little bar that you kind of can't see? In a wild-type lymph node, T-cells are not proliferating very much on their own; but when CTLA-4 is missing they proliferate quite nicely actually. You can see them proliferating right there. And if you stimulate them they proliferate about four times as well as if CTLA-4 is absent. So the bottom line is these data told us very, very clearly that CTLA-4 is a negative regulator that regulates both T-cell migration and proliferation.
So here’s the model actually that—that Dr. Kwon showed with CTLA-4—that CTLA-4 when it’s on the T-cell is a break; it’s a negative regulator. And the very insidious part of this frankly is here. When it binds to those positive molecules, it binds with greater affinity than does native CD28, so it sucks up those B7 molecules and they really can't signal towards—signal T-cell to become activated. Can we do anything about this? Yes; well immunologists are very good at making antibodies and the idea is if we make a monoclonal antibody that’s directed against CTLA-4—these are high affinity proteins; they’re generally made originally in mice—these antibodies can block that interaction and now the T-cells can proliferate normally if they’re supposed to and then traffic throughout the body.
What was this designed for actually? So the system was probably not designed to prevent your body from attacking its cancer. Probably it was designed to prevent autoimmunity or hyperactivity—hyperactivity in the immune response. And then once you block CTLA-4 then signal two appears normal. So Dr. Kwon showed you these data and actually I don’t know if you guys all caught the importance of this; this is really—this is really the seminal experience—experiment that led CTLA-4 blockade to move forward for prostate cancer. And what he did actually is Dr. Kwon is—is a surgeon right; so what he did was he—he didn't expect the immune system to cure cancer all by itself. And I think it’s a little bit naïve for us to expect that. What Dr. Kwon did was he took mice and he planted them; he gave them cancer, prostate cancer, TRAMP C2 cells and then he tried to cure them surgically. And we all know that for some men that works; some men are cured with—with a surgical resection of the prostate gland. But many men are unfortunately not. And this is how the mice looked actually, so he took mice off. He took mice; he did the surgery and unfortunately this is an aggressive prostate tumor that could not be cured with surgical—surgery alone.
However, when he followed the surgery with monoclonal antibodies that blocked CTLA 4, this allowed T-cells to become activated to traffic to the prostate tumors and to eliminate them. So what you see is what Dr. Hussain was talking about right, the idea that in—in this case some of the mice are in fact cured. They go onto have a long-term survival. It’s important to know that—that this is the very first application of CTLA-4 then was not by itself, right. It was in combination with something—here in combination with surgery. It turned out that as—as this agent developed, other combinations were studied and another combination which has turned out to be quite promising is the combination of immune checkpoint blockade with radiation therapy. So here’s another prostate—another—another cancer model; these are cancer cells growing in mice untreated. As we know from our patient experience, some patients probably are cured with radiation therapy by itself. And sure, some of these mice are cured by radiation therapy alone. But some eventually relapse, actually again just like men with prostate cancer.
If you combined radiation therapy with CTLA-4 blockade, you could wind up with what we’re looking for—that is a fraction of mice and hopefully someday men—cured of their disease actually and that’s shown here in the combination group around half the mice could be cured. Okay; great. And by this point you’re saying enough with the mice man; we’re not mice. We are men. Okay; we’re men with prostate cancer. So how can we do—how can we block CTLA-4 or use—block this pathway in men with prostate cancer?
You know Dr. Chinnaiyan talked about this a little bit and I just want to make sure that everybody is on the same page. So these are—this is what an antibody looks like. Monoclonal antibodies are generated in mice. They have two binding sites. They’re very, very high affinity; they’re as specific as any drug. Actually they’re more specific than many drugs. They bind in the sub-nanomolar range. An antibody—the ones that we use in the clinic—have two binding sites. One here and one here, so we draw them like Ys. Mouse antibodies are lovely but we cannot put those in humans because they’re made of what—mouse protein, right. So if you put a mouse antibody into humans, you can do it once; the second time, you wind up with a tremendous immune reaction and the antibody is completely unfunctional. In order to take these antibodies into humans, a couple of steps went through a—went through an evolution of a couple of steps. One was just the glue, the mouse proteins, the specific parts, the ends of the arms, onto a human antibody backbone using genetic engineering. Those antibodies are—are on your bottom left. Those are called chimera, part human, part mice, and in fact most of the antibodies in the clinic today are not human antibodies, they’re chimeric antibodies. Herceptin for breast cancer, Rituxan for lymphoma; they’re both chimeric antibodies.
However, using modern genetic technology, mice were made that have no antibody change of their own, okay. So these mice wouldn’t make any antibodies if you immunized them. What was next done was these mice were reconstituted with human immunoglobulin chains. So what happens when you immunize these mice is they make fully human monoclonal antibodies, and the antibody that’s been taken forward for—for anti-CTLA-4 is this one. It’s the one on your bottom right. It’s a fully human monoclonal antibody. The other thing that happens when you do this, right—so these are mice; so the proteins that you’re putting in are human, they’re very, very foreign. So you wind up with ample production of lots of high affinity antibodies that you can screen from.
Now the antibody that’s been taken forward for prostate cancer is very difficult to pronounce. So if you remember nothing from this talk maybe you can go home and learn to say this word, and I can tell you that even the folks of the company who now own the intellectual property for this—BMS often can't say this. So the antibody is pronounced Ipilimumab, okay. Often you hear Ipilimumab and you’ll hear other conjugations thereof, so it’s Ipilimumab. Ipilimumab has been taken forward through collaboration with the PTCC in several situations, and Dr. Higano is going to talk about that going forward. But I can just give you a little hint. So this drug has also been taking forward for melanoma. In 2010, last year at ASCO there was a beautiful exciting talk. Steve Hodi from Dana-Farber showed these data, these are patients with metastatic melanoma for which no real effective treatment exists, treated with either a control or with an Ipilimumab antibody. And what you can see is there’s a clear survival advantage. This is the first drug ever to show a survival benefit in melanoma in a randomized trial. And what you also see again is what Dr. Hussain asked us to look for. You see this tail, this group of patients with a very, very long survival and we want that to be everybody. That’s what we’re doing going forward.
Finally I would be a little remiss if I just didn't tell you what the future is like. Dr. Higano will talk to you about current trials. Since 1987 additional immune checkpoints have been discovered. In particular, one is known as PD-1. PD-1 is showing to be very promising in multiple cancer types and my lab was able to show that when you look at the T-cells that infiltrate the prostate gland and men with cancer, most of them express PD-1. So the idea is this might be another way to allow the immune system to proceed forward against cancer, particularly prostate cancer. And with that I’d like to close and hand the podium back to Dr. Soule and to Dr. Higano who will go forward and tell you how this—these agents proceeded into the clinic. Thank you.