A Historical Perspective on Radioligand Therapy and Novel Treatment Modalities in the Management of mCRPC - Neil H. Bander
February 6, 2023
Neil H. Bander, MD, Professor of Urology, Josephine and Bernard Chaus Professor of Urologic Oncology, Director, Urological Oncology Research, New York-Presbyterian Hospital-Weill Cornell Medicine
Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.
Charles Ryan: Hello, I'm joined today by Professor Neil Bander, Professor of Urologic Oncology at the Weill Cornell Medical Center in New York. Dr. Bander has been a pioneer in the identification and targeting of PSMA in prostate cancer. As we all heard earlier in 2022, PSMA Lutetium targeted therapy received FDA approval. What Dr. Bander knows is that this process has been going on in development for almost 30 or 30 plus years, and we're going to get a little bit of historical perspective from Dr. Bander today. Welcome, Neil. Good to talk to you. You have a long arc now of involvement in this story that's really maturing quite rapidly, and you must be very proud of your involvement from the beginning on this. Tell us a little bit about your feelings and your involvement in ... Let's just start with PSMA.
Neil Bander: Well, let me just say that I have been involved with PCF, the former CaP CURE pretty much from day one. I wasn't working on PSMA at the time, but it was a similar project, but I've been to virtually every PCF meeting since day one, every retreat. It was about 25 years ago that I got interested in a molecule called PSMA, which you may know is actually first described in 1987 by Gerry Murphy, who you probably don't know.
Charles Ryan: I know the name.
Neil Bander: Yeah. Gerry Murphy was a Hopkins trained urologist who became the CEO of Roswell Park and Gerry Murphy and some of his colleagues identified a molecule. It didn't have a name at the time, but it was identified by an antibody they had developed. Not much happened with it until the early 90s when Skip Heston at Sloan Kettering and his group cloned and sequenced the gene. And their work showed that this molecule, which they named prostate specific membrane antigen. They named it PSMA, because on the basis of their work, it did appear in fact to be virtually, absolutely specific for prostate cancer.
I wasn't initially interested in it in the early nineties because there already existed an antibody. I was trained in antibody development at Sloan Kettering by a fellow named Lloyd Old, who was a member of the National Academy well known in the tumor immunology world. And my goal from the beginning of my ... going back to 1980 when I first went to Sloan Kettering as a fellow, was to develop antibodies that would have the capacity or capability of being able to specifically target cancer cells in patients.
I started to say I wasn't that interested in PSMA at the time because there already existed an antibody to PSMA. But it turned out that a subsequent work actually from George Wright's group who was in Virginia, they determined that the epitope of the preexisting antibody was intracellular. And as soon as I learned that, I knew that that antibody was not going to be effective in a clinical setting. So we immediately set out to develop antibodies to the extracellular domain and we developed the first panel of antibodies that did bind the extracellular domain of PSMA.
Charles Ryan: The initial intracellular domain, was that the prostate scan that was around in the late 90s and early 2000s?
Neil Bander: Right.
Charles Ryan: I think in my medical practice I ordered one in 2003.
Neil Bander: And that was one more than I ordered. I mean, I knew from day one that was not going to be a successful antibody, and actually it's interesting from a historical perspective. If you go back to Murphy's original paper in 1987, they actually specifically state that it did not bind viable prostate cancer cells. It only bound prostate cancer cells, which had been fixed.
Charles Ryan: Interesting.
Neil Bander: In any case, we developed the first series of antibodies to PSMA that could bind living prostate cancer cells. The other interesting historical fact is that when Skip Heston's group sequenced PSMA, they did not see a known internalization motif, so they assumed it was not internalized. And prior to the existence of our antibodies, there was no way to really look because as we already said, the old processing antibody didn't bind viable cells. We assumed that it was not internalized, but when we looked, we were surprised to see it was internalized actually highly efficiently. And we actually did what I think were interesting studies. We did immuno electron microscopy. We actually were able to visualize the internalization of the antibody. You could see classic clathrin coated pits. It acted as really a prototypical receptor.
And in fact, if you go back to our first paper, which was in cancer research in 1997, we actually hypothesized at the time that there was probably a natural ligand that bound to PSMA as receptor and got internalized. And we actually tried to identify, which we failed at doing, but that in fact has turned out to be the case with the polyglutamate folate. We were fortunate in that we had support from PCF going right back to the early days. I was also personally fortunate in that at Cornell and New York Presbyterian, it was New York Hospital at the time, but has become New York Presbyterian Hospital, we had some very loyal patients and donors, donors who really wanted to make a difference. And those donors, either through PCF or directly through Cornell, gave my group the wherewithal to actually translate our basic science laboratory work into clinical trials.
Charles Ryan: Do you think some of that early support from the PCF is support that you wouldn't have been able to get from the NIH at the time? I think this was before the DOD was funding prostate cancer research. So I like to think that we were 25, 30 years ago in the space where people couldn't get funding for some of these big ideas like you had back then.
Neil Bander: Well, you may like to think it, but it was definitely true. And I think that was one of the things that Mike Milken realized early on was there was a definite need for more funding in the prostate cancer space. There was lots of money going to breast cancer and other types of cancers, but I think Mike has said it on multiple occasions, prostate cancer, being the most common cancer in men, was not getting its share of funding. And it really was at least part of the impetus of developing-
Charles Ryan: Well, there's the amount of funding, but then there's the funding more innovative, higher risk ideas that didn't have as much preliminary data. You've talked now about 10 years of preliminary data, I think, leading 1987 to 1997, more or less before you really could characterize the target. And now we're 25 years after that and we validate it as a therapeutic target, amazing work.
Neil Bander: Well, it's interesting, I've often thought that somebody should do a case study, whether it's PSMA or there are certainly many other examples in medical science where you see this very long arc from the original discovery to actually making a difference for patients. And somebody or a group should really do studies to understand why it takes us so long to do that. Yeah, I mean honestly, I felt somewhere between 20 and 25 years ago that being able to target PSMA was really going to make a difference. Honestly, it was a struggle to demonstrate that to the world, which is part of the reason it took as long as it did. But as you are, I think, well aware, if you just look at the history in the past, let's say five years, about five years ago, it really hit an inflection point. I mean, we wrote our first paper, as I said, in 1997, so I think there were three papers on the literature on PSMA at the time, and now there's thousands.
Charles Ryan: And I've been following the development of all of the antibodies in various forms over the course of the past couple of decades. And there have been many instructive failures, if I could call them that, where they were well executed trials and they didn't hit the mark in terms of a therapeutic outcome. And then it took iterations of that and improvements on that. And when one wonders why does it take 25 years for a target identified to a therapeutic validated, it's because it's not as easy as people think to hit targets. And you have to figure out, especially with regards to your work, I think was, what's the payload? What's the antibody? Et cetera, et cetera.
Neil Bander: Right.
Charles Ryan: So, speak to that.
Neil Bander: Well, I mean my view from the beginning was that PSMA was as good a target that exists in any cancer, and that the antibody ... and in those days, there were only antibodies that could target PSMA, that an antibody we had already demonstrated in patients was very capable of virtually perfect targeting. What I didn't know with certainty was what was going to be the effective therapeutic? Was it going to be antibody alone? Because in those days we thought antibodies in and of themselves could have therapeutic benefit. Was it going to be a radio labeled antibody? Because again, we knew that prostate cancer is a relatively radio sensitive disease, so targeting radio isotopes made sense. I was very interested in antibody drug conjugates. In my view, antibody drug conjugates was next generation chemotherapy where you could instead of perfusing the entire body with a toxic drug, you could target it directly to the tumors for all intents and purposes.
We did variety of trials. We looked at naked antibody, we looked at different radio isotopes, we looked at yttrium, we looked at Lutetium. Our Lutetium trial, which I think we published in about 2003, was the first trial of Lutetium in patients. And then we started doing antibody drug conjugates, where we had to work with companies in order to get the drugs that we needed to build those molecules. Yeah. And I don't have to tell you, it's expensive to do clinical trials. I think most people who in this area do clinical trials using drugs that have been developed at a company and they bring them into the institution and they do the trial. What we were doing is, I think relatively unusual, maybe even unique, is we really wanted to do the studies ourselves, which again, as you're well aware, the cost of clinical trials is enormous. We were fortunate, we had a lot of funding so we could do it, but we could only do it on a microscopic level compared to a drug company.
Charles Ryan: So I think that's a really interesting historical context. You said the first Lutetium study, 2003, 2002, something like that, which is amazing and lots of different shots on goal with different isotopes, and we're not done. Now we have a positive phase III study. We have an FDA approved product with Lutetium-177. There's another product with Lutetium-177 in phase III clinical trials. And there's opportunities, I think, moving forward to even continue to develop the antibody drug conjugate, et cetera. What are your thoughts on the future of where we go with all of this?
Neil Bander: Well, we're doing trials right now with the antibody targeting Actinium 225, an alpha particle. We completed our first trial, which my colleague, Scott Tagawa, has presented it at a couple of ASCO meetings. That was a single ascending dose trial where we saw a very significant activity and a good therapeutic window. I think we had somewhere around a 45% PSA 50 response rate from a single dose in unselected patients. And now we're doing a multiple dose trial with Actinium-225. Again, we don't know all the answers, right? This is research. Right? So we're looking at different schedules. We're looking at different doses as a dose escalation trial, and that trial is still running. But what I can tell you is it's a multiple ascending dose trial, as I said, and again, sick patients who are unselected, we're seeing fabulous responses. Again, Scott will present that data. It's it in the not too distant future.
And the other thing that we're doing is, again, I consider myself a translational scientist. So I work in the lab and my goal in the lab is to develop things that I can take in to patients. One of the things we saw in the lab that was again totally unexpected is that when you combine the antibody and the small molecule ligands, you actually get a synergistic dose to the tumor. And the other benefit of that is that if you stop to think about it, you'll realize that the adverse event profiles of the ligand and the antibody are mutually exclusive. The ligand targets in normal tissues, the salvor glands and the kidneys. The antibody doesn't target either of those. The antibodies metabolize through the liver. The other complimentary benefit we get is that we can use the ligand with Lutetium on it, which has already been demonstrated to improve survival. We can add Actinium to the antibody. So we have two very complimentary agents that in animal studies are synergistic, and we have a trial going on now that's open ... it's early days. I think we've maybe treated 10 patients so far. Again, it's a dose escalation trial, but the results are eye popping.
Charles Ryan: Very cool. Well, we look forward to seeing those, and I think it's been ... Thank you so much for the giving us this historical perspective. It's interesting how people think of 2022 as the beginning of the radioligand therapy era. And you're probably laughing at that because you know that perhaps the beginning of the radioligand therapy era began in 1987 with Gerald Murphy or 1997 with your identification of the various epitopes. But this certainly is not something that just popped onto the scene from nowhere. And you've been there behind the scenes this whole time, and congratulations on that important contribution to the therapy of men with prostate cancer.
Neil Bander: Thank you, and I will guarantee you the best is yet to come.
Charles Ryan: I love it.
Neil Bander: Yeah.
Charles Ryan: Thanks again.
Neil Bander: You're welcome. Nice being here.