Dr. Monty Pal welcomes Dr. Enrique Montero, research professor within the Arthur Riggs Diabetes & Metabolism Research Institute, to discuss his global journey in immunology and the pioneering work underway at City of Hope. The episode dives into the significance of the CD6 molecule on T cells - how its overexpression drives inflammation in conditions like type 1 diabetes and graft-versus-host disease (GVHD). Dr. Montero shares early insights from the first-in-human clinical trial of CAR Tregs for GVHD, noting promising safety and signs of durable benefit in patients who had exhausted other treatment options, and outlines the vision for expanding this technology to tackle type 1 diabetes and other autoimmune conditions.
In this episode of On the Edge of Breakthrough: Voices of Cancer Research, Dr. Monty Pal welcomes Dr. Enrique Montero, research professor within the Arthur Riggs Diabetes & Metabolism Research Institute, to discuss his global journey in immunology and the pioneering work underway at City of Hope. Dr. Montero shares how early clinical experiences with lupus inspired his lifelong mission to bridge basic science and clinical application, leading to innovative therapies for cancer and autoimmune diseases.
The episode dives into the significance of the CD6 molecule on T cells - how its overexpression drives inflammation in conditions like type 1 diabetes and graft-versus-host disease (GVHD). The duo discusses the development of targeted monoclonal antibodies and a groundbreaking approach using genetically modified regulatory T cells—CAR Tregs—to modulate immune responses, aiming not just to control disease but to regenerate damaged tissue.
Dr. Montero shares early insights from the first-in-human clinical trial of CAR Tregs for GVHD, noting promising safety and signs of durable benefit in patients who had exhausted other treatment options.
Looking ahead, Dr. Montero envisions expanding this technology to tackle type 1 diabetes and other autoimmune conditions, driven by a collective dream to move beyond symptom management toward true cures.
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Presented by City of Hope: www.CityOfHope.org
Dr. Pal (00:00):
I'm Dr. Monty Pal from City of Hope, and this is on the edge of Breakthrough Voices of Cancer research. Each episode, we bring you the minds behind the science, the stories behind the data, and the breakthroughs that could change everything. Let's dive in. Welcome everyone to On the Edge of Breakthrough. I'm your host, Monty Pal, and I'm a medical oncologist here at City of Hope. I'm delighted to introduce Dr. Enrique Montero, who's a research professor in the Arthur Riggs Diabetes and Metabolism Department here at City of Hope. Enrique, welcome to the program today. Thank you. You know, it's just remarkable to me. You've been here at City of Hope for 10 years. I've been here for about 20 or so, and you know, as I think about, you know, everything that you've accomplished career-wise, I see so many places where perhaps our careers may sort of segue in the future, and we're gonna get to that in just a moment. Um, but I was actually really quite enthralled by your training. So you, were you born and brought up in Cuba, I take it? Yes. And you did your, uh, early education there through PhD work as well?
Dr. Montero (01:08):
Yeah, I, I mean, I was born in Cuba and I finished my MD degree in also in Cuba with a specialty in clinical immunology. And then I move into more in the basic research. Um, and the idea or the concept behind was to develop a novel immune therapies for, uh, for cancer and immunity and the, and that was the, the basis of my PhD program.
Dr. Pal (01:38):
And we're definitely gonna come to that in just a second. I'm just curious, you know, when I was in medical school, the, the choices that you typically think of are, you know, family medicine or pediatrics or general surgery or what have you, right. I mean, it takes a certain type of individual or maybe experience or something you encountered with a patient to drive you into the field of immunology. What, what was it in your case?
Dr. Montero (01:58):
So, I think that my first, very first patient in the medical school was the third, uh, year. Uh, she was a very young patient that she, uh, uh, develop, uh, or start with symptoms and, and signs that affected multiple parts of the body. At the end, the diagnosis was, uh, lupus
Dr. Montero (02:21):
And
Dr. Montero (02:22):
A very, uh, uh, difficult, uh, disease to treat. She passed away six months, and that was the very, probably the most difficult, uh, time for me when I was in my medical school. And then I decided probably I have to do something else. You,
Dr. Pal (02:37):
You know, I have to tell you, I remember in medical school as well, very vividly treating patients with lupus and, and it's just the most challenging thing, right? I mean, in many ways it was also the state of many fields in oncology at the time. We had no good treatments. You might try steroids, you might try immunosuppressives, right? But no good way to treat the disease. Uh, so I, I definitely see where you're coming from and how that might sort of steer you towards novel avenues for therapy. Right. Um, you, you know, beyond the training that you had in immunology in Cuba, you actually have just this amazing sort of world tour, I'll call it, of different places that you've been, you've been to the Wiseman in Israel, you've been to Portugal, you've been to Zurich, Switzerland for your training. Uh, tell me how those opportunities came about and maybe just, you know, gimme a little tidbit about what you learned at each one of those places.
Dr. Montero (03:24):
I have, I have been trying to work in, in between two fields, let's say, cancer around community, and also trying to work in, in between two different areas, basic science and clinical application. I had the chance to go to Switzerland to work, uh, uh, with, uh, Franco Cabali and, uh, eh, just in clinical trial for novel immune therapies. Okay. Just to learn how to do translational science.
Dr. Pal (03:48):
What sorts of treatments was he looking at that point in time?
Dr. Montero (03:51):
At the time was to, to learn how to try or how to evaluate patients, uh, with, uh, in that particular case with cancer, receiving novel drugs, how to try, or how to evaluate first in human studies. Got it. How to check toxicity, how to check, uh, some, I mean, to get some flavor of the potential therapeutic effect. How do we can understand the, the doses that we probably have to during the trial. I, I think at that time, I was, uh, mainly involved in some of the growth factors that, uh, now are very, uh, uh, well applied in, in cancer. And that was a phenomenal experience, learning how we, I mean, after moving in, in the, in the development part or the discovery first development, and then how we can, uh, do the transition into, into first in human study, first time that you, uh, inject a, a drug. So that's the experience in Switzerland. And I think that immediately afterwards, I moved to Pastor Institute in France.
Dr. Pal (04:54):
Okay.
Dr. Montero (04:54):
Where I moved more, I mean, it was a, a, a big shift because it was from seeing patients every day receiving new drugs to, uh, a, a lab with, uh, Antonio continue that is one of the, uh, leaders in the field of, uh, autoimmunity immune regulation. Uh, and to do some basic science with him to understand how the immune tolerance happen, how we can, how the body or how the immune system can control the overreaction against your own tissues. And I, I think that the, uh, working with him, he's a, I will say that sort of a, sorry. And after layer of an in the field, tolerance has been considered as a, as a lack of autoreactive cells in one individual. And the interpretation is if you don't have the, uh, this, uh, self reactive, uh, immune cells, you will not have a immunity. And he was, uh, probably pioneering the idea that, uh, the immune system is beyond that observation, that we may still carry on self reactive immune cells, and still the body is able to control or modulate that response.
(06:14):
And rather than being dangerous, probably these self reactive cells are, are convenient to prevent the development of tumors. I think that was the, the, the, the phenomenal experience I got with, uh, Antonio. And, um, and as part of the, or the continuation of that story was the, I mean, why, um, uh, I moved to, to the Biman Institute with Adam Cohen, who was, uh, or he's, I would say that this is the, the one of the most brilliant minds in, in immunology. And, and he has a probably not so popular concept that is called immunological ous. So that we have in the immune response and immune repertoire, uh, we have, uh, different antibodies or, or, or cells that are able to recognize every part of the body.
Dr. Pal (07:09):
Okay.
Dr. Montero (07:10):
So the immune system is a sort of a communication system, uh, as, I mean, the way that probably we are communicating today, but, and, and the, the function is to, to maintain the homeostasis of the, of the body, not only to prevent the or to control infections, but mainly has a physiological process of, uh, of, of healing what is wrong and preventing the, the emergence of tumors. So that's the, I think that that was the, probably the, the, the blocks that just made part of my initiation in the, in this film.
Dr. Pal (07:53):
Uh, I think that makes a lot of sense. So you had sort of the, the clinical phase one experience in Switzerland. You had the experience of, you know, getting deep in the lab at the Pasture Institute at the Wiseman City of Hope, incidentally has a lot of collaborations with the men that are still ongoing. It's a really well established bridge that we have, uh, to Israel, in fact. Um, you know, I think that that is a good segue into maybe discussing some of these really pioneering discoveries that you've made. Um, and, you know, just for the audience here, you know, we're gonna talk about a molecule called CD six. Um, and if you look at white blood cells in general, these are sort of coated with various markers. Uh, they're given these, uh, terms, CD one, CD two, CD three, and so on. Um, but you've really helped us understand what CD six is doing at the surface of the white blood cell in particular. Maybe you could elaborate on that for our audience a bit.
Dr. Montero (08:44):
It means it's, uh, just a, a way to, uh, it's a short way to say that something is, uh, is a molecule is expressed on the cells. And even if we don't know what is this one, we are giving a, just, we are tagging this with a name
Dr. Pal (08:59):
And, and tell us what CD six does. When CD six is at the surface of the T-cell, what, what's its function?
Dr. Montero (09:04):
That particular marker is expressed on, mainly on T-cells. Let's a t lymphocytes. Those are involved with the, eh, so we have a sort of a, a classical division in immunology that is, uh, we have antibodies or we have T cells doing, uh, the process of, uh, of helping the body in, in, in, in controlling or, or inflammation or infections or whatever. And so the, the CD six in particular is expressed mainly, mainly on, on T cells, and is, uh, is a molecule that is usually has fluctuations once the cells are, uh, let's say in the normal state, or they are overactivated. If they are, if the cells are overactivated, you will have more CD six express on the
Dr. Pal (09:51):
Cells. Okay.
Dr. Montero (09:52):
And this, uh, and, and in particular when the cells are over expressing the CD six, this overexpression is linked or is associated with the capacity of the cells to, to be more inflammatory. So let's say inflammation, uh, is linked to the overexpression of the CD six molecules and, and, and T cells. And that's exactly that. Uh, it's, uh, pharmacological differences. What brings, uh, us to, uh, the opportunity to say, okay, why don't we try to moderate those cells over expressing CD six.
Dr. Pal (10:30):
So this is a very logical continuum. You've just explained to us that CD six coated T cells are really responsible for inflammation. Right. Um, and so perhaps, uh, technique or technology that could mitigate CD six T cell activity could potentially help with diseases where inflammation is a problem. Right.
Dr. Montero (10:48):
Absolutely.
Dr. Pal (10:49):
Um, and, and talk us through this, because I guess there's a couple of different clinical states that City of Hope focuses on where this would be applicable. One big one, and this reflects the department that you're in, is diabetes, right? So, you know, we always think of particularly type one diabetes as being autoimmune in nature, maybe driven by some of that inflammation. Uh, tell us about the application of these CD six technologies there.
Dr. Montero (11:12):
Our, our, uh, perception or our, uh, hypothesis behind o of, I mean, af after this finding that, I mean, CD six or expression is linked to inflammation, is how we can target this molecule instead of, uh, let's say if we have a, a, what, what we probably is very popular now, the this monoclonal antibodies, uh, that they can, uh, is a, like a is a molecule, a small molecule is only one 50 kd, I mean one 50 kilotons. That can, we can use, uh, like any regular antibody that we develop against vaccine or against any infection, but we produce in the, in the, in the lab. So how we can, uh, benefit from using the technology of antibodies to target the CD six molecule and to try to modulate the cells that carry the overexpression of that molecule. So the, the, the principle behind, and this is a, a clear difference with the, our, uh, the previous work in, in this area. So the previous perception was that, uh, if you target the, uh, infl, the, the cells associated with the inflammation, if you kill the outdoor reactive cells, you will control the problem. But there are some observations that probably do not match with this, uh, hypothesis, because after killing the overreactive T-cells in, in some other studies has been found that you have to continue the treatment for a very long time.
Dr. Pal (12:48):
Mm-hmm
Dr. Montero (12:49):
Otherwise, when you stop the treatment, the cells will regrowth again in your body, and the autoimmune process will continue, the inflammation will continue.
Dr. Pal (13:00):
Sure. And that's tough for a disease like type one diabetes, right? Yeah. Because you know you're gonna be on a lifetime of treatment. Most people when they're diagnosed or you know, teenagers, right. Relatively young. And so I see what you're saying. If, if you wanna target CD six right, in a disease like type one diabetes, and if you wanna use an antibody, a single drug, you're gonna have to be using that, you know, for eons. And, and of course that leads to the issues of cumulative toxicity, cost, et cetera. So, so tell us how we can sort of circumvent that.
Dr. Montero (13:29):
I think that, I mean, the second just to, to, to also, to put in the context of this idea is, uh, we consider that probably killing the, the cells, the, the inflammatory cells will not do, I mean, all the benefit that we are expecting for the long run. So what we considered was that targeting CX probably we can reeducate the immune system so we will not kill the cells.
Dr. Pal (13:50):
Okay.
Dr. Montero (13:51):
So we'll modulate the cells in the way that they will stop being overreacting against the self tissues, and they will, um, they will just, uh, re uh, rewire the internal interactions to behave like a non, uh, inflammatory cell. So in that way, so we are reeducating what was, uh, going, uh, uh, wrong in this patient with, uh, type one diabetes. Um,
Dr. Pal (14:23):
And tell us how you're doing that. Is that, is that with a different type of technology?
Dr. Montero (14:27):
Yes. Now, uh, so there, there are like two options. So we have the option of the antibody. We already have developed an antibody that was, uh, that is specific for the CD six molecule. This antibody has been efficient in other indications modulating the, the inflammatory cells in other indications like, uh, pori acids and, uh, and, and, and rheumatoid arthritis. But type one diabetes is like a, probably the, uh, is a, is a higher bar. So it is, uh, knowing that multiple, uh, uh, attempts have, they have failed in modulating the, the process. So they, the technology that we, we apply here is something, uh, novel I think that based, and it's based on the, the, the old experience that City of Hope has developed developing CAR T cells for cancer. But in that case, CAR T cells, meaning that we have a a and, uh, a T lymphocytes that has, uh, we insert, let's say, to simplify the idea with a sort of an antibody that will give the specificity for a particular, uh, um, uh, molecule or CD that is expressed in the, in a tumor. And then we enhance the inflammation of this, uh, inflammatory, uh, capabilities of the regular T cells to act against tumor. In our case, what we did was, uh, the reverse of the story. So now I'm coming back to the, to the cancer and community
Dr. Pal (16:03):
Connection. Well, and I'm, I'm glad you brought it up this way, because we had Dr. Foreman on Stephen Foreman a couple of weeks ago. And so we were talking through the, uh, program here in CAR T-cell therapies. And I think our unilateral focus was really on how we use CAR T-cell for cancer. And that's a very different application from what you and I are talking about. Right. Because there we're really trying to sort of hit on, uh, a foreign entity, if you will, right. Within the body here. You know, the goal is to not necessarily get rid of an invader, so to speak. Right. Uh, IE cancer, we're really trying to sort of regulate the body's own tissues, right?
Dr. Montero (16:37):
So, uh, yep. So is, uh, is regulate and also regenerate the tissue. So that's something that probably is not, um, mean, uh, uh, because I mean, in principle, you can control a disease, but if you have, like in, in diabetes, you have a tissue that is already, uh, not only, uh, invade or in, in, uh, is all these inflammatory cells are going inside the tissue and start destroying the tissue. You have to control that process. You have to control those cells. But at the same time, after controlling the cells, you have to facilitate the regeneration of the tissue.
Dr. Pal (17:15):
Right.
Dr. Montero (17:15):
And that's exactly what we are trying to do here. So instead of using the t uh, effector cells associated with inflammation, so what we are using in our technology are, uh, t lymphocytes with that we call, uh, uh, having a regulatory function. So this is a soup group of, uh, lymphocytes is only around 10% of our, uh, army of T cells, and they are able to regulate the, uh, inflammation. So those cells, in principle, they are, they have the responsibility to, to keep the, the, the response on check. So you, I mean, they prevent the overreaction against your, your tissue sometimes, uh, fails and sometimes you don't have the enough, enough number of cells to do that. So what we are doing in our case with our technology is we are taking from patients taken out from the body, these, uh, regulatory cells, even in tiny numbers, then we put them ex VI in culture, and we, uh, modify genetically these cells with the specificity of the CD six antibody that we developed earlier
Dr. Montero (18:34):
Mm-hmm
Dr. Montero (18:35):
Dr. Pal (20:05):
Got it. In this patient. That's so interesting. So, so tell me how it's working out in clinical practice. Is this something that right now is in clinical trials and type one diabetes?
Dr. Montero (20:14):
Eh,
Dr. Pal (20:15):
The
Dr. Montero (20:15):
Initial trial? We have a, I mean, because this is, this one is a, is a typical first in human study.
Dr. Montero (20:21):
Mm-hmm
Dr. Montero (20:22):
Dr. Montero (20:29):
Mm-hmm
Dr. Montero (20:30):
Uh, this is a new acquisition. So City Hope, uh, we get, uh, probably the first, uh, uh, authorization from the, uh, FDA to perform a clinical trial using a car, tre. And, and because it was the first inhuman study, uh, we were required to do in patients with, uh, let's say more, I mean that patients that are, they have less option that an individual with, uh, I mean other, uh, indications like, uh, diabetes or, or pori or psoriatic acids
Dr. Pal (21:06):
Or, or, or things like that. And that makes sense. 'cause I think that, you know, if you've got this high risk, you know, high reward technology, right? You may not want to use it in a setting initially, initially, like type one diabetes where you do have the option of the patient going on to, you know, chronic insulin therapy and so forth, or psoriasis where there's the, you know, anti TNF agents and so forth. So I, I, I think what you're saying makes a lot of sense. So what indication did you settle on then after talking to the FDA?
Dr. Montero (21:32):
Yes. I mean, also a built on top of the, of the capabilities developed at City Hope. So we know that this is, uh, city Hope is also leading, uh, institution in bone marrow transplantation.
Dr. Pal (21:43):
Yeah.
Dr. Montero (21:43):
And one of the consequences of bone marrow transplantation is that, uh, I mean, a patient may develop, uh, a, a reaction of the transplanted cells against the, the recipient against the indi the individual doctor who receive the, the, the, the marrow. So in that case, uh, I mean the, this disease that is called graft versus host disease, uh, was the indication that we started. So we want to control the reactivity of the transplanted cells against the body of the recipient individual.
Dr. Pal (22:17):
Okay.
Dr. Montero (22:18):
And, and that was the, the first trial that was approved by
Dr. Pal (22:21):
The FDA. This is great because graft versus host disease is something that I, I haven't treated since I was in fellowship, but I just remember how daunting it was. You know, you, you envision the patient who has leukemia, right? Who, or perhaps lymphoma. And they undergo what's called an allogeneic transplant where they're getting stem cells or bone marrow from another individual. You know, they're very immunosuppressed, uh, you know, for an extended period of time. So they're already prone to lots of infections. And then that graft that they get, you know, which is intended to fight off an existing cancer, can start reacting as their own organs, right? So you can end up with really severe and critical diarrhea. You can end up with really horrific skin changes. I mean, these are really pressing problems. So I applaud you for coming up with a good strategy for us to kind of try to mitigate graft versus host disease.
Dr. Montero (23:07):
Yes. And, and, and if we check, I mean, if we, if we compare, I think that the, the, the GVHD is, is, is a very close disease in terms of, uh, the expression to lupus
Dr. Montero (23:18):
Mm-hmm
Dr. Montero (23:18):
'cause it's, uh, you have multiple organs affected as you
Dr. Pal (23:21):
Oh, that actually makes sense. Yeah, indeed.
Dr. Montero (23:24):
Yeah. So then, uh, we have, uh, and that's also part of the, of the, of the limitation of the, of the current therapies for, for Crohn, GVHD, because you have a skin damage, you have, uh, even, uh, damage in the, uh, oral damage or in the eyes, or, or, or, or of the livers, or you have multiple organs affected.
Dr. Pal (23:42):
And ironically, you're just layering on more and more steroids in most cases, right? Yes. To try to immunosuppress patients or cyclosporine. And, you know, just for context for folks in the audience, uh, you know, if you end up using all of these immunosuppressive drugs, you know, that risk of fatal infections goes up, manyfold. So, you know, it really belies why we might want a technology like this.
Dr. Montero (24:03):
Yes. And, and probably, uh, an additional value of our strategy. So let's say that the car Tex, uh, they have not been, uh, I mean, has been also, um, I mean, part of the strategy of, uh, of other institutions and other even, uh, the, uh, new, uh, companies are emerging just to work in the field of CAR Tex. Um, and the strategy has been using, uh, these regulatory cells specific for one particular CD or molecule in a particular organ,
Dr. Montero (24:40):
Let's
Dr. Montero (24:40):
Say if it is a diabetes, to have a, a, a car that is specific for insulin,
Dr. Montero (24:47):
Okay.
Dr. Montero (24:48):
For GA or for another, uh, anti express in, in type one diabetes. Uh, the problem in, in GBSD, if we follow the same, uh, I mean, uh, a strategy is that because you have multiple organs affected, so you may need multiple, uh, car tres. So one that is specific for, uh, a CD that is expressed in the skin.
Dr. Pal (25:14):
Okay?
Dr. Montero (25:15):
One that is expressed in the liver, one is that is expressing in the eyes. And then in that case, it's, it's, uh, I mean, it's complicated in terms of, uh, of, uh, of technology. Right? And also it's complicated in terms of, uh, of, uh, I mean the pharmac economics of the application. Now, is yours different? Is it, is it one, tell me how, in our case, what we, instead of go of, instead of going after or using a car that is specific for one particular organ, we use a, I mean, the car that is specific for CD six that is specific for the, for T cells. Okay. Inflammatory cells. And then we go directly to the, the, the cell that is causing the disease is not to the organ mm-hmm
Dr. Pal (26:05):
Okay. Oh, wow.
Dr. Montero (26:06):
And then in that case, we don't need multiple car TX because it's a T-cell mediated disease
Dr. Montero (26:13):
Mm-hmm
Dr. Montero (26:14):
So then we can regulate the, the inflammation in every organ targeting the, the cell that is causing the problem.
Dr. Pal (26:24):
Got it. Okay. That makes sense.
Dr. Montero (26:25):
So, uh, and that's the reason why GBSD is the perfect, uh, initial indication for, for our
Dr. Pal (26:31):
Novel strategy. Now, are you able to share with us any of the early insights that you have from the clinical trial? I don't want you to, you know, break any barriers of confidentiality. And by the way, I, little birdie told me that you've actually got, uh, an oral presentation at ASH for the data. Is that
Dr. Montero (26:47):
Right? That's true.
Dr. Pal (26:49):
Okay.
Dr. Montero (26:49):
So I think that, I mean, uh, that we received the approval, uh, I mean, uh, about two years ago, uh, from the FDA, and then we started the trial in, in, in GBSD, uh, six patients have been treated so far. I think we have a phenomenal team, both, uh, in the, I mean the, my group and, uh, doing their basic, uh, signs, uh, with, uh, where, uh, collaborators like, uh, Steve Foreman and Christine Brown and, and, and, and Jamie, uh, Warner in the, uh, area of, uh, of, of manufacturing of the, this cell therapy and also part of the discovery. And we have the clinical team with the, EH, am Maddi, uh,
Dr. Pal (27:38):
RA and Rio Nakamura. I'll just mention for our audience too, Rio Nakamura is a very dear friend, and, you know, he, he and I have actually collaborated on some different strategies to mitigate GVHD, and in my case, to really sort of do the opposite, maybe augment immunotherapy, uh, using probiotic strategies. And so we've, we've worked together there, but I had no idea that he was actually involved in this space. He's very passionate about trying to find new strategies for GVHD.
Dr. Montero (28:03):
Yes. He's amazing. He has been, uh, he's, uh, I mean, searching for any option, any, any novel approach that can help, uh, his patients. And I think that was, that's the reason why, I mean, we just, uh, connected quickly in with this, uh, opportunity. And then, so the trial is, is ongoing now with the first six patients. Uh, eh, we have to, to say that. I mean this, because this one is the first in human study. The initial, uh, objective was to check, uh, safety and feasibility of the, of the, this, uh, new approach. And, uh, and for that, we have to start with a very, very low doses of the therapy that we are, uh, developed. And we were not expecting to see any, uh, therapeutic efficacy or signs of, uh, of improvement in these, uh, heavily treated patients. So in mind that the initial patients are, uh, are, um, accepted for the study, uh, um, are usually those that are half already fail for the previous, uh, available therapies.
Dr. Pal (29:11):
Oh, yeah.
Dr. Montero (29:12):
Or even the combination of those, uh, therapies.
Dr. Pal (29:14):
Right.
Dr. Montero (29:15):
And these are, this is, this is the group of patients that we have, uh, uh, already, uh, dose with this, uh, novel therapy. So, um, the first patient has already passed the first year after fusion.
Dr. Pal (29:28):
Oh, that's amazing.
Dr. Montero (29:29):
Okay. Good. And the first observation we have is that the, the, this novel approach is safe.
Dr. Pal (29:37):
Okay.
Dr. Montero (29:37):
We have not seen any sign of, uh, of, of severe toxicity or damage in the, in the body of this individual.
Dr. Pal (29:45):
Did that patient's GVHD get better, um, in due time or
Dr. Montero (29:49):
So in this patient? The first observation, so let's say, I mean, uh, uh, one of the individuals, uh, uh, ion very young individual, uh, with this GVHD, very, uh, a lot of limitations in terms of, uh, physical activity and, and, and, uh, and then this patient receive, uh, uh, before he was receiving, uh, up to six different therapies, and he was not able to control the, the disease after injecting with the, our approach, of course, for the trial, we have to stop the previous, uh, uh, treatments or the ongoing therapies. So we have to use only this one plus something that is, uh, I mean, uh, base, uh, um, a, a basic therapy for for for, for for GVHD. But it's not, I mean, we know that doesn't work in this individual, but I still, it's recommended to keep a low dose of that, uh, medication. So in this individual has been stable first and then start, uh, after a few months. And now comes to the idea of why we like to, we would like to, to think on, uh, meaning in reverse for any new drug, we want to have a long-term effect. So this patient start with a, a disease stabilization, and then start with a, I mean, uh, responding meaning that the patient, uh, start, uh, just reducing the symptoms. The
Dr. Pal (31:22):
Symptoms, the symptoms got better, right? Yes. Symptoms, yes. Okay, go ahead.
Dr. Montero (31:24):
And, and now, I mean, the, uh, has been, uh, still to today is, has a partial response.
Dr. Pal (31:32):
Okay.
Dr. Montero (31:33):
But the, with this tiny dose, this tiny dose, and we cannot change that. The two, uh, additional observation is that this patient first has, uh, has not required to go back into the previous therapies. So he's stable able, uh, without any additional drug and was injected sort of, uh, one year ago. Right. That's great. Well, that's really interesting. Good. And the other thing that is quite, uh, surprising is that the functional activity of this individual, the capacity to, uh, to live, uh, his, uh, regular life
Dr. Pal (32:12):
Right,
Dr. Montero (32:12):
Has increased, uh, I mean substantially. He's, uh,
Dr. Pal (32:16):
He's doing more activities. Oh, well, that's a, that's a nice way to sort of segue into, you know, perhaps, uh, this ASH presentation. So we're excited for you to present your data at ASH this year for, for the audience. Ash is the American Society of Hematology, and it's really kinda the premier organization to present data around, you know, drug therapies and novel approaches just like this. So I I can, this is gonna be one of the spotlighted presentations there. Congratulations.
Dr. Montero (32:42):
Thank you. I think they have an excellent motivation, but not only to continue with this trial, now we are in the second dose level,
Dr. Montero (32:50):
Right.
Dr. Montero (32:51):
That we are expecting to increase even the, the response we receive also, uh, an authorization from the regulatory agency to reinfuse these individuals that, that will help consolidate the clinical effect. But I think that the, what is in mind of our, uh, team, particularly the the clinical team, is that we have probably, we are building the opportunity to expand the use of this novel approach in, into other indications like Type one diabetes.
Dr. Pal (33:21):
Wonderful. Well, that's, that's super exciting, and we're gonna have to have you back in coming years to tell us where this particular technology sits. It seems like it's gonna advance quite far along, you know, I was just curious getting back to what we started with, which is this, you know, really sort of amazing. Uh, and I'll say, you know, sort of semi circuitous trajectory that you've taken in your career. Part of what you've done ahead of coming to City of Hope is you've worked in industry, uh, you were in La Jolla and faculty for a period of time. I, I always loved to get to know what sort of drew people to the institution. I, I personally am a little bit boring. I grew up a couple of miles away from here, so, you know, I've been wanting to come to City of Hope I've ever since I was a child, perhaps. But tell me about yourself. What ultimately brought you to City of Hope as opposed to other opportunities?
Dr. Montero (34:06):
I think it's quite simple, quite, uh, straightforward. So then, I mean, working in, uh, in, uh, uh, for example, LA Jolla Institute, LA Jolla Institute for Immunology, like, uh, probably the, the, the one of the best institutions for, for in this field, in the field of immunology. And it's mainly focusing, uh, in basic science. And, but the translational component is quite, uh, limited, uh, and requires the association with other, uh, I mean hospitals or, or clinical institutions. City hopes is like a, the place where you have everything at, I mean, at once. So you have here, uh, I mean the, the lab for basic science, you have a, you have manufacturing facilities, you have a, a culture of, uh, of, of, uh, of quality control and interaction with the regulatory agencies. And you have a, a, a robust and, and phenomenal clinical group that will help in the process of translation of the, the discoveries in the lab till patients. And that's, that was actually the reason why City Hope, uh, city Hope is the, the place where we can close the cycle. So we can go from the basic science till the clinical application, learn from the trials, from the outcome of the trial, and then to develop the second wave of, of, uh, of science or, or the new, the noble drugs. And that's exactly where we are right now.
Dr. Pal (35:40):
I, I have to agree with you, I've had the same experience kind of working in the microbiome space and seeing, you know, compounds really sort of come from, you know, more or less the laboratory into patients into phase one, then phase two, now phase three trials. I mean, it's, it's just remarkable what you're able to do when you have everybody on site. I, I was actually at our microbiome symposium yesterday, um, which was held by Rob Jank, who, uh, just came over to run one of our microbiome core facilities. Terrific guy who, uh, hails from MD Anderson previously. Um, and, you know, we, he had a bunch of investigators there from other institutions, um, which shall remain nameless. Um, but they're in the Southwestern US and they all said the same thing. They sort of wish they had that close proximity between the basic scientists, the translational scientists, and, and the clinician, you know, just to sort of complete the loop, if you will, as you said. Um, so that makes a lot of sense. You, you know, we always sort of close out the program by asking our guests a very difficult question, but I'm gonna throw it at you anyways. Um, and the question is, the title of this podcast is On the Edge of Breakthrough Voices of Cancer Research. What does on the edge of breakthrough mean to you?
Dr. Montero (36:51):
I think it's, it is just trying something that is not obvious brilliant. Something that is, uh, that goes beyond the common sense, what is called the common sense. Uh, and, and, and, and aiming just to change the, the, or help patients to change the, the expectation they have now with a suffering, any particular disease, how we can, uh, bring back to a normal life, this individual. It's not only the dream of controlling a disease, it's not only the dream to regenerate the tissue, it's just to, to heal also the, the mental status that patients could be patients at some point, but they can go back into the regular lifestyle after an innovative therapy is, is used in this, uh, individual.
Dr. Pal (37:45):
Brilliant, brilliant. I love that. Very simple answer. You know, just going beyond the obvious, but it's so true. You, you basically have taken, you know, this CAR T cell technology that we at City of Hope have been talking for years about to fight cancer and sort of, you know, repurposed it in a different way. Again, with Car Tregs, very, very different construct, but now you're actually fighting autoimmune disease, right? It's, it's a, it's a brilliant, uh, manifestation of what you just said there. I think. Uh, well, Enrique, it was a real delight to have you on the program. And again, I hope to have you back in coming years to really kinda give us a sense of where this technology has advanced.
Dr. Montero (38:20):
Thank you for invitation again, and Ash presentation to have this work already. Uh, moving in GVHD, now we want to go in type one diabetes. We want to help patient with type one diabetes. And then what else? We want to go beyond, not only to have a drug that may help these patients initially, but also to cure them. And that's a dream that I'm sharing with my colleagues, and that's our dream. And when you have a collective dream, probably things will come to reality at some point.
Dr. Pal (38:50):
Indeed. Well said. Well, pleasure to have you. Thank you. Thanks for tuning in to On the Edge of Breakthrough. See you next time for more insights from the front lines of cancer research and care.