Good afternoon, everyone. My name is Janani Sundararajan, and I am a senior research associate here at Chardan. It is my pleasure to introduce our next guest for today's conference, Steven Kelly, President and CEO of Carisma Therapeutics. Thank you for joining us today, and the format for this session is going to be a roughly twenty-five-minute fireside chat. If there are any audience questions in the meantime, please raise your hand, and we'll hand you a mic. Okay, thank you for joining. To start off, could you give us an overview of Carisma Therapeutics for those that are new to the story, and can you touch on key upcoming catalysts?
Sure. Well, thanks. Thank you very much for inviting us. I appreciate Chardan's invitation to Carisma to participate. So Carisma is the world's leader in engineered macrophages. We have developed a platform that has basically looks at one of the most powerful cells in the body and ways to tool that and drive it towards therapeutic applications. If you look at our pipeline chart, you'll see a host of different things. We start off in oncology, and so we have an ex vivo approach in oncology, a HER2-targeted CAR-Macrophage or monocyte currently. We have an in vivo strategy, where we're looking at we have a GPC3 targeted in vivo CAR-M. We have a mesothelin-targeted CAR-M as well, using a next generation CAR construct.
Beyond oncology, we have looked at ways to take macrophages and drive it into a therapeutic application in fibrosis. And then, most recently, we announced opening up our work into the area of autoimmune disease.
Great, so let's touch on all of those things.
Okay.
Let's start with your platform. So your platform, as you mentioned, is focused on genetically engineering myeloid cells, primarily macrophages and monocytes, to express CARs and target tumor cells. So could you speak about how this approach is differentiated from other types of cell therapy approaches and how it's particularly useful to target and kill tumor cells?
Sure. I think the big reason to look at macrophages is their multi-modality mechanisms of action. So CAR-T cells, no one's going to argue they're incredibly good at what they do, which is to kill other cells. They're fantastic. But there are some deficiencies when it comes to solid tumors. One is tumor access, one is overcoming immunosuppression, things like that. Macrophages have a way to kill directly, so they do that through phagocytosis or macrophage is the big eater, and so they can kill through phagocytosis. They also are a cell type that can get into tumor. They go to sites of to go into tumor. They're the most common immune cell that you'll find in a tumor.
And so they're also involved in things like homeostasis, and sort of modulating the sort of immunosuppressive or inflammatory environments. We looked at them and said, "Okay," well, and the last thing they do is they can drive an adaptive immune response. They orchestrate that immune response. So we looked at it and said, "Okay, can we take a cell, have it recognize and traffic into a tumor, and will it have direct killing activity, remodeling the TME, and presenting antigen?" And that was the inception of the idea back when people were evaluating CAR T for solid tumors, and so that was the direction we went.
This was back, what, I don't know, six, seven years ago at UPenn, and the first approach was to take a CAR targeting HER2, and it did all of those things. We were able to show traffic in the tumor. We were able to show direct killing. We were able to show recruitment and activation of other immune effector cells. We were able to show antigen presentation, and importantly, we were able to show immune memory.
Mm-hmm.
in the models that we were doing.
Great. So can you briefly touch on, you know, how you actually go about engineering these cells and, you know, highlight some characteristics that you will be looking for, in terms of a manufacturing standpoint?
Sure. Yeah, so the way we do it, for our CAR-Monocyte process is we have a patient, pre-mobilized with G-CSF for three days subQ. We have them do apheresis, then we collect CD14 positive monocytes. We transduce those cells directly. So in the past, we would differentiate the macrophages ex vivo and then transduce. We now transduce the monocytes directly, and then right prior to cryopreservation, we give them a cytokine that boosts them towards macrophage differentiation. The entire process is done in one day. We can make 10 billion cells. They're M1 polarized, and we know that after administration, they will differentiate into macrophages. So that's the process. It's really quite straightforward at this point in time.
We can reproducibly generate these cells at consistent quantities that are 90% M1 polarized, or 90% pure, et cetera. So that is a process that we think that we can move forward with on a regular basis.
Got it. Okay, so then let's jump to your programs. You know, you touched on your HER2 targeting program, which is your current lead program, CT-0525, an ex vivo autologous CAR-Monocyte program targeting HER2-overexpressing solid tumors. So can you start off by describing the design of CT-0525?
Sure
and, you know, expand on how it addresses the unmet need in this space?
Yeah. So we were the first ones to ever administer an engineered macrophage to a patient, and we learned a lot in our first approach with CT-0508, which was a CAR-Macrophage. We were able to show that we can reproducibly manufacture, we can safely administer, we were able to drive anti-tumor activity, but we also identified some potential deficiencies in the macrophage approach. Number one is the number of cells that are making it into tumor and how long they're sticking around. We have transitioned to a CAR-Monocyte, which directly overcomes these issues. We can make more cells. We can make ten billion cells versus two billion cells. We are able to demonstrate that they will traffic the tumor better along a chemokine gradient.
We have a 40-fold improvement of getting into the tumor with the monocyte product, and we've shown a longer half-life. A 45-day half-life ends up resulting in a 10-fold increase in sticking, in persistence. So we designed this cell. We're now in a phase I study, where we're looking at this HER2 overexpressing solid tumors. It's a basket design. If we use historical precedent of 0508, about half those patients will be breast, the other half will be on the GI tract. We're currently evaluating 3 billion cells in a dose escalation phase, up to 10 billion cells, and we'll be able to show each of those activities I mentioned before, and are we able to overcome what we saw were deficiencies in the first approach?
Got it. So I mean, you mentioned your first approach, your 0508, which is the CAR-Macrophage program, also in HER2 expressing. So you have some clinical data with that program. Can you briefly describe what that data is?
Yeah.
And yeah.
Yeah. So it, like I said, we've treated about 17 patients. Initially, we were doing monotherapy, and we had to do a dose escalation as well with that patient population. We showed the things that we wanted to show, the ability to traffic the tumor. We were able to use various techniques to show the presence in the macrophage. We used ctDNA as a measure of persistence, and so-
Mm
... we would see what we tended to see is that in high HER2-expressing patients, we were able to show a significant decline in ctDNA as a biomarker of activity, but we also saw a rebound in about four weeks, and so that was important for our subsequent strategy. We also were able to demonstrate stable disease in the HER2 3+ patient population, several of those patients. We also noted that these are late-stage patients, probably sixth line and up, and we saw an exhausted T cell phenotype.
So our approach was to look at those markers and say: "Okay, can we overcome those exhaustion markers with the addition of a T-cell checkpoint inhibitor?" So we added pembrolizumab to the protocol, where we saw an increase in T cell clonality, we saw an increase in effector CD8 memory cells. We saw an increase in PD-L1, which is indicative of responsiveness to the addition of pembro. So overall, I think the clinical data was directionally pretty exciting, and it enabled us to again move into and overcome those challenges with the 0525.
Got it. And so you mentioned this, you've incorporated learnings from this program into your trial design, for your CT-0525. So can you and you touched upon the trial design as well. Can you briefly expand on exactly how this trial is structured, the patient population, and the endpoints that you will be looking at?
Yeah. So it's a phase I dose escalation, two cohorts, a three billion cohort and a ten billion cohort, in HER2 overexpressing solid tumor patients. Again, it'll be a basket design, so we would expect to see probably half the patients in breast. Most of them have been treated with prior Herceptin, and more and more likely treated with prior Enhertu-
Mm-hmm
... in their previous courses of disease. So the design is really to get up to the second level, which is the 10 billion level. And then we'll move into a cohort three. The goal in the cohort three is to look at what. So what are the choices we have? We have bolus administration, we can have repeat dosing, we have 10 billion cells to work with, so like five cycles of 2 billion cells, for example. Then the other axis would be with pembro or without pembro, so it's like a 2-by-2 matrix. We believe that the most likely place to show immediate activity before we start tailoring those would be look at repeat dosing and the addition of pembrolizumab.
That's likely the direction we're going to be taking in cohort three.
Mm-hmm.
But first, we have to demonstrate safety and feasibility of making ten billion cells, as well as the trafficking to tumor and persistence and antitumor effect in the monotherapy. And so that data will be coming out towards the end of this year.
Okay.
And then the cohort three will be a next year event.
Okay, got it. So yeah, as you mentioned, you know, you have data coming out by the end of this year, and so will you be, like, talking about how you go ahead with cohort three after that, at that point?
Right.
Yeah.
I think the important things are, do we have the ability to make a large number of cells and safely administer a large number of cells to patients? And so that's the primary endpoint before we move into cohort three. I think the other aspects are all the translational dataset, where we're looking at cell number and tumor, the persistence of those cells over time, the ability to have increased T cell clonality, and drive that sort of expansion within the tumor microenvironment. Those are success. That's, in our mind, that's a success for cohorts one and two.
Mm-hmm.
Then cohort three, like I said, is probably the repeat dosing plus pembrolizumab, and that's where we'll be looking for objective response.
Got it. Okay, and so once you have that, like, from a bigger standpoint, what are the next steps for this, for this program, and even from a regulatory?
Yeah
... standpoint?
I think that once we've established a regimen that works well and meets a sufficient hurdle for driving forward, and again, I think we'll know that next year, then we move into a phase II study, and we start driving towards earlier lines of therapy, because right now we're getting pretty late-stage patients, but we'd like to be just post-HER2, so probably in the third and fourth line setting. I think that's the place where we want to be, and we'll have to select a tumor type that makes the most sense. While we haven't seen any differences in which tumor types we're targeting today, I think we'll have to select a tumor type, as the FDA is not quite ready for a tumor-agnostic approach.
Got it. Okay. So do you have anything else, that you want to highlight about CT-0525 before we move on?
I think that 0525 gives us a great shot to demonstrate CAR-M in oncology. I think that the cell number is fantastic. I think that the program we have and the plan for cohort three are really give us a legitimate shot for demonstrating the first cell therapy, I think, in solid tumors. And, you know, I think they're really excited about the prospects there.
Great. So look forward to seeing your data by this year-end.
Yeah.
Okay, so now moving to your in vivo oncology programs that you're working on, in collaboration with Moderna.
Yeah.
Can you briefly start off by describing how that collaboration is structured?
Yeah, so it was a couple of years ago, two and a half years ago, we were talking about, you know, how could we do this in an off-the-shelf approach?
Mm.
And it just so happened we were talking with Moderna's research team, and we had the ability to engineer macrophages and engineer monocytes. They had the ability to target macrophages and monocytes with a lipid nanoparticle, and they had mRNA technology. And so through several rounds of conversation, we entered into a collaboration where we leverage both the company's expertise, our ability to engineer the cells, their ability to get the product into the cells and have it expressed. And so the idea here is an off-the-shelf in vivo CAR-M. So you administer an mRNA encapsulated in a lipid nanoparticle, it goes to circulating monocytes and tissue-resident macrophages, and it transfects them, and they express the CAR. Does everything that we just talked about for our ex vivo program, but does it in an off-the-shelf approach.
Now, there are, of course, you want to make sure that you can get cells to macrophages, and those macrophages can go to tumor and have the same activity. You want to make sure that you can repeat dose them.
Mm.
So mRNA is a short expressor, so you want to be able to repeat administer. And so we checked a lot of those boxes in our conversations, and entered into this collaboration, where it was a five-year partnership on 12 oncology targets, that would be $180 million up front, complete funding by Moderna for all the work that Carisma does. We get about $20 million a year from them for our research work. And on the back end, there's $3 billion in milestones, about $250 million per program, and a good royalty as well. So we put that in place about two and a half years ago, and we've had a very successful run so far over that period of time.
Great. So can you describe any preclinical proof of concept data that you've generated in this space so far?
Yeah. So, so number one, we wanted to demonstrate that we can get this mRNA to myeloid cells.
Mm.
That was early work that we did, and the majority of the LNP is going to target monocytes, macrophages, and dendritic cells. About 98% of the immune cells are myeloid cells. And so we're really pleased about doing that. Then we used HER2. We have a lot of models around HER2, so we put a CAR construct in that targeted HER2, and we were able to demonstrate good control. We presented that data last year at SITC, where we were able to show control of the tumor and no growth in the mice, in the majority of mice, and no metastasis as well. So it was a really good data set as a proof of concept, and so we like I said, we presented that.
Yeah.
That's not part of the collaboration.
Mm-hmm.
So, the work that we're doing, the initial target we're going after is GPC3 for overexpressed in hepatocellular carcinoma, and that's where we started moving into work with Moderna on the first development candidate.
Got it. So earlier this year, you nominated your, the first development candidate that you just spoke about in GPC3 expressing solid tumors, including hepatocellular carcinoma. So what makes that a good first indication to go after?
Yeah. If you were to look at what would happen if you took a bag of macrophages or monocytes and administered them to a patient, they would go right to the liver.
Mm.
So localization is one of the key things that we're seeing here. So the low-hanging fruit is getting our cells into the liver to have an effect. And so that made it a very ideal test case. It met all the other characteristics, you know, of an antigen target, doesn't shed, doesn't internalize, et cetera. But the fact that it's in the liver was really a great first test case.
Got it. So where are you in this program currently?
Yeah, so we just announced the nomination of the development candidate, so it's a couple of years' worth of work to get to that point. And the next step, that was really... It was a handoff. So we did all the design and early development work, hands it off to them. They do the finishing, the preclinical, tox work, start working on the protocol and GMP manufacturing. We get a milestone payment, and it hands-- they just, they take the ball and run with it. There are more people, we believe, working on this first program than employees of Carisma. So it's just like, what-- it's amazing to see what-- how they're taking it and running with it. We take our attention and drive it back to the next antigen target that we're working on.
Got it. Okay, so you also recently expanded your collaboration with Moderna.
Yeah
... for two in vivo CAR-M therapies in autoimmune diseases. So can you expand on your strategy here?
Yeah, this is an interesting conversation. So while we were continuing to be one of their, it's hard to say, little Carisma is one of the Moderna's biggest partners.
Mm
... in sort of the biotech space, but we get a lot of attention within their teams. And so their other therapeutic groups are like: "Oh, how could we use a CAR-M in our approaches, whether it's..." You know, we looked at a number of different ones. The first ones that stepped up were autoimmune, and the autoimmune team said: "We would like to use your same approach, your CAR-M approach for some unique targets that we have." And so we had a pretty extended conversation with Moderna, and what we elected to do is take of those initial twelve targets, we took two of them-
Mm-hmm
... and said, "We will nominate those in autoimmune disease." I think it's an important growth of the therapeutic applications of macrophages. I think it's an important growth area for Carisma as well, because this is not exclusive in the field of autoimmune disease. It's two antigen targets that we can go after, and so we can really start driving these forward. We can't really say what the targets are. There are some unique targets that actually are really exciting, and leverage the biology of macrophages, and we can learn along the way, and so we think that we have two really cool approaches. It's funded by Moderna, so we can learn along the way, leveraging our macrophage biology and engineering expertise into a new tool.
Great. So let's shift focus a little bit to your liver fibrosis program. So you've guided to nominating a development candidate in this space in the first quarter of next year. So can you briefly describe the preclinical data that you've generated here to date?
Yeah. So this is another... again, it really drives towards the power of the macrophage. We are, we were looking at places, again, what could we do? We've learned so much about macrophages. We've learned so much about how to engineer them and drive them to, for, to different purposes. So we got the idea from, actually, Stuart Forbes in Scotland is the first person to take macrophages, un-engineered, and administer them to patients, to liver fibrosis patients, and was able to show to arrest the progression of disease. We thought, "That's really cool." I think it was, like, a fantastic application, and we started thinking about, what could we do as Carisma to, to enhance that basic activity?
We have a lot of engineering tools. We have a lot of vectors. We have a number of things that we can do. What we did is we looked at the addition of an anti-fibrotic factor and an anti-inflammatory factor to the cell. Think of this as creating a macrophage. It's not CAR-based, so they're not going and eating something. They're going to a place, and they're producing these factors. Macrophages will go to liver preferentially, so you can sit there and create a micropharmacy that produces these factors on a regular basis. We made these cells, and we first went into an early model. It's a toxin model using carbon tetrachloride as a liver toxin.
Creates liver fibrosis, and it's about a six-week model, and so we administered these macrophages that expressed relaxin, anti-fibrotic, and IL-10, and we were able to show complete resolution back to normal. And so that was a pretty fantastic first outcome in our approaches. And so we then set the bar a little bit higher and said, "Okay, what about a model of MASH, where we're looking at a six-month model where you have a high-fat diet and a liver toxin?" High-fat diet plus carbon tetrachloride. In this case, we saw about a 70% improvement. And so pretty, a pretty high bar to get to for these models of MASH, and we had a great outcome.
We continue to do work in the area, and so there are some other factors or other payloads that we're looking at for the macrophage. Our goal is to have a final construct by Q1 of next year. But we'll have some data at AASLD around some of these other approaches we're looking at too.
Great. So, I mean, how would you consider advancing this space? Like, I mean-
Yeah
... do you think you would do it internally, or?
So, we historically have been primarily an oncology company, and so we have a lot of great oncology expertise, both, you know, on the clinical side and some of the preclinical work. I think that, for us, we're open to collaboration. We have a great, fantastic collaboration with Moderna. I think we would be open to a collaboration, but at the same time, you know, if we had investor enthusiasm around it, I think that developing it ourselves would also make a lot of sense. Whatever we can do to accelerate that development is the most important thing. We think we have a fantastic idea. Let's get that into the clinic as quickly as possible.
If we can do that through our own internal funding or through partnership, that'll be sort of a decision point where we can get it-
Mm
... accelerated.
So one question on your cash position-
Sure
... and runway, and how you see that fitting with your overall strategy?
Yeah
... of moving-
Yeah, so it-
the program forward
... based on face value, we have a lot of things going on at the company, which we do. We have a couple of ex vivo programs, a couple of in vivo programs, we have fibrosis, things like that. The good news is that about half of what we're doing is being funded by Moderna in the in vivo space. So the GPC3 is funded by Moderna. We have four more oncology targets that are being funded by Moderna, and we have two targets in autoimmune being funded by Moderna. So our burn is not as large as you might think, 'cause we're getting cash in on a regular basis from them.
I think that if you look at our balance sheet, we have cash into Q3 of next year, and so we're looking at, you know, how do we enhance that runway through, obviously, equity financing and partnering activities, and so both of those are top of mind, and we're looking at what are the right inflection points to drive either one of those actions forward.
Great. And so coming to the final question, what would you say investors are missing about the Carisma story?
You know, I think it's easy to lump us in with all of cell therapy. You know, CAR T, CAR NK, they've been around now for twenty years, and so I think that a lot of people understand how those cells work. And I think there's been ups and downs with autologous, allogeneic, in vivo, there's a whole bunch of activity there. I think we're a unique effector cell. I think we have unique applications that stand apart from the other cell therapy approaches. I think that we have meaningful value inflection points coming forward, clinical data oncology, development candidate in vivo oncology. We have a liver fibrosis program development candidate coming up with a sort of a rapid transition into the clinic.
And so I think there's a lot going on with our cell type, and importantly, there are milestones, very near-term milestones, as we progress the company.
Great. I want to see if there are any audience questions. If there are not, then we have come to the end of this session.
Okay.
Thank you very much for joining us today.
Absolutely. Thank you very much for having me.