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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, a good friend and colleague, Dr. Oliver Sartor, who is a Professor of Medicine, and the Medical Director of the Tulane Cancer Center, as well as being the Laborde Professor of Cancer Research in New Orleans, Louisiana. Thank you so much for being here with me today, Oliver.

Oliver Sartor: Well, thank you, Alicia. Always like to be with you.

Alicia Morgans: Wonderful. Well, I love to talk with you, because I learn every time we discuss things. And today I'd like to hear your thoughts on BiTE therapy in prostate cancer, which, as we discussed right before starting this recording, is really getting so exciting. And I think is probably one of our new and upcoming approaches to treatment for men with advanced disease, if not earlier on, as we see these therapies developed. So I'd love it if you could just start by telling us what is BiTE therapy?

Oliver Sartor: Yeah. It sounds like some sort of dog that might sort of take you to the cleaners, but it's not. It's a bispecific T-cell engaging antibody, B-I-T-E. And it turns out, that BiTEs are actually approved in certain diseases, like AOL. They are a proven form of therapy. And they are relatively new in prostate, so we do not have a lot of experience, but it turns out that they have some activity. And in fact, some of the patients have really robust responses.

So yes, there is excitement about the BiTE therapy, and they are continually evolving. It turns out, that everybody thinks they might have a better mousetrap, and so, lots of activity in the field. In fact, as I looked at it, I think there are 10 different companies that are pursuing BiTEs, in one form or another, in prostate cancer. So a very provocative area right now, very rapidly evolving. And quite frankly, a little bit promising. I like what we are seeing.

Alicia Morgans: Well, and it's, I think, really exciting for men with prostate cancer to have the opportunity to really use an immune targeting approach. And I'd love to hear how these are designed. What are they targeting most commonly, and how do we really get the treatment, or the immune response, to those prostate cancer cells?

Oliver Sartor: Yeah, great question. And so we go back to our old friend PSMA, and so we all know that PSMA is overexpressed from many prostate cancer cells, so it makes a really nice target.  And then, as it turns out, the other end of the bi-specific T-cell engager, actually, binds to CD3, and CD3 is the T-cell receptor. And if you bind a CD3, you actually activate the T-cells. And so what you end up with is, binding on one part of the antibody, the prostate cancer cell, the PSMA, the T-cell engagement part via CD3, you activate the T-cell, and through the release of a whole series of cytokines, granzymes, et cetera, you can actually cause cell kill. So it's a very provocative concept. You do harness your own immune system to be able to target whatever it is your bi-specific is built to.

By the way, it doesn't have to be PSMA. There's also a STEEP1 targeted bi-specific antibody. I think as we go forward, we are going to learn a lot more about this. They are trying to learn how to modulate the immune system, and actually, believe it or not, kind of tone it down, a little bit. Because we've had side effects, including something called cytokine release syndrome, so we don't always want to blast the immune system and activate it beyond all comprehension. We actually want to have kind of a modulated response. And that's been part of the evolution in the therapies here, is trying to, how to get it right, if you will, kind of get it to the right size.

Alicia Morgans: So let's dig into that a little bit because I think this CRS, or cytokine release syndrome, is something that we as a field are really going to have to understand well if we are going to be able to use these BiTE type therapies. Now this, as you said, is an immune overactivation. What does it look like clinically? And what is being done to really, I guess, find the just-right amount of CRS? Because a little bit seems to be good.

Oliver Sartor: Mm-hmm (affirmative). No, good point. So it turns out that CRS is basically an inflammatory response. And by the way, you see it with CAR T-cells, as well. So you can develop things like a high fever, and you can develop things that are a bit scary, like hypoxia. You can develop lower blood pressure, you can potentially develop some rashes. You can develop liver function abnormalities, etcetera.

In the old days, we kind of did it with Interleukin-2. If you ever gave IL-2, you would induce this cytokine release. That's old school, but now, this is new school.

So there are a couple of things you want to do. Number one is, you probably want to tone down the half-life of the antibody and extend it out a little bit, so you just don't have a big burst of antibody. Being half-life extended can have some potential benefits. In addition, there are some novel bi-specifics that are actually, binding to different parts of the CD3, so you don't activate it quite as strongly. One of the molecules now, AMG-160, which is one of the better-known ones, binds, it really engages the T-cell receptor.

But now, there is one from a little company called TeneoBio. They have a thing called TNB-585. And that particular molecule doesn't engage quite as robustly, but you don't have T-cell exhaustion, and you perhaps, have a little less CRS, at least, in the animal models. So just now, we are getting into clinical trials. We can't talk about clinical data, because we just don't have it.

But on the other hand, there are other things you can do, as well. Number one is you can start with a little priming dose, instead of a big dose. You can give corticosteroids, you can give fluids prophylactically. So by the combination of kind of smaller doses, a little more extension when you give the drug, a little more extension, perhaps, than the half-life, giving some corticosteroids, being careful and cautious, you can actually make these toxicities pretty manageable.

Alicia Morgans: And I think, that will be so important, and will definitely, require education and comfort of the physicians in the community, as we continue to do this because I remember giving IL-2, and we always did it in the ICU. This, of course, required an inpatient stay, very close monitoring, and, as you said, things like steroids and things like fluids, to try to maintain blood pressures and these kinds of things. Do you anticipate that as these approaches to treatment, as the BiTEs continue to develop, and as our comfort level improves with them, we will be able to use these treatments a little more broadly, and perhaps, use them in a community setting, perhaps, outside of an ICU?

Oliver Sartor: Yeah, I think so. And I think there are going to be a couple of things that are going to happen. Number one is, the companies are going to get better. Not just about the molecules themselves, but also, how to modulate the CRS, in and of itself. And that can be handled, like I said, with dosing, with priming, with steroids, with fluids, a variety of prophylactic measures that you can take.

But on the other hand, I think, as we educate physicians about these therapies, the physicians will be more adept. And so I see evolution, both on the physician side, as well as the product side. And right now, we are getting better. There are actually some pure outpatient protocols that are underway now, and it is close to prime time for the outpatient setting. Not quite, but it's getting really close.

Alicia Morgans: I think that's fantastic. And I'd love to hear, as we look towards the future, and look to where we might be, what would your message be to the community, as we think about this?

Oliver Sartor: I think number one, we need to look at bi-specific approaches as being provocative and interesting. It's a novel way to target those elements on the surface of the cells. And in this case, it's without radioactivity. Of course, I'v known from a little bit of radioactivity. This is without radioactivity.

I think, that as we view these trials, moving forward, we need to view them in an optimistic manner, but also with a little skepticism. We need to be optimistic about the responses that we are seeing. We need to be a little bit skeptical about how well they can be tolerated and administered in the clinics. And as we go forward, just as in most areas in medicine today, I anticipate real progress. Smart people, working hard, can make real progress in medicine. We've seen it with COVID. We've seen it in prostate cancer. And I think, we're going to see it with the BiTEs, as well.

Alicia Morgans: I think we will too. And I think that's a fantastic message to send to our patients too, as we all come together as a community, and we work towards this common good. With them participating, of course, I think we can really make a difference, and I'm excited to see where this goes. So, thank you so much for sharing your insights. As I said before, we always learn when we hear from you, Dr. Sartor. We appreciate your time and your expertise.

Oliver Sartor: Thank you so much, Alicia. Appreciate the time.