Welcome to day three of Evercore ISI's HealthCONx . Very pleased to be joined by Steven, who is CEO of Carisma. And this is a company working on a really cool sort of iteration on cell therapy, deploying macrophages, actually, which I think have some really unique properties and some potentially very interesting applications in areas where CAR- Ts really haven't shown too much progress yet. So with that, I want to turn it over to our leader here, and he can take it away with a company overview.
Sure. Thanks, Liisa. I really appreciate the invitation to participate. So Carisma is an engineered macrophage company. We, you know, we've spent a lot of time developing a deep understanding of macrophage biology. We've been able to develop a number of tools around how to engineer those cells to have differential effects, different targets and things like that, and now we're deploying them in therapeutic purposes. We've started off and have been, for a while now, looking at oncology as the place to deploy an engineered macrophage, a CAR macrophage. They have distinct properties and mechanisms that stand apart from the CAR-T, CAR-NK approaches that we think will lend itself to positive outcomes in solid tumors. In addition to that, we have looked at other applications that include liver fibrosis as a growth opportunity for us.
And then lastly, as we've developed this biology, we've been looking at different modalities. So we have an autologous approach currently in the clinic, with our CT-0525. We have an in vivo approach that we partner with Moderna, that enables us to accomplish the same things with an LNP mRNA approach. And that is development candidate stage, driving towards IND with our partner. And we've dabbled in other approaches too. So an allo approach, we have explored that as a possibility. So what I would say that we do is we take the core cell, the macrophage, and it's a fit for purpose. So we engineer it to do what we want to accomplish, and then we have a modality, whether it's autologous, allo, or in vivo, to deploy it and really drive therapeutic outcomes.
Talk us through some of the advantages of using macrophages.
Yeah. So a macrophage, so it's a very ubiquitous cell. It's throughout. You find it throughout the body. It's found in every tissue of the body, and it's responsible as sort of the first responder, if you will, of the immune system. So it orchestrates a lot of the other effects of the immune system, T-cell driving T-cell recruitment and activation. It's responsible for tissue homeostasis. So if you have a tissue that's sort of straying one direction, inflammatory can pull it back. Or if you engineer it, you can drive something towards an inflammatory approach. So I'll first address your question about how would it be different in the role of a solid tumor cell therapy approach. There are several distinct features that stand out.
One is the ability of a macrophage to make it into a tumor. There's been a real problem for CAR-T approaches in solid tumors. Certainly in hematologic malignancy, they're fantastic. They kill exquisitely. But getting into the solid tumor, so being able to extravasate and get into tissue and have an effect is something that T-cells can't do. And NK cells are similar. Macrophages are very easily can traffic into a solid tumor. Their mechanism is three-part once they arrive. One is the ability to phagocytose, so killing directly through phagocytosis or eating. Macrophage means a big eater. And so they can eat the cells that they've been told to eat. Number two, as part of the tissue homeostasis, you can polarize these cells to produce cytokines.
So we take our cells and make them a pro-inflammatory phenotype, and they produce cytokines that warm the TME, take it in an immunologically cold environment, make it a warm environment. They also recruit in other cells as the process. So you can see an influx of T-cells. You can see dendritic cells come in, et cetera. And then lastly, macrophages are professional antigen presenters. And so as they eat through the tumor, they're going to process and present various neoantigens, or new epitopes from that patient's tumor to the T-cells that recruited in, driving an adaptive immune response. So you have a concept of epitope spread, not just your antigen target of choice, but some unique antigens from that patient's tumor, and again, driving durable long-term immune memory.
What about lymphodepletion requirements?
Yeah. So that's obviously central to the CAR-T approaches. You want engraftment and you want expansion. With macrophages, you don't need to do that. So it's a very clean process where we mobilize patients with G-CSF to create more bone marrow-derived monocytes in the blood. We harvest those cells through apheresis, and then we transduced them with a proprietary vector and readminister them. They don't need engraftment. So they can go in, and they can circulate through the blood, and then arrive at the various organs that we've targeted. And so it's not. There's no need for lymphodepletion. And so I think that presents a fairly attractive proposition both to patients, 'cause it's safer for patients, but also to physicians as well.
One thing that's really interesting about macrophages, right? They have these two phenotypes. They have the M1, the M2. So they can do pro-inflammatory, anti-inflammatory. And that actually could have some very important consequences and potentially maybe some safety issues. So how do you control for like, you know, one versus the other? And where might you want to use one phenotype versus the other? What does that actually afford you too on the upside?
Right. Right. Yeah. So classically it is M1 or pro-inflammatory or M2 immunosuppressive. There's actually a huge continuum in that, a lot of plasticity in the cell. What we want is an M1 macrophage. And so you can think about historically what people have done. Everyone knows that the tumors, solid tumors are heavily populated with macrophages. They're typically tumor-associated macrophages or TAMs that are M2 polarized. And so their function in the tumor, they've been co-opted by the tumor, is to have an immunosuppressive effect. And so that's. I think there have been therapeutic approaches to either eliminate TAMs or repolarize TAMs. Our approach is to polarize the cells, and we can do that by using. It's actually a function of our adenoviral vector that polarizes those cells, and it sets up a feedback loop.
When the CAR engages, it continues to drive that M1 polarization, and what it means is that when the cells are there, they're gonna produce these pro-inflammatory cytokines. It actually, they are able to dampen the existing TAMs in terms of what they can do. Now, if you did not have this, sort of drive towards an M1 and you're locking them into M1, you're basically adding additional TAMs into the tumor, and so that really is would be problematic. I think to your second question, what it gives us is the ability, if we have the ability to drive cells any direction we want, we can tune them, so oncology, we want a pro-inflammatory cyto, a macrophage. We've also made, macrophages, glial cells, so brain, macrophages. We can drive a macrophage to eat protein aggregates in an M2 phenotype, so we have no inflammation.
So antibodies for, you know, whether you believe the Aβ or tau hypothesis, we can remove those aggregates. Monoclonal antibodies will produce inflammation. Macrophages that we've done, we've worked with don't. So you have a lot of flexibility with the biology of a macrophage.
Okay. Great. So let's start going through your portfolio and.
Okay.
Yeah. Let's start with, I guess your lead compound where you are now. I know we're kind of gonna get some data soonish.
Yes. Yeah. So our lead program is CT-0525. This is a HER2-targeted CAR monocyte. And so monocytes are the precursor cell to macrophages. They differentiate into macrophages in tissue. So monocytes circulate through peripheral blood, they extravasate, they arrive in tissue, and then they differentiate. So this is a program. We learned a lot in our prior iteration, which was CT-0508, a CAR macrophage. We demonstrated the ability to localize. We demonstrated safety. We demonstrated ability to manufacture. But we also saw some limitations, which were cell number getting into tumor, and then persistence of those cells. And so we made this switch earlier this year in April to a CAR monocyte approach. And the goals here are to increase the number of cells. We can make five times the number of cells if we make a monocyte.
It's a shorter manufacturing process too. It's a one-day process. And we found that they traffic better, which is not terribly surprising because monocytes are a peripheral blood cell. So they traffic about 40 times better than a macrophage, which is a large sticky cell. And the last thing that we found, which I think directly addresses one of the limitations of a macrophage approach, is that the persistence is 10 times greater. The half-life of a CAR monocyte, even after differentiation, is 45 days versus about four to five days with a macrophage. So this is a program that's in dose escalation stage right now. We're looking at 3 billion cells and then 10 billion cells. And what we're looking for is safety, manufacturing feasibility, and overcoming those limitations, which is localization in the tumor and persistence of those cells.
What setting are you looking at these in?
Yeah. So HER2 positive malignancies, we are looking at a basket design. So if we use historical data on the CAR macrophage program, about half the patients will be breast, and we're now leaning into a HER2 3+ population. So breast is the number one indication. And then the rest of the tumor types would be in GI cancers.
Okay, and so when should we look for data?
In Q1.
Okay.
Q1 we'll be able to report that out.
Okay. And, are you getting data in real time?
Yes.
Okay. Anything you can share, or?
It is, no.
Okay. All right. Had to try. And can you talk about your strategy with pembro using pembro?
Yeah. Yeah. So the other thing that we saw is, so in this patient population, obviously HER2-positive malignancies have been treated for, you know, a couple of decades, first with Herceptin. I think that launched in like 1998 or 1999, and then as time has gone on, there have been other products, Perjeta, T-DM1, and most recently Enhertu , and so we're looking at, you know, patients that are HER2-positive post all these other interventions. What we find is that our patients on a phase 1 study have been treated with six, seven, eight lines of prior therapy. If our primary goal is to drive that adaptive immune response, so killing is great, but really what we want is to harness the adaptive immune system.
You're really faced with a challenge because these patients have a beat-up immune system. You have T-cell exhaustion. The use of our CAR monocytes or our CAR macrophages drives further exhaustion markers. And our goal with adding a T-cell checkpoint inhibitor is to overcome that exhaustion and make sure that we can have a very strong adaptive immune response. What we saw with our prior program, CT-0508 plus Pembrolizumab, that we were able to see an increase in T-cell clonality. We saw exhaustion markers go down. And so we think the addition is going to be important, especially in later stage patients. You know, we'll find if as we can move further upstream, we'll see if it's necessary.
But we think just to ensure that adaptive immune response is gonna be a necessary part of the therapy.
Okay, so what level of response would you like to see in this population? And kind of what are next steps after you read out this data?
Yeah. So at the dose escalation phase, I'm, we're not looking for a response. I think that that is, it's an N of six total patients, three at three billion, three at six billion. That's really not what we're looking for. What we're looking for is overcoming the limitations. I think as we drive farther forward, I think that you ask our CMO, Gene Kennedy, he would say at a minimum you need a 20% response rate. That's reasonable in a solid tumor, late stage solid tumor patient. I'd probably like it to be slightly higher at a 30% response and some durability to make sense in the context of the cell therapy outcome.
When you say overcoming limitations, and that's what you wanna see in this study, so what specifically are you looking for then?
Yeah. So it's accumulation in tumor.
Okay.
Early on what we saw with the macrophage, if you do a field, you do a biopsy and you see a field, we were seeing one in two cells at most in a patient. What we wanna see is a significantly higher proportion of our cells making it into tumor. With murine models, we saw about a third of cells making it to tumor, a third into liver, and then a couple of other tissues, spleen was another one. We wanna make sure that we can recapitulate what we saw in the murine models where we're getting a significant proportion of cells getting into the tumor.
What is that amount?
So I would like it to see around 30% or so.
Okay.
It's you know, every tumor is it's really hard to actually quantify. You can show localization and you can get a proportion of the cells administered, but there's you know, disseminated disease, so you don't necessarily see that. The other limitation we wanna overcome is persistence. So in the previous work we had done, we were seeing around 30 days or so, where we would see the disappearance of the cells. And that's where we think a monocyte approach is gonna help as well. So if we can see that consistent presence of those macrophages having that therapeutic pressure against the tumor for an extended period of time, that's really important. The other thing we're gonna be looking at is you know, as we evolve into subsequent cohorts of patients, we're looking at repeat administration.
So that'll be another direction we go.
Okay. So then, the next steps after this trial would be?
Yeah. So we'll evaluate the data, and the next steps are to look at a most likely what we would look at is repeat dosing. So if we have 10 billion cells to work with, we would be looking at a series of five times 2 billion cells. So that would be over a 15-week period. And because, you know, you asked about pembro, we'd probably add, we're likely to add pembro into that as well. So that's on an every three weeks basis as well and continues on. So that's really the direction we would be going.
Okay.
with the further development.
Okay. Great. So let's talk about your partnership with Moderna.
Yeah. Yeah. It's been a great partnership. We've been working with them for the last three years. So they obviously are leaders in mRNA. They also have LNPs to deliver cells. We had this, the macrophage engineering. We started the conversation like three and a half years ago. The idea is to use their LNP to deliver an mRNA that will, you know, express our CAR in circulating cells. So we've been working on it. We just announced a few weeks ago that we have a lead program, a GPC3 targeted LNP mRNA construct that is driving towards the clinic. It's GPC3 is overexpressed in hepatocellular carcinoma. It's a, you know, it's a great program. They're super enthusiastic.
The good news is, not only are they enthusiastic about this, but we also have 12 targets in total with them, and fully funded by Moderna. And on the backend, $3 billion in biobucks. And so it's a really good relationship that is funded against multiple targets. And then, most recently, last quarter, we expanded our collaboration to look at autoimmune disease as well for a couple of the targets within the collaboration.
Okay. Wonderful. What kind of autoimmune disease?
Yeah. So we haven't disclosed the targets. They have been very cagey about until it's a development candidate. They don't like us to share what those are. But I can say that they're not the CAR-T, CD19 CAR-T approaches. We're looking at B cell elimination. But it's actually looking more fundamentally at the sort of both tissue resident cells and the inflammation associated with them. But I can't say either the indication except it's a rather broad category of autoimmune disease and a couple specific targets that.
When do you think we might, you know, some of these Moderna programs might start making into clinical development?
Yeah. The first oncology program, I'm hopeful that'll be in the clinic next year, and so again, I can't talk about the timelines, but I think that development candidate was just announced and typical drug development timelines are about a year or so, so I think it will be in the clinic next year and data readouts just really highly dependent on enrollment. It's a disease with high unmet medical need, hepatocellular carcinoma. The autoimmune targets is a little bit more work to do. I can't really drive sort of like a guide to a timeline there, but it's a new concept. We're excited about what they are as well. We need to you know get the proof of concept before we have a lead.
What's your involvement in the Moderna partnership in terms of like, what do you contribute? What do they bring to the table? What are your economics?
Yeah, so the beginning, we basically do the design, and so we do all the discovery work. We do a number of preclinical models to the point of development candidate. At development candidate, it's a handoff, so they pick up the final tox work, manufacturing, and clinical development, and they will commercialize. In terms of the economics for us, we get all the work we do is fully funded by Moderna. We have milestones in place. We have $250 million in milestones per program, standard development and commercialization milestones, and then we have a royalty on sales.
If this strategy of in vivo, sort of using the body as a factory really for this stuff works out, does that cannibalize your own sort of monocyte program?
So we have an autologous program. I think that as you know you think about other cell therapy approaches, CAR-T was autologous. A lot of work went into allo. There's a lot of work going into in vivo. I think that everyone looks at a fit for purpose to see if they can actually reduce costs and make it more accessible for patients. In some respects, yes, if we had exact same antigen targets, it would be cannibalization if it works. On the other hand, it's a five-year partnership. At the end, we've learned an enormous amount about in vivo. We can start to apply that to our own antigen targets as well. It's a learning process. We have different sets of antigens.
You know, what we're really driving towards is the best patient outcomes and, you know, economically what makes the most sense as well.
Okay. And then finally just wanted to hit on sort of some of the new data you presented in liver fibrosis at the recent AASLD meeting.
Yeah.
That was kind of a fun place to you guys pop up.
Right. So again, it comes down to macrophages and what they can do. In this case, if you think about liver fibrosis, there's, you know, obviously a lot of work going on in the space. What we have found is that there is, so Kupffer cells are liver macrophages. And as MASH and other approaches sort of die down, you end up killing hepatocytes. And typically what happens is Kupffer cells clear them out. Efferocytosis is the clearing out of the dead cells. As the disease progresses, we'll just take MASH, as it progresses, you lose the ability to have efferocytosis, which then starts this big cascade towards liver fibrosis. The loss actually is something called TIM4 on macrophages. So they can no longer recognize dead hepatocytes.
What we've done is constructed engineered macrophages that replace TIM4, the efferocytosis marker. We have an anti-fibrotic that we've looked at and an anti-inflammatory. And so we've seen very significant, positive outcomes in a number of different models. The data we presented at AASLD, our academic collaborator that identified TIM4, he says in these models, the CDA-HFD model, he's never seen such striking outcomes with any other molecule. So we were excited about it. It's a, you know, probably targeted for a later stage patient, F4 patients. We're driving towards an off-the-shelf approach.
I guess you could be beyond F4 MASH though. It could really be any sort of.
So, right. So, TIM4, TIM4 loss occurs in alcohol, alcoholic liver disease, viral, liver disease. And so that TIM4 loss is, restoration of efferocytosis is really important. And it's not just isolated to liver fibrosis. TIM4 seems to be implicated in other fibrotic disease like lung fibrosis and things like that. So we're excited about this as a growth opportunity, understanding macrophage biology and driving into new therapeutic applications.
Great. Well, it's time to wrap up, but I just wanted to end on if you could just comment on your cash runway.
Sure. Yeah.
And then also, 2025 catalyst.
Yes. So cash runway into Q3 this year. We need to do some things there, and then catalysts are CT-0525 data in Q1, a development candidate nomination for liver disease in Q1. We will have, hopefully, an IND with a GPC3 program later in the year, and then as we look forward, driving towards an IND with our fibrosis program.
Okay. Great. Thank you very much.
All right. Thanks, Liisa.