Hi, good morning, everyone. I'm Ananda Ghosh, an associate at H.C. Wainwright. I would like to welcome Gavin MacBeath, CEO of TScan Therapeutics. Gavin, please.
Great. Thank you very much, and thank you to the organizers for the invitation to talk today. So I'm gonna just take 20 minutes this morning to introduce you to TScan, give you a broad overview of our programs. For those that are not aware. Sorry, the slide advancer is not working. Is there any other slide advancer I can use?
Okay, I'm gonna say next slide a lot. So we are a publicly traded company, so I will be making forward-looking statements. Okay, there we go. So just as a broad overview of the company, we were founded back in 2018, so we've been in business for about five and a half years. And we are a fully integrated next-generation TCR-T therapy company.
So the company was founded on a proprietary discovery platform that enables us to discover new targets for TCR-engineered T-cell therapy, as well as, high-affinity naturally occurring TCRs for that therapy. And using this platform over the last, five and a half years, we've built a large pipeline in oncology. In fact, we have eight different, agents in the clinic right now, two that are in use for heme malignancies and six for solid tumors.
We've also built our own GMP manufacturing platform. We actually don't use lentivirus for our manufacturing. We use transposons, which gives us a lower cost of goods overall, but also really speeds the development process. And then finally, the platform is broadly applicable, not just to oncology.
We're also using that platform to discover the targets of T-cells in autoimmune disease, and we have an ongoing partnership with Amgen to discover the targets of T-cells in Crohn's disease, so just by way of background, if you take a look at the field of immune oncology, what we've learned over the years is that it's really your T-cells, your conventional T-cells, that are driving these remarkable clinical responses that we've seen.
In fact, what we've learned from checkpoint and TIL therapy is that T-cells can have remarkable activity in solid tumors because they're able to see the full range of targets in a tumor cell, right? Either extracellular proteins or intracellular proteins. The only challenge is that most patients don't actually have the appropriate T-cells to recognize their cancer.
If those T-cells just don't exist in the patient, they can't respond to therapies like these. The real, you know, breakthrough in the field was the advent of CAR T therapy, where we learned that you can genetically reprogram a patient's T-cells with a new receptor that will then redirect them to recognize their cancer. This has clearly had, you know, amazing activity in heme malignancies, but unfortunately, to date, we just haven't seen the translation of CAR T therapy to solid tumors. Really,
TCR-T, it's really the best of both of these worlds. Instead of engineering the T-cells with a chimeric antigen receptor, we engineer them with a naturally occurring T-cell receptor. This can now see the full range of targets, not just extracellular proteins, but intracellular proteins as well.
What we've seen from both academic work and work at companies like Adaptimmune and Immatics is that TCR-T has very promising activity in solid tumors. As I'll show you today, we also think that TCR-T has very promising activity in heme malignancies as well. Just to sort of introduce you to the biology here. A T-cell receptor, which is shown in blue, recognizes two things.
It recognizes the cancer-specific antigen, which is the pink circle. It's a short peptide derived from a cancer-specific protein. For example, PRAME is only expressed in cancer cells, not normal human adult tissue. The TCR is also recognizing the class one HLA that is presenting that antigen. The challenge here is that there are actually thousands of different HLA types.
And so because you have to match the TCR to the HLA, this could present a challenging problem. You'd need a new TCR for each HLA. But the good news is that there's certain very common HLAs, and in fact, if you focus on the six most common HLAs, 90% of people in the United States are positive for at least one of those six HLAs.
The most common HLA is A0201. You see a lot of companies with TCRs recognizing A0201. But what we've chosen to do as a company is focus on the six most common HLAs so that we can provide broad coverage to the majority of patients with cancer, both in the US and around the world. So this is what our current pipeline looks like.
You can see at the top in yellow, our two programs in heme malignancies, which I'll talk about next, and then six different TCRs in our solid tumor program, where the goal of this program is not just to provide a patient with a single TCRT, but to actually give them a combination therapy, to give them multiple different TCRs simultaneously. So let me start by talking about the heme malignancies program. This is a program that's been in the clinic now for about a year and a half.
So here we're meeting an unmet need, in the space of heme malignancies. Although CAR T therapy very clearly addresses B-cell malignancies and multiple myeloma, there's really no CAR T solution for myeloid cancers, because you can't remove all of a patient's myeloid cells. They would die of fever and neutropenia.
So instead, we have a different solution that really relies on the only curative treatment in the heme malignancy space, in diseases like AML, and that is to get an allogeneic hematopoietic cell transplant. And right now, about 7,350 patients a year in the U.S. get allo transplants, and about 60% of those patients are completely cured by that procedure.
The problem is that if you relapse following transplant, the prognosis is very poor. In fact, there's about a 75% mortality rate within a year of relapsing. So the unmet need that we're addressing here is to prevent relapse and make transplant fully curative in these patients.
The way this works, and the slide is a little bit complicated, but what we're doing is taking advantage of natural genetic differences between the patient and the donor. In this slide, I'm illustrating the patient cells in pink and the donor cells in blue. What we do is we identify patients whose blood cells all express a given antigen. In this example, it's HA-1.
We match them with a donor that doesn't express HA-1, so their blood cells are HA-1 negative. If this patient undergoes an allogeneic transplant, then post-transplant, all the new blood cells that get generated from the donor's stem cells are HA-1 negative. They come from the donor, so they should be blue, whereas any residual cancer in the patient is patient-derived and is HA-1 positive.
So what we wanna do is remove any residual cancer to prevent relapse in this patient. So while the patient is undergoing the transplant, we take T cells from the donor, which, of course, are HA-1 negative, and we engineer them with a TCR that recognizes this antigen. And so then, as soon as the patient has recovered from the transplant, typically about three weeks after the transplant, we give them their first infusion of engineered T cells.
And at that point, those T cells recognize only the residual cancer, but they don't touch any of the new normal blood cells that come from the donor. So it's a way to very cleanly eliminate residual cancer to prevent relapse. So this is the structure of the phase I trial that we've been running now for about a year and a half. It's a dose escalation study.
We're in the third dose level of the study. We actually included a control arm in this study. So in pink, the control arm, patients are just getting standard of care, allogeneic transplant, and in the treatment arm, the patients are getting transplanted and then receiving one or two infusions of our engineered T cells.
And the expectation in this particular patient population, this is a very high-risk population, is that about 22% of patients will relapse by six months, about 33% by a year, and about 42% by two years. If a patient makes it past two years, they have a very low risk of ever relapsing. So those patients are almost all of them are cured.
So far, the last data cut that we released publicly was in April, and at that time, we had eight patients in the treatment arm, eight patients in the control arm, and it was very well balanced between the treatment and control arm. You can see in terms of the underlying disease, we had a mixture of AML, MDS, and ALL.
In terms of high-risk mutations, several of these patients had high-risk mutations, such as P53 mutations or FLT3 mutations in both the treatment and control arm. One of the things that we've been doing, I mean, obviously, we're trying to prevent relapse, but in order to get an early read on efficacy, we look at two key biomarkers.
So the first is we look to see if there's any residual cancer in the patient. So if the patient has detectable cancer, they're called MRD positive or minimal residual disease positive. If they don't have detectable cancer, they're MRD negative. So we do that assay in bone marrow biopsies. And then we also look to see if they just have any detectable patient-derived cells, both malignant and normal cells.
This is called donor chimerism. If you cannot detect any patient cells, they have complete donor chimerism. Those patients are obviously at much lower risk of relapse than patients that have detectable patient-derived cells. So what we're looking for is complete donor chimerism in these patients, and that we can assess in regular blood draws. So this is what the current data cut looks like. This is the control arm of the trial.
And so what I'm showing here is eight patients with various disease types, and the pink circles represent incomplete chimerism. They still have detectable patient cells left. And you can see there's a lot of incomplete chimerism in these patients. In fact, at this point, three of the patients relapsed. The third patient died from their relapse. A fourth patient actually died early on right following the transplant.
That's control arm patient seven. What we're seeing in the treatment arm is a very stark contrast to this. So in the treatment arm, all of the patients, as you can see from the first blood draw, were initially incomplete chimerism following the transplant, but then those yellow diamonds indicate where they got their infusions of engineered T cells.
In every case, as soon as they got infused with engineered T cells, they exhibited complete donor chimerism, so those T cells targeted any residual patient cells, eliminated them. In only one instance, which is the second patient, which was a patient at dose level one, only after ten and a half months did we start to see patient-derived cells in that patient. It turns out those were in the non-malignant cell population.
We do the chimerism assay in different subsets of cells. This appeared in their CD33 positive cells or their myeloid cells, whereas this patient had a T cell ALL, so their cancer was in their T cells, but the chimerism was in their myeloid cells. In this case, we don't believe this patient is at any higher risk of relapsing based on that result.
So right now, literally, eight out of eight patients are relapse free, with no detectable cancer cells. And the median follow-up time at this point is over ten months in these patients, with three patients over a year. What I'm showing on this slide is the MRD assays. So this is the bone marrow biopsies, where we're looking for any detectable cancer. Blue indicates MRD negative.
Again, you can see on the treatment arm at the bottom that all of the patients are MRD negative at every reading, including that second patient that had that detectable chimerism. But even at one year, their bone marrow biopsy was completely clean. And then, in terms of dosing, we are treating these patients at three different dose levels in the dose escalation.
So far, we've seen no safety concerns, and so we believe that dose level three will be our recommended phase two dose. What I'm showing you here is the level of circulating T cells in the patients on the left, at dose level one, where they received a single infusion of T cells, and on the right, at dose levels two in blue, and green is dose level three, where they received two infusions of T cells.
And you can see very high, sustained levels of circulating T cells in these patients, indicating those T cells are there, and presumably conducting immune surveillance to prevent any cells from coming back. Just a quick word on safety. So the key safety concerns in engineered T cells is typically CRS, and in the case of transplant, GVHD.
We have seen no CRS as a result of the infusion of T cells. All the CRS that we've observed in this trial has been immediately following transplant before they got their first infusion of engineered T cells. And then at the bottom is GVHD. And of course, these patients experience GVHD, all patients undergoing transplant do.
But we've seen no imbalance between the treatment and control arms, so we don't believe the engineered T cells are adding to their GVHD symptoms at all. So just a quick word on the market size. So right now, as I said, 7,350 patients a year get transplanted in the U.S. with AML, MDS, and ALL.
We can address about 3,000 of those patients because they have to have the HLA type A0201, which is about 42% of people in the U.S. We're looking to expand that down the road, but right now, we can address about 3,000 patients a year in the U.S.
If you go to Europe, it's about a similar number, slightly higher frequency of HLA A0201 in Europe, about 47%. So about 6,000 patients addressable in the U.S. plus Europe, with the current clinical program. But we do see a lot of room to expand with this program, and in particular, if we add new TCRs for other HLA types, this will enable us to almost double that market size.
There are other opportunities, both in oncology and in non-oncology indications like sickle cell anemia or beta thalassemia, where this type of therapy could be equally applicable. Ultimately, we view this as a very large opportunity of up to 20,000 patients a year. Just shifting gears in the last few minutes to our solid tumor program.
In solid tumors, we think there's a very difficult challenge, a very different challenge from heme malignancies, and that is that solid tumors are notoriously heterogeneous. Not every tumor cell in a tumor expresses a given target. We can illustrate this with this immunohistochemistry image of two melanoma samples. On the left, we've stained the sample with an antibody that recognizes MAGE-C2, which is one of the targets in our pipeline.
In red is stained for MAGE-A4. What you see is that some of the cells are red, so they're MAGE-A4 positive. Other cells are green, they're MAGE-C2 positive, and there's actually very little overlap. If they were overlapped, we would see yellow cells, right? What it's showing is these are distinct patient tumor cell populations that are expressing each of these targets.
If you were to treat a patient with just a MAGE-A4 TCR, you would only kill half their tumor cells, and then their tumor would rapidly regrow. To really get long and durable responses, we need therapies that can address this heterogeneity. Our strategy as a company has been to build a collection of TCRs, which we call our ImmunoBank, that addresses different targets and different HLAs.
So the rows of this ImmunoBank represent different targets, like MAGE-C2 or MAGE-A4 or PRAME, and the columns represent the different HLA types. And we're populating this ImmunoBank so that when a patient comes along, we would test their tumor to see what targets are expressed in their tumor, what HLAs are still intact, and then we would go to that bank and select the best two or three TCRs for that patient, and that becomes a customized multiplex therapy.
So we think this is how to address that heterogeneity problem in solid tumors. In addition to multiplex therapy, we're also further enhancing our therapies by building TCRs, T cells, that are resistant to the tumor microenvironment. So all of the first-generation TCR therapies only engineered cytotoxic T cells with the TCR.
But in order to include helper T cells, which is a key component of the immune system, what we do is we co-deliver the CD8 co-receptor along with the TCR because helper T cells don't have their own CD8. So if we provide it, then our final product is a mixture of cytotoxic and helper T cells, and those helper T cells provide the cytokine support that further enhances the activity of the cytotoxic T cells.
But in addition, because TGF-beta is a very immunosuppressive signal in solid tumors, we wanna make sure that our T cells are not shut down by TGF-beta. And so we also include in our engineered T cells a dominant negative form of TGF-beta receptor 2. So this renders our T cells resistant to TGF-beta. They can continue to proliferate even in the presence of this hostile tumor microenvironment.
So overall, we're focused on targets that are frequently expressed in these immune-rich cancers, like lung cancer, melanoma, head and neck, cervical cancer, where we know that T cells infiltrate, we know the signals are there, and so we've chosen to focus on targets that are often co-expressed in these cancers because of their high prevalence, so this is where we are so far with our ImmunoBank.
Right now, we have six different TCRs in the clinic. They've all cleared IND. They're all in the same clinical trial... and we're gonna continue to build this bank as we move forward. In fact, later this year, we'll file an IND for a MAGE-A4 TCR, as well as early next year, another IND for another PRAME TCR for a different HLA type, B*07:02.
So as we build this bank, we're providing more and more options for patients that come in. So this is what our clinical trial looks like right now, and we were fortunate to get agreement with the FDA on a path to treating patients with multiplex therapy early on in phase one. And so what we agreed on is that we would first test each TCR individually to make sure they're safe on their own.
So each TCR gets tested at two different dose levels. Dose level 1 is 500 million T cells. Dose level 2 is 2 billion T cells. And then as soon as the TCR has cleared dose level 2, any TCR that's cleared dose level 2 becomes eligible to be combined with any other TCR that's cleared dose level 2.
So at dose level three is where we start to treat patients with multiplex therapy. So at dose level three, patients will receive two different TCRs, two successive infusions on the same day, and then we'll also give them a repeat of that infusion twenty-eight days later. So that's what we're really, you know, gearing up to do as a company.
And so just to kind of level set where we are right now with this trial. So we announced first patient dosed about three months ago, but because this trial, all six of those cohorts proceed in parallel, we can enroll all six of those arms simultaneously. So we're not slowed down by that staggering.
So we've put together a screening protocol to identify patients that would qualify for these therapies, and then, we're, you know, able to enroll them relatively quickly, once they're ready for the clinical trial. And so what we anticipate, what we're considering success as a company is if by the end of this year, we can get to a point where several of these TCRs have cleared dose level two, then as we move into 2025, that really sets us up as a company to start collecting a meaningful data set on patients treated with multiplex therapy.
So what we're looking for this year is to see signs that we can rapidly enroll this trial, that we can successfully manufacture product for this trial, and that we can clear, from a safety perspective, dose levels one and two, so that we can start multiplex therapy. We do not, by the way, expect that dose level one is a therapeutic dose, right?
This is clearly a subtherapeutic dose based on the experience we've seen in the TCR therapy field, at 500 million T cells, which is why we're really focused on trying to move quickly through dose levels one and two, so that we can get to dose level three, which we consider to be a therapeutic dose. Then let me just end with this slide.
As I said, right now we have six different TCRs in this clinical trial. If you focus on the right, this is the frequency of patients with different cancers that would qualify to receive multiplex therapy. For example, if you focus on the first category, head and neck cancer in light blue, that asterisk indicates where we are in this clinical trial right now.
We have six different TCRs, which means that right now, about 10%-15% of patients with head and neck cancer would qualify to receive at least some two-way combination of those six TCRs. But as we add the MAGE-A4 IND later this year, we'll get to seven. You can see that number jumps fairly rapidly, you know, dramatically, because MAGE-A4 is fairly frequently expressed in head and neck cancer.
And the same is true in melanoma, lung cancer, and cervical cancer. So as we build this bank, and as we get to 10 TCRs in the bank, now a substantial portion of patients will qualify to receive multiplex therapy. So that's where we're heading as a company, and we intend to update the street on where we are with the solid tumor trial through a KOL call at the end of the year. Thank you for the time.
Thanks very much, Gavin. If you have any questions, then this is the time. Yeah.
Yes.
Quick question. With respect to the likes of non-small cell or some of the solid tumor, what line of therapy are you getting in at?
Sorry, what?
What line of therapy?
Yeah. So, this is a phase one study in oncology, so, everyone has exhausted all available lines of therapy, at this point. We do anticipate that this could potentially be used in second and third line therapy, you know, following checkpoint therapy and targeted therapies for those that have, you know, appropriate mutations.
In relation to that, if it has been through certainly chemo, you know, take pembro and whatever, you know, you're potentially going to have exhausted T-cells.
Yeah, so...
Immunosuppressed too. Just wondering, do you think the therapy itself will deal with that? Because obviously, tumor microenvironment-
Yeah.
Quite complicated.
Yeah. No, so this is one of the advantages of ex vivo engineering of engineered T-cells, is that the manufacturing process, you're exposing those T-cells to IL-2, IL-7, IL-15, you know, cytokines that basically rejuvenate and recreate a young T-cell population. We study this phenotype of our engineered T-cell product. We see, you know, stem cell memory phenotype in our product.
So even in patients with, you know, that have been heavily pretreated, manufacturing process kind of rejuvenates those T-cells. That's something that you don't get, for example, with T-cell engagers, right? You are relying on their endogenous T-cells as the state they're in in the patient. But with ex vivo engineering, you do have that opportunity to rejuvenate the cells.
You don't think that with respect to the mutations that are, say, non-small cell, whether you've been distracted by that at all? You think that, you know, like a STK11 or something like that, there wouldn't be any sort of differences, or is that just something, you know
Yeah, that, that we'll look at down the road. I mean, right now, this is an all-comers phase one study. But yeah, as we plot sort of a registration path in each of these diseases, we'll take, you know, all those nuances into account.