Founder Stories: Jeff Bluestone, Pioneer in Tregs & Co-Founder and CEO of Sonoma Biotherapeutics

Welcome to Ask the Expert. This is our pop-up digital cafe where we have a short sharing of slides and then just a really hopefully robust discussion about what's going on with different scientists. And everyone, I think, on the call knows that Dr. Jeffrey Bluestone is one of the leading immunologists in the field of T-cell activation and immune tolerance research. This led to the development of multiple immunotherapies, including the very first FDA approved drug-targeted T-cell co-stimulation to treat autoimmune disease and organ transplantation, and the very first CTLA-4 antagonist drugs approved for the treatment of metastatic melanoma. So he's a huge leader on the stage of type 1 diabetes research, and— oops, sorry, I'm going to omit somebody— he's also served as the executive vice chancellor and provost emeritus at UCSF and was the former director of UCSF Diabetes Center. And now he is heading up and starting this brand new venture at Sonoma Bio. And we're really excited to hear what's going on and how it's going and have people ask questions. So welcome. Thanks again.

It's a pleasure to be here. I'll start off by admitting I did not prepare any slides. I didn't know that, but I'm always good at answering questions. So hopefully—

Okay, that's fine too.

It's focused on that. Um, maybe at least I'll start out by giving an introduction, uh, at least to Sonoma Bio and, and what we're trying to accomplish. Um, and a lot of that, of course, is built on my academic career over the past, uh, many decades. Um, but I think, uh, really reflects where we are now in the space of immune tolerance and how to actually achieve a durable and long-lasting treatment for patients with autoimmune disease, including type 1 diabetes, and the idea that we can take advantage of the immune system's own ancient efforts to try to maintain an immuno— an immune homeostasis so that we live a balanced life, recognizing foreign agents when we need to, viruses, bacteria, but yet not but not attack our own body inadvertently. And I think what we have learned over the last few decades is that really the immune system is filled with a bunch of checks and balances that really allow us that ability to respond rapidly and effectively against foreign invaders. And for the most part, be able to control those responses and balance those responses so that we don't get undo overly active immunity. Now, one thing we've learned the last 2 years is that coronavirus and COVID-19 have taught us a lot about how that yin-yang can really backfire. Most of the people who die of COVID die of a dysregulated immune response. They don't die from the virus. The immune system actually does a great job of responding to that virus. It just gets so zealous in doing it that it starts destroying tissues in the lung and, and you end up— so, so it really is an ex— is an experience that we've now had, which tells us how important this control is. So what have we learned that I think is relevant in this regard? Well, I think what we've learned is, is that a combination of cells and different specialized cell subsets in the immune system and specific proteins that are expressed on those cell subsets have been the way that we have that check and balance system going. In the case of the cells, obviously the effector cells, those cells that target the foreign viruses and cancers and bacteria, those cells themselves have to be controlled and do that through a series of what we now call checkpoints, which are selective molecules on the surface of those cells that are designed to shut down or to quiesce those responses, molecules like CTLA-4 and PD-1. So when you get a good active response, which depends on recognition of antigen, activation, then what we call co-stimulation and cytokine expansion, that bolus of positives then can get offset by these brakes that are put on the cells. But in addition, what we've come to appreciate is that there are also specialized cells in the immune system that are designed to keep the immune system balanced and in check as well. And the cell population that many of us on this call and that I've been working on for a long time now, these so-called regulatory T cells, Tregs, are really designed for just that purpose. They survey the body, they're sentinels running around, and when they see immune systems that have been overzealous and out of control, they have a series of activities, almost a polypharmaceutical factory, that are designed to shut down these. And it really does require all hands on deck. It uses growth factor modulators, it uses metabolic modulators, it produces regulatory cytokines, and the cells also will directly shut down antigen presentation, all designed to keep the immune system in check and not overzealous. Now, unfortunately, in autoimmune disease, those two systems, the effector cells and these regulatory processes, often go awry. And they go awry in part because of the genetics of the person, and in part because of the environmental exposures that they've had. And so the effector cells are not easily shut down by these checkpoints and other cell types. And the regulatory cells aren't as effective as they might otherwise be. So, I think that all this has led many in the field, and ourselves included, to think if we can help the system out, if we can help to rebalance that system, that we might be able to initially shut down ongoing autoimmunity, and— but maybe even eventually to get in early enough to prevent a lot of the damage that it causes. And so the approach of Sonoma Bio has been to take advantage of both sides of this balancing act. On the one hand, we're developing a biologic that will actively and selectively eliminate a number of effector cells that are responsible for destruction of the tissue. In diabetes, these are islet antigen-specific, beta cell-specific cells, and do that in a way that allows us to condition or debulk the patient to make them more able to control this immune response by eliminating a lot of the armory that's there to destroy that tissue. And then the second part of the company is developing cell therapies, and particularly Treg cell therapies, that can be targeted to tissues that are at risk of being destroyed and provide through that the ability of these cells to shut down locally the inflammation that's out of control and thus avoid systemic immunosuppression and avoid the, the targeted effector cells in that tissue themselves. And the The way we do this is not unheard of, is in fact now a very successful approach that's being taken in cancer, which is to provide on these cells a receptor that allows them to recognize an antigen that's present within the tissue that's being attacked. So there are two ways to do that. One is to use a T-cell receptor itself, which recognizes antigen. And the other is to use this synthetic biology approach, which is a chimeric antigen receptor, which is a fusion between an external entity, a monoclonal antibody that recognizes a protein, and the internal signaling domains that will drive those regulatory T cells to function. And by putting these CARs on these cells, they get to the site, they recognize antigen, they deliver a signal, and hopefully they'll suppress locally. So what we're trying to do is not unheard of in the space. Space, but it's really exciting that there are now 6 or 7 companies that are actively involved in this, and really does suggest that we're going to give this a good shot and see if this, if we, if this combination of the, of the T effector depleting agent with the effector cell suppressors, the Tregs, will lead to a durable response. And the nice thing about cell therapy is it's a living drug. And so as a living drug, the idea is once you've put this into the patient, those cells will proliferate, they'll survive long-term, and allow for a one-and-done treatment that we won't have to continually inject like every day these cells into somebody. And then I'll end with one last point, and that is just that these are high-risk and high-reward studies. I think we're at the, earliest days of this, and some of the people on this, on this video have really provided a lot of the fundamental research that's allowed us to really get as far as we can. And, and the work that's been supported, especially in the diabetes field, has really allowed us and others to really pursue this aggressively, given the, the challenges that are ahead for any cell therapy program. I feel like our field has benefited enormously from the kind of research that's been done in academia and supported often by philanthropy. So why don't I stop there?

That's great. That's a, that's a great, you know, high-level view. It's awesome that you guys have entered the fray here with all your knowledge and background and your experience in the field. I think it bodes very well for, you know, getting something to clinic. So I did want to just, you know, sort of give a shout out. Vertex had a big day yesterday, right? And they showcased that they had success in a patient with an implant. And I just wanted to talk a little bit about therapeutic windows. So it looks like, you know, obviously this could— your therapy, the T-REG therapy you're developing could be really effective in an early therapeutic window prior to diagnosis, like in the prodrome. But also what about its role in, you know, you know, in patients that are undergoing like a Vertex implant?

Yeah, well, I think it's, uh, you know, it's, it's something to think about. Um, I should say that there's a clinical trial now being conducted at UCSF, um, using Tregs in islet transplant setting, working with James Shapiro up in Edmonton. And the concept is exactly what you said, which is, can we, um, help to avoid any immune response that might be generated against those foreign islets? Now Remember that the approach that Semma and now Vertex has taken is to try to create an immune-cloaked or an immune-hidden cell so that the immune system doesn't play an important role.

But just in case—

Leo, I know Leo and a lot of people who live around me know my thought about that is the immune system is incredible. It can detect a single amino acid difference in a singular protein. My sense is that you can run, you know, but you can't hide. And I think we could well end up with a cell that is far less immunogenic, which I think would be great. But it may well not be, especially in patients that are presensitized, which are diabetic patients already have a strong immune response. I think it may be hard to develop a totally immunologically inert cell. So I think there is a role for active immune regulation in that context. I think it was one exciting area, work that was started in my group by Linda Vo, and there are other people working on this, which is to try to develop Tregs out of iPS cells, and thinking that you might be able to use the same iPS cell to create the beta cell and create the islets so that you have a matched regulatory population to go in. You know, when you look in the future, you can imagine a scenario where even under the best circumstances, off the shelf, beta cells won't be perfect, and by including regulatory cells or some other tolerogenic combo therapy could be quite effective.

Yeah, no, it seems like there's a lot of room to move around. I see that representative from GentiBio is here, so that's cool too that we have other people that are in, um, going after it in the industrial space. And, um, I also just wanted to give a shout out to, uh, you know, Marcus, uh, Klein-Wutfeld, I'm sorry about my pronunciation. He's here from Gent, Belgium, and also Yasmin Hosseini from King's College London, now Qwell. They both have some really interesting papers recently. Markus in August with the fast and efficient editing of human FOXP3 Tregs. He set the stage saying robust and fast protocols for genome editing of the Tregs are limited. His group has improved upon this, as shown through the paper, and then Yasmine came out in July with her paper, chimeric antigen receptor modified human Tregs that constitutively express IL-10, and they maintain their phenotype, and they're potentially suppressive. So both of these scientists are kind of wading into refining protocols, I think. How do you envision that as academia and industry can move together in this whole refining of protocols space? Or is it possible? What are your thoughts?

Well, you know, I, I, my career has all been about collaboration and building teams and creating value in working together. So I would love to believe that the same thing will hold up here. I mean, Doug Melton, you use the example of SEMA, that was work that came out of his academic group that he started SEMA. And, you know, that's been a great partnership now with Vertex. I think that the King's College folks, who I know very well, are good friends of mine, or people have trained with me. I think they will be exceptionally committed to working across the King's College and Quell space. So I think there's going to be a lot of opportunity for collaboration. I think what's been missing historically is this sense of value, the value proposition on both sides of that fence. I used to show a slide where you would see it was, you know, pharmaceutical companies throwing a bunch of money over the fence and then the academia is throwing science and nature papers the other way. I think it's productive, but I don't think it really creates the value proposition that can be created now because you've got in companies incredible investment in technology, often far exceeding what an individual academic lab can do, so that the ideas that academic labs come into can be executed now in ways that they could never be executed before, given the investments that companies have in technology. So it's more than the money. It's now the technology and the smarts. I mean, industry has a lot of really smart people. Many of which have come from academia, academia, myself excluded, but there are some really smart people. In my company of the 70 or so employees now, I think we're about a third, a third, and a third academia, small biotech, and pharmaceutical folks. And it's been amazing to watch them around the table talk about that. So given this new way to think about how do you do collaborative science in a more, coherent and cohesive way, I think we can build on the successes we've had already in a much faster way going forward. I think also that it's important to realize that each of us have our limitations. The ideas that academic scientists can think through and create are unparalleled. I mean, the basic science is essential. We're only at the very end the beginning here, and the basic science is essential. So planning how do we integrate those things, it's not— we're not done, we're just starting. But I think also the value, the proposition of industry really is greater than, than the finances. And so as we, um, as we start building these collaborations, hopefully we'll, we'll be even more efficient and effective than we were previously.

Yeah, well, the finance can, you know, help, you know, bring the best tools to bear and get some of the best minds, you know, together, and it's an incentive. So I think that there's a lot to be said about it as a facilitator to drive, to really drive.

Yeah, no one's turning down the money as far as I can tell, which is fine.

I think scientists should be rewarded for their for their long hours and deep thinking. Is there anyone else who'd like to unmute themselves and ask some questions? This is the time. Wow, crickets, really? Come on, somebody.

I guess I have a quick question if I can. Sorry, did I jump ahead of you? No. Yeah, I'll be very quick. It's just so this two-pronged approach to biologics and T-REX, would we give them at the same time? We're going to give the T-REX after there's been some debulking already. I'm just curious in a maybe very general sense. Yeah, I think there's a lot to be said for sequential treatment, um, both in terms of how do you make sure that you have both a safety profile and you have an efficacy profile for each one individually. So you can imagine if you treat one with one, you get the information about that before the other. But I do think that there's a scientific reason for it as well. What you don't want to do is to have prolonged treatment unless you can create an incredibly specific debulking agent like an antigen, a peptide-specific T cell depleter, then you want to avoid long-term treatment with a drug that could eliminate cells. So I think short-term debulking, come back in. There's some good publications, both in transplant by Kishi Tang, and in diabetes by a group in Florida, showing that a short-term treatment to debulk can lead to a very increased effectiveness of your antigen-specific Tregs.

And that's the sort of approach of prevention bio right now. They're coming in with the vaccination and then they're coming in with their protocol following it. You know, they're sort of like, you know, just sort of coming in and delivering the medication or the cell, whatever it is, in very short windows. So yeah, it sounds like that might be the way of the future. I think I think Lucy Walker was trying to say something earlier. Yes, so along the similar lines, actually, I was thinking about the debulking approach, and I was wondering about how age plays into that, you know, how you would consider that in younger children given, you know, additional thymic activity, and also thoughts around the lymphopenia that that you generate. Maybe you could just talk a little bit more about those areas.

Yeah, without getting into a lot of depth into our program, I can speak to teplizumab, the anti-CD3 program, that prevention. And if you look at that data, first of all, had no problem going into kids. I mean, obviously, prospect of benefit's important and safety, and that's prime. But you can get into kids. With some of these depleting drugs. But also what's been, I think, important to realize in the talisman work over the last 34 years is that there's never been any evidence of real increases in infection. There's been zero evidence of cancer. And the cells repopulate really quite rapidly in the peripheral blood. And my guess is that they actually don't get as depleted in the tissue as we did some studies with OKT3 back in the early '80s, that the amount of depletion in the tissues is even less than in the peripheral blood. I think that this debulking idea, this is not lethal radiation and a bone marrow transplant. This is a short-term acute loss of effector cells, subsets of effector cells in some cases, that doesn't impact on immune responses. I have very little concerns about the safety, but obviously if you're going to go into children, you want to make sure that you have a good safety profile. I have a question. This is Young. Hi, Young. Hi. I have question about antigen-specific issues. So like the successful examples, anti-CD3, IL-2, they all systemic bias the Treg functions, while your target will be islet-specific or is all specific for homunculus or whatever antigens that Treg recognize. Yeah, so the general approach that many companies are taking, including others on this call, are really focused on targeting a protein or peptide antigen present in the tissue that's being destroyed. And the reason for that is a combination, I think, of specific activity. We've learned in a lot of animal models that that cell Tregs that are specific for a particular antigen work with many fewer cells and with much higher activity. And to some extent, safety, that by targeting a particular antigen in a tissue, the off-target effects are likely to be less, and therefore, there's the chance for systemic immunosuppression might be reduced. So I think that's the argument. I think one of the things that's really exciting about Treg therapy is this concept of infectious tolerance and bystander suppression, which translate— those are two kind of, you know, kind of key words for me, which is for infectious tolerance, the idea that these cells will recruit other cells into the site that potentially have regulatory activity themselves. And so you get more bang for the buck at the site in a more generalized control and local regulation. And bystander suppression, meaning that although the cells may be specific for a single protein or antigen, that because of their polypharmaceutical activity, they actually suppress locally in cells that see different specificities. So you get actually a broadening of the activity beyond the specificity of the cell. And that's a big advance for a big difference than, for instance, a CAR T cell in cancer, where unless the tumor expresses the antigen, it's not going to be killed. So I think this gives us both specificity, selectivity, and enhanced functional activity in the local tissue, while I think enhancing the safety signal and the off-target possibilities.

Yeah. What can we say about the role of the gut, the human gut, microbiota and regulating Treg development. And, you know, obviously the type 1 diabetics come into the disease with microbiome dysregulation. So, you know, and there's definitely a role for the microbiome interface with Tregs. So, can you do anything there? Can you work in from that route to either make sure that environment is perfectly suited for the Tregs you're delivering?

Yeah, I think it's a really interesting field right now. I think there are sort of 3 areas where you can think about the microbiome. One is the metabolites that are being made by some of these bacteria, which seem to promote Tregs. And I think that, you know, that's going to be a really important area to understand how the Tregs that we develop in and treat the patients with respond to those metabolites. And if we can enhance that interaction, that can be a real positive.

Short-chain fatty acids?

Yeah, butyrate. And yeah, I think the second thing is actually there is evidence that Tregs can recognize some proteins expressed by bacteria, certain bacteria. And so One can even imagine, I'm not sure in diabetes, but perhaps in diseases like Crohn's disease or ulcerative colitis, actually targeting bacteria directly with the Treg as a way to enhance local regulation in that setting. I think it'll be really interesting to see how that happens. Then the third is that the majority of cells that are considered regulatory T cells in gut, some may argue whether my term majority is correct or not, but a lot of the cells that are present in there are actually generated in that site through what we call an induced peripherally derived. The repertoire of those cells is likely to be quite different than the repertoire of Tregs that are developed that emigrate from the thymus. Maybe one might be able to take advantage of those cells in terms of their unique repertoire,, in being able to shut down, autoreactivity, more effectively, either, directly or in combination, with other, drugs. My, my concern about that population is that at least in our hands, um, they seem to be, uh, less stable and more likely to lose their FOXP3 expression. So companies like Genti and Marcus and others who are focusing on modulating the cells with various FOXP3 modifications could end up getting a quite stable population out of that cell population as well. I think there's a lot of opportunity there, and I think it'll be interesting to see. I'll make one last wacky thing which people are doing. We've been doing some stuff with Michael Fish back on this at UCSF. When I say we, I had an old mentor, Frank Fitch, who used to say, whenever I say I, I mean we, and whenever I say we, I mean they. So now when I say we, I mean they. So the people at UCSF now are working with Michael to actually incorporate peptide antigens within the microbiome bacterium, so that actually you can actually use it as a delivery system for tolerogenic peptides, which I think could be a quite cool Yeah, that's very cool.

I like that. I'm going to go dig into that after this call and look to see what he's doing. Is there anyone else who'd like to sort of ask a final question before we want to just respect your time here and thank you so much?

Yes, yes. So first of all, thanks for inviting me. So it's really interesting. Actually, I have an unrelated question. So is your company also looking already into, so, some treatments for cardiovascular disease? I mean, it's widely neglected yet in, let's say, classical immunology, but I think there's also great potential for direct transfer to treat hypertension or atherosclerosis. Yeah, great, great question. What we've said publicly is that we're very interested in what I would call non-classic immunological settings of inflammation. Certainly cardiovascular would fall in that bucket, as do what we have talked about, certain neurological, neuroinflammatory conditions. Again, a plug for UCSF, we just treated our second COVID patient with Tregs with the idea that we might be able to shut down found some of the dysfunction. And you can imagine that if you could create an off-the-shelf Treg that, that, that sort of you had ready to go frozen down in the ER, that a lot of things, whether it be cardiovascular or stroke or ARDS, things where you need an immediate treatment that would shut down inflammation that's not an autoimmune disease, that Tregs could be appropriate for that kind of activities. So I think there's a burgeoning opportunity here, and I think you mentioned one really interesting area for using Tregs beyond the immunological diseases that we've been focused on today.

Interesting. Let's see, Yasmin, I'm sorry, I saw your hand and I didn't really see it down the bottom because I had shut that down. So yes, please, please ask your question. Oh, great. Thanks. Hi, Jeff. Just on the back of the bystander suppression infection tolerance comment that you made. Um, do you think a multiple dosing approach will be necessary, or do you think like a single dose therapeutic Tregs could induce the state of tolerance?

Yeah, so I, you know, we all have our hopes, wishes, um, and certainly mine is, uh, the one and done. What we do know is that the cells that we work with— when I say we, I mean the UCSF— um, are long-lived. We've seen these cells in the circulation at least a year out. So I think there's possible that we can have long-term efficacy. But I'll also point out an old study done by Herman Waldman now over 20 years ago showing that when he gave Tregs in an allo transplant skin graft setting and waited 3 months and then got rid of the Tregs he injected, the animals didn't reject their graft. So in that setting where infectious tolerance was argued mechanistically to be important, You didn't need the cells to live forever. So, you know, do I like the cells would live for a long time? Sure. Do I hope that they'll also bring other cells in that will enhance and maybe even replace the cells we put in over time? Sure. But if we have to do a treatment every couple of years, assuming we can freeze these cells down and have them readily available or even develop an off-the-shelf, I I think we have to be prepared for doing repeated treatments if that's what's necessary to maintain their efficacy.

How, how easy is it to freeze these cells down?

Well, as I tell people in the lab all the time, it's really easy to freeze them. It's the thawing part that becomes a little bit more challenging. So we freeze these cells down. No, the answer is that there are now, I think, several companies. We're one of them, um, that have a protocol for cryopreservation that looks quite robust, and my expectation is that we are going to be working with a frozen product.

That's cool. That's handy. Um, yeah, I mean, it's— this is a really interesting, uh, new frontier that you guys are creating, and everyone, not just guys, is creating. And I think it's, I think it's really one to watch. I think it has a lot of places to add value. If you want to talk about the value prop, as we just discussed, it has a place in autoimmunity, it has a place potentially in, you know, high-risk settings like the ER. And so I just really can't wait to see how this, what the next steps are and what papers are coming out next, really. Thank you again, everyone. And just to conserve everyone's time and to, and to be conscious of that, thank you, Jeff, for joining us. And it was just amazing, an excellent discussion. And I look forward to seeing what's coming from everyone's laboratory next. Have a great rest of your day, everyone.