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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana Farber Cancer Institute. I'm so excited to have here with me today, Dr. Neil Bander who is a Professor of Urologic Oncology at Weill Cornell in New York. Thank you so much for being here with me today.

Neil Bander: My pleasure.

Alicia Morgans: Wonderful. So I wanted to talk with you about the history of radiopharmaceuticals, where they've been, and where we are going in the future. And I know you have a keen sense of this process. I'd appreciate it if we could start with the development of radiopharmaceuticals, at least the more modern ones, where they came from, and where you think they are ultimately going to fit into our landscape.

Neil Bander: Well, the more modern ones, I guess in GU Oncology really began, I think, with our work going back about 20 years now, 18 to 20 years where we started targeting PSMA with the antibody that we developed at Cornell, which we call J591, it was the first antibody to the extracellular domain of PSMA.

And because of that, it was really the first antibody that could bind viable prostate cancer cells. The prior antibody, you may remember originally called 7011 and later called Prostasin, which did become an FDA-approved imaging agent bound to an intracellular epitope.  And that really is a very suboptimal biological circumstance. And it is why that imaging agent, while it was better than MRI at the time or CT scans for that matter, it was really not a particularly good imaging agent.

So we started back around 2001 imaging patients with, initially Indium-111, and then we started some therapy studies with Yttrium-90 and Lutetium-177.  And Lutetium-177, which is a beta emitter also has the benefit that it does emit some Gamma Rays, so you can directly image Lutetium-177.  And we saw from basically the first patient that we imaged that we were getting essentially perfect targeting of all the metastatic sites in these patients, including in many cases seeing sites that were not imageable by bone scan or CT.

So we were getting literally a visual report that our targeting was literally on target. And we did a number of studies. We published them in JCO and Clinical Cancer Research and other publications, which showed not only were we getting highly accurate, highly sensitive, and highly specific targeting of the tumor sites, but we were seeing PSA responses in a significant proportion of patients.

But at that timeframe, 2001 to 2010 I would say, radiopharmaceuticals were really not a very popular option in the Oncology field.  Pharmaceutical companies didn't want to deal with them because of the intrinsic half-life of the product, and there also had been, as you may remember, two antibody-targeted radiopharmaceuticals that were FDA-approved for the treatment of non-Hodgkin's lymphoma and as commercial products, those failed. In fact, I don't think they are any longer available. They just didn't get used by the Oncology community in large, partly because you could achieve very similar results with the use of Rituxan plus chemotherapy.

So there wasn't really a need for those, so that commercial failure also dissuaded pharmaceutical companies from getting into the field. I think that the sea-change began with the use of Radium-223 in prostate cancer and the somewhat unexpected finding that you actually improve survival in those patients. And then, of course, the PSMA radioligand retrospective studies that started coming out of Germany showed both very good tolerability plus very good PSA responses.

So that confluence of events beginning around 2015, 2016, etcetera, really stimulated the field. And then of course you had the publication of two patients who had really extreme responses to a PSMA targeted ligand carrying Actinium-225, an alpha particle. And that really, again, just ignited the field.

And of course, now you have the publication in the New England Journal of the VISION trial with PSMA-617 lutetium where you had significant improvement in progression of disease and survival. So the field is off and running and I think you will continue to see, I don't think I know, you will continue to see a lot of activity in the area, which is not surprising because we're studying or treating cancer that we have known for a century is a relatively radio responsive solid tumor, maybe the most radio responsive solid tumor.

And we now have clear ways to be able to target radiopharmaceuticals to disseminated prostate cancer sites wherever they are in the body. And we now have clear phase 3 data that demonstrates that those are capable of improving survival. So we are just at the tipping point.

Alicia Morgans: Well, and I think it is so exciting to be at the tipping point. And thank you, for running through that history. It's also really interesting to see how these agents have developed, of course, radium being an alpha particle, as you mentioned. And then lutetium is here as a beta particle. So at least the therapeutic arm is predominantly beta. I wonder if you have thoughts as we move into the future about whether we will ultimately see more benefit from alphas, more benefit from betas, or if maybe it will take combinations or sequencing of these types of agents overtime to get the different types of radiation to really help us hone the activity of these agents. What are your thoughts on that?

Neil Bander: Yeah, so I think it all goes back to the different physical properties of alphas versus betas. So alphas are roughly three orders of magnitude, more potent than a beta particle, a thousand to 5,000 fold more potent. They also are much more precise. Their range is let's say 50 to 80 microns, so just a few cell diameters.  With a beta particle-like lutetium-177, you're talking about a range of millimeters. And if you are talking about another beta particle, Yttrium-90, the range is even longer.  So there are advantages and disadvantages to alphas and betas. Betas are better for treating larger volume diseases. Particularly if you're going to treat bulky disease, you may want to go with Yttrium-90 because of its longer range.

The downside is that you get more bystander effect. So if you're dealing with a disease like prostate cancer, where the predominant site of metastatic disease is in the bone marrow and you target these radiopharmaceuticals to the bone marrow with the longer-range beta particles, you are radiating more of the bone marrow. And what we've seen in our alpha particle trials is that we get significantly less myelotoxicity from a targeted alpha particle.  And we combine that with the fact that we get more efficacy from its potency. I think clearly the field and what you literally see in the radiopharmaceutical field today is there is a substantial movement towards alpha particles.

One of the impediments of that is the reality that alpha particles like Actinium-225 are not readily available at commercial levels. And that has been one thing that has impeded the field for a while.  But the government has actually stepped in, the Department of Energy, over the last, I'll say several years, I can't pinpoint exactly. It's been three to five years.  They have recognized the value of making an alpha particle-like Actinium-225 available. So the Department of Energy has been gearing up and is continuing to gear up to make the supply available. It actually comes from nuclear waste if you will. So they are the major source of Actinium-225 at the moment. In addition to that, there are commercial suppliers which are stepping into the field because they have also recognized the importance of Actinium-225.

So you have a company called TerraPower, which is funded by none other than Bill Gates and some other of his Microsoft colleagues putting in hundreds of millions of dollars to develop Actinium-225 at a commercial scale. And that's just an example. There are several other companies which are doing this.

And actually from my perspective, when we started getting into Lutetium-177, as I told you a short while ago, back around 2001, we actually did the first human trial of intravenously administered targeted Lutetium-177. And at the time people said to me, well, if you succeed, where are you going to get Lutetium-177? Cause there was only one source for that at the time.  And my view was that if we show there is a clinical benefit to the Lutetium-177, people will come into the field and make it available. And that is exactly what has happened in the past. And I think that's exactly what is happening now with Actinium-225. So it will be available.

And I think you also asked, how do I see this playing out, alphas versus betas?  We have a lot of, at Cornell, we have a lot of preclinical data, which we have not yet published because it's still in my view of work in progress, that shows actually the combination of an antibody targeted alpha plus a small molecule ligand targeted beta is really an optimal combination.  We actually see a synergistic effect of combining antibody targeting with ligand targeting. The antibody actually improves both the uptake and the retention of the small molecule ligand within the tumor. So you get better dosing from the small molecule ligand plus you get the dose delivered by the antibody alpha.

And so beyond that synergy, you also get the complimentary benefit of an alpha particle plus a beta particle because as we talked about earlier, the beta particles are better for larger volume disease, but they are not particularly good at small volume disease, and by small volume disease I'm talking about a disease that is at the level of PET resolution or below.

So lesions that you either barely see on PET or do not see on PET at all with PSMA PET imaging, those lesions are not well treated by the beta particle, but they are optimally treated by the alpha particle. And in fact, if you look at the beta particle studies, the PSMA-617 lutetium studies virtually universally, they report that the progression is in the development of what they refer to as new lesions.  Those are the sub-image of the lesions that didn't get treated by the lutetium agent that then progress. And those are the optimal targets for an alpha particle. So that combination I expect will be the way of the future.  And again, in our preclinical modeling, that's exactly what we see in senographe models across a range of models. So I think that is the direction from a therapeutic perspective.

Alicia Morgans: That is really fascinating to think about. And thank you for walking us through that. I think that's going to be actually just a really novel way for people to think about this in the field. So as you think about the future and you've given us some sense of the direction, what would your summary be, or your message to clinicians as they are trying to plan or hope for the use of radiopharmaceuticals in men with prostate cancer?

Neil Bander: We are just scratching the surface right now. We have the first agent in PSMA-617 Lutetium, which where I think there is little doubt it will be approved in the coming months. It's just additional clinical validation that A) PSMA is an excellent target and B) That you can get anti-tumor benefit by targeting a radiopharmaceutical to it.

I think what we will clearly see is there will be other ligands that come along.  PSMA-I&T has gone into a phase three trial now.  That is very similar to PSMA-617. They are also targeting Lutetium-177. So I think that is likely to be another successful agent.

One point that we haven't discussed yet is when you put an alpha particle on those ligands, while you can see very good responses that we talked about earlier, it's really not a tolerable product because of salivary gland and lacrimal gland toxicity.  But here again is one of the benefits of the antibody targeting an alpha particle, because the antibody does not target the salivary glands or the lacrimal glands and it also doesn't target the renal expression of PSMA. So again, the benefit of that combination is those two agents both successfully target the tumor, but their normal tissue biodistributions are not overlapping.

So you can deliver both agents, get not only an additive but a synergistic dose to the tumor in the absence of increasing toxicity. So again, I think what we will see, and we've already started the trial at Cornell of the combination antibody alpha plus small molecule ligand data.  We are on the second cohort in that phase one study. But I definitely think that is the direction we will be going in.

Alicia Morgans: Well, I think that was an incredibly exciting way to think about radiopharmaceuticals and I have to say, between these agents combining them and the other combinations that we are using in metastatic hormone-sensitive disease, and even earlier, I think that what we're hearing from you and from others is that over time we are making strides in dealing with and attacking prostate cancer.

And there may be a time when we are able to ultimately eradicate much if not all of these cells using these combinations and moving things forward. So I sincerely appreciate your explanations and your teaching as well as your giving us hope for the future. We appreciate your time.

Neil Bander: Well I do see a future where when we can move these agents earlier in the course of the disease, which I think we certainly can do in prostate cancer.  We will start eradicating the disease in patients instead of just slowing it down. And I believe we will have the ability to cure a significant proportion of patients with otherwise aggressive diseases. So I think the future is very bright for prostate cancer patients with these agents.

Alicia Morgans: I do too. Thank you so much.

Neil Bander: You're very welcome.