Hello, and welcome to the TCRX Virtual KOL call. We ask that you please hold all questions until the completion of formal remarks, at which time you'll be given instructions for the question-and-answer session. Also, as a reminder, this conference is being recorded today. If you have any objections, please disconnect at this time. Gavin MacBeath, you may begin.
Thank you, and welcome everybody to our event this morning. I do want to remind everyone that we are making forward-looking statements, and we are a publicly traded company. So I am very grateful to be joined by Dr. Ran Reshef, the Director of Translational Research of the Bone and Marrow Transplant Program at Columbia University.
And he will be presenting this morning the results of our phase I study, the ALOHA study of TSC100 and TSC-101 in patients with AML, MDS, and ALL undergoing allogeneic transplant with reduced intensity conditioning. So we're going to start with Dr. Reshef presenting the results of the study, and then we'll move to how we as a company are viewing the results and the development plan that we've put together based on recent interactions with the FDA under the RMAT designation.
I will talk a little bit about the market opportunity and expansion opportunities for the program, and then at that point, we'll move to Q&A specifically focused on our Heme program. Following that, I will provide an update of our solid tumor program and our strategy for 2025 moving forward, and then move to a Q&A section focused on the solid tumor program. So with that, I want to turn it over to Dr. Reshef, who will take us through the phase I data.
Thanks so much, Gavin, and thanks for having me and for allowing me to present the preliminary result of the phase 1 ALOHA trial in patients with AML, ALL, or MDS, as presented last night at the American Society of Hematology Annual Conference in San Diego. Next slide. Disease relapse remains the leading cause of death after allogeneic bone marrow transplants, or as they are referred here with the more correct name, hematopoietic cell transplantation .
Especially in older individuals who generally undergo a reduced intensity transplant, roughly 40% of patients with acute leukemia or MDS relapse within two years from transplant. Most of these relapses actually occur within the first year, and relapse after transplant is very difficult to treat, and unfortunately, in more than 80% of the cases, results in early death.
Relapse after transplant is the problem that TSC100 and TSC101 are designed to resolve in a disease-agnostic manner. These are adjuvant engineered TCR-T cells that target HA1 and HA2. They are derived from the transplant donor who is a healthy individual, and were designed to eradicate residual patient-derived hematopoietic cells post-transplant that could contain malignant cells and therefore could cause disease relapse. Next slide.
On the ALOHA study, patients who were positive for HA1 or HA2 are paired with HA1 or HA2 negative donors. The same donor that is used for the transplant provides T cells that are used to generate the TSC products and stem cells that are used for the transplant, undergoing two separate collections for these two purposes.
After transplant, the new healthy blood cells are then donor-derived and therefore HA1 or HA2 negative and are protected against the TSC activity, whereas any residual patient-derived cancer or other blood cells that are HA1 or HA2 positive will be selectively eliminated when the TCR-T cells are infused early post-transplant. This should lead to rapid achievement of what we call full donor chimerism, a state in which no patient blood cells remain in the body. Next slide. The TSC products are being tested in a multi-arm phase 1 trial in which subjects are assigned to treatment arms if they are HA1 or HA2 positive and have a mismatched donor, or to the control arm if they are either negative for those antigens or do not have an appropriate donor.
In the treatment arm, the patients receive one or two TSC infusions after transplant, and in the control arm, subjects receive a standard transplant without any cell infusions and are followed on the same study schedule for comparison. Importantly, the cells are infused without any lymphodepleting chemotherapy, given that at these early time points, they are still profoundly lymphopenic from the transplant itself.
The key eligibility criteria are listed here. They include adults with AML, ALL, or MDS, which are the most common indications for allogeneic transplantation, undergoing their first allotransplant, and are eligible for reduced intensity conditioning. The key endpoints are safety and efficacy, and exploratory endpoints include donor chimerism and minimal residual disease, for which the study uses a high-sensitivity next-generation sequencing assay done in a centralized lab. Next slide. These are the baseline characteristics of the subjects who have enrolled so far.
I would focus on the two rightmost columns, which compare the experimental and control arms. As of the November 20th data cut, 22 subjects have received at least one TSC infusion, and 12 patients have been treated on the control arm.
The median post-transplant follow-up was 5.1 in the TSC arm and 7.1 months in the control arm, and as expected in reduced-intensity transplants, which are generally offered to older and more frail individuals, this patient population is enriched for high-risk cytogenetics or high-risk molecular features, including six subjects with TP53 mutations in the TSC arms.
Adverse genetics or pretransplant MRD positivity was found in 81% of treatment arm subjects and 77% of control subjects, consistent with a study population at high risk for relapse after transplant. Next slide, please. The study uses a 3+3 design, and there have been no dose-limiting toxicities.
Therefore, the majority of patients have been treated on dose level three, in which five million cells per kilogram are given about 21 days after transplant, and a second infusion of 20 million cells per kilogram were given approximately 40 days later. Next slide. Here you can see the data for expansion and persistence of the genetically modified cells. We have seen a clear dose-persistence relationship. Persistence was highest for dose level three, which was about four-fold higher than dose level two, and about 16-fold higher than dose level one, as measured by area under the curve.
Additionally, as you can see, persistence of TSC cells was observed for greater than one year in every subject who had that length of follow-up, suggesting the potential for long-term immune surveillance, which may help keep these patients in remission and continuously prevent relapse. Next slide, please.
Adverse events of special interest are presented here. Again, I would focus on the two rightmost columns, which compare the totality of the experimental arms and the control arm. There were no infusion reactions. Grade 2 to 4 GVHD rates were similar between the TSC and control arms, with grade 3 or 4 acute GVHD rates of 9% in the treatment arm and 8% in the control arm, consistent with what's expected from this type of transplant.
CRS rates were also balanced between the arms, with most CRS occurring after transplant in both arms, given that CRS is a common side effect of transplant nowadays due to the specific GVHD prophylaxis regimens that we use. Only two TSC-treated subjects had CRS after a TSC infusion, and none of them were above grade 2, and there were no cases of ICANS described so far. Next slide, please.
Shown here are the grade 3 and greater treatment emergent adverse events seen in more than 5% of subjects in either arm. Most of these adverse events were expected, consistent with post-transplant adverse event profile, mostly hematologic and some others that are generally related to the conditioning regimen. Now, what about efficacy? Next slide, please.
There have been two relapses on the treatment arm and four relapses on the control arm, leading to a relapse rate of 8% in the treatment arm versus 33% in the control arm, which is more in line with what's expected from this type of transplant, reflecting a hazard ratio of 0.28. Next slide. Event-free survival, consisting of events defined as either relapse, a clinical intervention for impending relapse, or death.
This was substantially better and statistically significant in the treatment arm with a hazard ratio of 0.3, consistent with the potential of TCR-T treatment to reduce the risk of relapse or death after transplant. Next slide. This is a little bit of a busy slide, but I'll try to go through this and explain it. It shows the achievement of full donor chimerism in all subjects in the treatment arm.
Initially, after transplant, if you focus on the row that says day 21-28, some subjects on both arms had mixed chimerism, as expected after reduced-intensity transplant. This is indicated by the red crosses in the early post-transplant period. This universally converted to complete chimerism after their first TSC infusion on the experimental arm. In contrast, in the control arm, mixed chimerism continued to be observed for prolonged periods post-transplant.
Three subjects required clinical intervention for worsening donor chimerism, and four clinical relapses were observed. In the treatment arm, two subjects relapsed. One subject had extramedullary CNS relapse, and another subject died recently of a suspected clinical relapse. Let's talk a little bit further about these two patients, so the first patient is TSC101 at dose level three, a 65-year-old male with AML who did not respond to induction chemotherapy and was basically taken to transplant with refractory AML after reinduction chemotherapy at nadir, meaning that the patient never achieved a complete remission, and the patient passed away at day 129 post-transplant with a suspected relapse.
We're conservatively considering this a death from relapse while going through the detailed information about what happened during that death. At TSC100, dose level three, there was an additional patient who had a relapse. This is a 59-year-old male with AML.
And in this case, the donor apheresis for manufacturing occurred after G-CSF mobilization for the stem cell collection. And we know that manufacturing could be challenging after G-CSF mobilization, and that was, in fact, the case here. And that is due to a high number of neutrophils in the collected product. A repeat manufacturing was required due to not achieving the required cell dose for dose level three.
Both infusions in this patient were delayed as a result of that, day 41 and day 97, as opposed to day 21 and day 61. And relapse observed only in the CNS at day 139 post-transplant with no systemic relapse so far. Neither of these circumstances, refractory AML or manufacturing with G-CSF mobilization, would be permitted in the upcoming pivotal trial. Next slide, please. This slide shows the MRD negativity rates.
Prior to transplantation, which you can see in the red and blue rectangles on the left side, 50% of patients on the treatment arm and 54% of patients on the control arm were MRD positive. However, after transplantation and the first TSC infusion, every treatment arm subject achieved MRD negative status in all bone marrow biopsies. In contrast, as you can see, four out of seven control arm subjects remained MRD positive after transplant and either relapsed or required clinical intervention. Of the two TP53 positive subjects in the control arm, both relapsed and died within six months of transplant, which is unfortunately the case for the majority of TP53 mutated patients undergoing reduced-intensity transplant.
In contrast, of the six TP53 positive subjects in the treatment arm, one died of non-relapsed cause prior to any TSC infusion, and of the rest who did receive TSC infusions, none relapsed so far, including one subject who is close to two years post-transplant. In summary, next slide, please. Infusions with TSC100 and TSC101 were well tolerated with no dose-limiting toxicities in a toxicity profile that is generally consistent with a standard transplant.
TSC100 and TSC101 TCR-T cells have been detected for greater than one year post-infusion and have a clear dose-persistence relationship. Two TSC-infused subjects, 9% only, relapsed after TSC infusion as compared to a third of control arm subjects so far. The median time to relapse was not available in the experimental arms versus 160 days in the control arm. EFS strongly favors the treatment arm with a hazard ratio of 0.3.
These data support the continued evaluation of TSC-100 and TSC-101 as adjuvant TCR-T cells to treat residual disease and prevent relapse in subjects with acute leukemia or MDS undergoing hematopoietic cell transplantation. Thank you very much.
Great. Thank you, Dr. Reshef, for sharing these data, so at this point, I'm going to now talk about how we're taking these data and moving forward into a pivotal trial design. So obviously, we're very excited by these data.
It is very rare to have a program at an early stage of clinical development that has a hazard ratio of 0.3 for event-free survival, and so as a result of these exciting data, we were able to get RMAT designation from the FDA for this program. So that's the Regenerative Medicine and Advanced Therapies designation, and so we met with the FDA a couple of months ago and had a very productive meeting.
They were very excited about the program, and we were able to get very clear feedback on what it is that we need to do to put together a registration program for this registration path for this program. So the meeting focused on two main areas, CMC and clinical. In CMC, we are working on a manufacturing process that is commercial-ready.
So there are a few changes to the manufacturing process that make it more robust and more compatible with commercialization, including lower cost of goods. And so one of our questions for the FDA was, as we move to this commercial process, do we need to do a bridging study, or is analytical comparability of the two processes sufficient? And they did confirm that analytical comparability is sufficient to support this commercial-ready process.
We also asked about the potency assays that we're planning for the program, and the FDA did indicate that these are sufficient to support a pivotal study. On the clinical side of things, there were three main areas that we wanted to focus on. The first is obviously the proposed patient population. This trial is being conducted in patients with AML, MDS, and ALL undergoing allogeneic transplant.
And the FDA said that this patient population was acceptable for a pivotal trial and that it was acceptable to expand the donor pool. We've been doing haploidentical transplants. They said it is acceptable to expand the donor population to include mismatched unrelated donors as well. Second question that we dealt with was, what is the endpoint that would support a full approval for this product?
The FDA confirmed for us that, like other programs that have used this in the past, relapse-free survival is an acceptable and appropriate primary endpoint to support full approval. Finally, and most exciting from our perspective, we talked a lot with the FDA about the control arm for this study.
The FDA supports our use of an external control arm using data from the Center for International Blood and Marrow Transplant Research, or CIBMTR, and that matching patients in CIBMTR to patients that we treat on the treatment arm is acceptable and would support full approval. This is very good news for us. It really enables us to very carefully match patients on the control arm that have the same characteristics as patients on the treatment arm.
So we think it's going to be a much more well-balanced study, and it provides a faster path to approval. So as we looked at this program and tried to plot out what is the best route to approval, we noted that historically, this program began with TSC100, which targets the antigen HA1. It was the first antigen to be discovered as a minor histocompatibility antigen mediating graft versus leukemia effect in patients undergoing transplant.
But if you look at the patient population, about 60% of people are HA1 positive. And of course, you also have to have the HLA type A*02:01, which means about 24% of patients would be eligible to receive the therapy. We estimate that we have about a 90% chance of finding an appropriate donor for patients that are eligible for TSC100. So that makes it about 20% of the total population of patients undergoing transplant.
However, as we look at HA2, HA2 is actually present in 97% of eligible patients, and we estimate about an 80% chance of finding a negative donor for a patient that would be receiving TSC101, so when you look at these two products, TSC101 actually captures the majority of patients and really almost every patient that would be eligible for TSC100.
In fact, in the clinical trial to date, 19 out of the 22 patients that we have infused to date would have qualified for TSC101. Some of them were assigned to TSC100, but really, TSC101 captures the majority of the addressable patient population, and so as a result of that, our strategy moving forward is to actually focus entirely on TSC101, a very simple path in which we would put together a pivotal trial with TSC101 in the treatment arm and a synthetic control arm.
So in this trial, we would treat subjects with AML, MDS, and ALL undergoing transplant with reduced-intensity conditioning, the same population we used in the phase one. We would expand the donor pool to include mismatched unrelated donors as well as haploidentical donors. And the enrollment would be in a ratio of one to three.
So for every patient that receives TSC101, we would find three patients in the CIBMTR database that have the same patient characteristics. Because HA2 is present in 97% of the general population, there is no need for companion diagnostic. We would not have to test for HA2 positivity. We would, of course, have to test for the HLA type, but that is part of standard of care in the transplant field. So the primary endpoint in the study would be relapse-free survival. And as I said, this would support full approval of the product.
Key secondary endpoints would include overall survival, time to relapse, and event-free survival. Then, based on a target hazard ratio of 0.6 with 85% power, this study would require about 140 treatment arm subjects. Based on the current rates of enrollment in the sites that are open for our phase 1 study, we anticipate that we would see a readout for the study in 24 months.
We would initiate the study in the second half of next year with the readout supporting full approval of the product in the second half of 2027. If you look at the TSC101 patients on the current study, this is what the relapse-free survival curve currently looks like. There are 12 patients that have received TSC101, 12 patients in the control arm. Right now, we're seeing a hazard ratio of 0.2.
In the pivotal trial, we'd be targeting a hazard ratio of 0.6. We believe this is a very conservative goal for the phase three study and well supported by the data coming out of the ALOHA study. I want to shift at this point and talk a little bit about the addressable patient population. Just to show you what the current breakdown of transplants are in the United States. In the U.S., as you know, there's two different types of conditioning therapy.
There's reduced-intensity conditioning, which is shown in blue on the left, and myeloablative conditioning, which is shown in yellow on the right. Out of all transplants in the U.S., about 30% of transplants, if you look on the Y-axis, about 30% of transplants occur using haploidentical or mismatched unrelated donors, which is the donors that we would use in our pivotal study.
It's this dark blue segment that captures the target population in our planned pivotal study. If you look in CIBMTR and look at what the two-year relapse rates are for patients in each of these segments, you'll see that currently about 42% of patients relapse by the two-year mark of patients with haploidentical or mismatched unrelated transplants receiving reduced-intensity conditioning.
You can see that if they receive myeloablative conditioning, the relapse rate is lower, but the non-relapse mortality is higher due to their very immunocompromised state. There are no statistics breaking down myeloablative versus reduced-intensity conditioning, but across both of those conditioning regimens for matched unrelated and matched related donors, we see about a 30% relapse rate at two years. The hazard ratio that we're targeting in this pivotal study, as I said earlier, is 0.6, and this translates to about a 57% reduction in relapses.
That would equate to about an 18% relapse rate at two years. So that's what we're targeting in our pivotal study. If this study is successful, we would be greatly improving the outcomes of patients undergoing transplant with reduced-intensity conditioning if they are receiving our engineered T cell product. And so what we anticipate is because this is a lower relapse rate than is achieved in these other areas, that we would start to see a change in clinical practice in which centers that normally would use a matched unrelated donor would instead use a haploidentical or mismatched unrelated donor in order to qualify for our therapy.
And similarly, we anticipate a change in clinical practice in which some patients that would normally receive myeloablative conditioning would instead receive reduced-intensity conditioning to undergo unlabeled use of our TCR engineered T cells.
So if we look at the current clinical practice, there's about 450 patients a year in the United States that would currently qualify for our therapy if this product were approved given our current pivotal trial design. If we do see some shift from matched unrelated to haploidentical transplant or mismatched unrelated, that could increase the addressable patient population to about 1,000 patients per year.
And if we do see some conversion in the use of myeloablative conditioning to reduced-intensity conditioning, this could go up to as much as 1,800 patients a year in the United States alone. If we look at the transplant practice in Europe, it's very similar to the U.S. There's actually more transplants that occur in the 44 EU countries as compared to the United States. And so the current practice supports, again, about 450 patients a year.
But if there is a shift from matched unrelated to matched related, this would increase it to about 1,300 to 1,400 addressable patients in Europe. And if we see some conversion from myeloablative to reduced-intensity conditioning, this could go up to as much as 3,000 patients a year in Europe. So between the U.S. and Europe, we're looking at anywhere from 1,000 to 5,000 patients a year that could potentially qualify for this therapy depending on the degree to which we see a change in clinical practice.
And then we have done some preliminary work engaging with payers and leading transplant centers that research has confirmed the value messaging and supports a change in clinical practice that we're proposing would occur to some degree based on a positive result in this pivotal study.
We have recently seen approvals of TIL and TCR-T therapy, the recent approval of Tecelra, and a pricing of $727,000. We feel that our product would fall into this range that includes Tecelra. So we're seeing strong clinical efficacy and safety, high unmet need, and a very defined patient population. And so we believe that this supports a pricing in the range of $500,000-$750,000.
So I want to shift focus at this point to talk a little more broadly about this program and where we are heading with it as we move forward. So again, we're very excited about the results that we're seeing with TSC101, TSC100 as well, of course. But the question is, how can we expand this program to include additional patients that aren't currently being addressed?
The most obvious way is to focus on patients with other HLA types that are not being addressed by TSC101. So again, HLA-A*02:01 covers about 42% of the U.S. population. But we now have a product in our pipeline that we've moved into R&D enabling activities that addresses a hematopoietic restricted antigen on the HLA type HLA-A*03:01. And HLA-A*03:01 is present in about 24% of the population.
There is some overlap with HLA-A*02:01. And so between these two products, TSC100 and TSC101, we'd be addressing about 55% of eligible patients. And again, with a probability of finding a negative donor around 80%, this would in total capture a large segment of the patients undergoing transplant therapy. So what is TSC102?
TSC102, what we've realized in this program is that most often, to find a donor that's negative for the antigen, the easiest way to do that is to find a donor that's negative for the HLA type. And so what this means is that we don't actually need to focus on polymorphic proteins, so proteins that have single nucleotide polymorphisms in the addressable antigen.
We can rely on a universal source of hematopoietically restricted antigens. And CD45 is a protein that is expressed in all hematopoietic cells, including hematopoietic stem cells. It's very hematopoietic-restricted. You don't see it in any non-hematopoietic tissue. It's a large protein and so has many well-known epitopes that are presented on high-frequency HLA types.
In this case, we can put together a whole suite of products that target different antigens derived from CD45 and then pair patients with donors that are negative for that HLA type. Again, TSC102 targets an antigen presented on the HLA type A*03:01. In this case, the patient would be A*03:01 positive and the donor would be A*03:01 negative.
If you look on the bottom left, what you'll see is that CD45 is abundantly expressed and it's very homogeneously expressed across patients with AML and ALL. In fact, it's expressed to an even higher degree than the protein that the HA2 antigen is derived from. We're very excited about this product. Preliminary preclinical evidence shows that it has very high activity, very rapidly kills cancer cell lines derived from heme malignancies. We have now added TSC102 to our pipeline.
It's in IND enabling activities, and we anticipate filing an IND for this product in 2025 and incorporating it into the ongoing ALOHA phase 1 study, so as I said, the most obvious expansion opportunity for this program is to expand to other HLA types, and we feel with three additional TCRs, we can cover the majority of patients undergoing allogeneic transplant in the US and Europe.
There are other areas that this program can expand to down the road, including expanding the types of transplants that it can address, so there are patients that are too frail to receive even reduced-intensity conditioning, but perhaps in pairing with minimal conditioning, we would be able to expand the population of patients that goes to transplant, and at the other end of the spectrum, there are patients that are relapsed or refractory and that would not normally go to transplant.
If we could pair our product with, for example, myeloablative conditioning in combination with the TCR-T cell product, that could potentially address that patient population as well. And then finally, there are some additional areas in oncology as well as in some non-hematologic malignancies that could potentially be addressed by this program. So overall, we feel that this is a very large potential opportunity, many ways in which this program can expand moving forward.
So just to update our next steps and milestones, so we're going to continue to enroll patients in the ALOHA phase 1 study. We are shifting to the commercial manufacturing process in Q1, and so we'll continue to enroll patients with that process in the first half of the year. We'll be transferring that commercial process to an external CDMO. That work is already being initiated.
We'll obviously have an end of phase one meeting with the FDA to finalize the pivotal trial design. And then we're on track to initiating a pivotal trial with the manufacturing at the external CDMO in the second half of next year. So our plans moving forward is to launch the pivotal trial in the second half of next year.
And then we'll continue to update the phase one data through presentations at major medical conferences, including the conference that we just presented at. And so next year, we'd be able to provide data on two-year relapse rates from the ALOHA study. So with that, I want to move to a question and answer period focused on this part of the presentation. And so I think we're going to start with questions from analysts, but I'll turn it back over to the moderator.
At this time, we'll open the floor for questions. If you'd like to ask a question, please press Star 5 on your telephone keypad. You may remove yourself at any time by pressing Star 5 again. Please note you'll be allowed one question and one follow-up question. Again, that is Star 5 to ask a question, and we'll pause for just a moment. Okay. Our first question comes from Sam Slutsky with LifeSci Capital. Your line is now open. Please go ahead.
Hey, everyone. This is Anshul for Sam. Congrats on the update and excited to see the path forward as well. I guess one question I had for the KOL who was presenting today, Dr. Reshef, at what threshold is this hazard ratio clinically meaningful where it does become standard of care? And what does that fall relative to the 0.3 that we're seeing in the ALOHA trial and then the 0.6 threshold going forward as well? And then the last question, how does that result compared to other trials in this setting?
Yeah, so it's a good question, and thank you for that. I think the standard of care is fairly easy to change given that relapse is the predominant reason for mortality after transplant and remains that way, and we've seen quite a bit of disappointment with various maintenance strategies or various modifications to conditioning agents.
I personally think that even a hazard ratio of 0.8 or 0.75 will be sufficient to change standard practice and to lead to expansion of the indication the way Gavin presented it, moving this type of intervention to the myeloablative setting or more precisely moving more patients from the myeloablative setting to the reduced-intensity setting, which should further improve their outcome because you would also get a reduction in non-relapse mortality.
So, I think the preliminary data are way ahead of anything that would change the standard of care, and the conservative assumptions and designing the pivotal trial are appropriate and would be more than sufficient if successful to change the standard of care. And could you repeat the second question? I'm sorry.
I guess how does this result, this hazard ratio result and then maybe the 0.6 benchmark for the phase 3 trial, how does that compare to other trials in this transplant setting?
Yeah, so I don't know that there are many ongoing trials that would address this and that have already preliminary findings at this level. Maintenance or consolidation studies have primarily been the predominant ones in the field of preventing relapse post-transplant. And those have either failed to show any benefit or showed incremental benefit that is not ideal and involves toxicity of the agents that are being used themselves.
Either it's combinations of HMA plus something or FLT3 inhibitors and other agents in the maintenance setting. Sorafenib is one agent that has shown even a survival advantage in FLT3 mutated AML post-transplant, but it is so difficult to tolerate and to give that it is hardly ever used in the U.S. and even in Europe, its use is fairly minimal. So I'm not familiar with any program that has preliminary findings at this level and with this many patients.
Thanks so much. Appreciate it.
Our next question will come from the line of Vikram Purohit with Morgan Stanley. Your line is now open. Please go ahead.
Hi, good morning. Thank you for taking our questions. We had one on just some of the practical considerations related to TSC100 and TSC101. Dr. Reshef, could you speak a little bit about what resources and infrastructure a center might need in order to administer this type of therapy and what some of the, I guess, logistical considerations and training requirements might be just to operationalize the use of something like 101? Thank you.
Yes, of course. So since this is built on a standard transplant platform, then the increment in resources or required infrastructure is fairly minimal. This is already something that's designed to be performed by centers that are transplant centers and not outside of that. The added components are an additional collection from the donor, but this collection can occur almost back to back with the stem cell collection within sometimes even less than a week apart.
So logistically, it does not add significant burden to the donor who's already volunteered to donate stem cells. So they just need to undergo one extra collection. And of course, it means an apheresis procedure. This is not an off-the-shelf product, but that's the beauty of it, that it would come from the same donor that's used for the transplant. And this is a major driver of this long-term persistence that we're seeing.
These cells are basically incapable of getting rejected because they're going into a recipient who's already been engrafted with stem cells from the same donor. Of course, we need the cell infusions, which on the trial has been given in the inpatient setting.
Given the benign toxicity profile that we've been seeing so far, at least my anticipation, and Gavin might speak to that, in the pivotal trial, we might be able to just do them outpatient since there's really no good justification or no justification that we've so far observed in the ALOHA trial why this has to be done in patients. The increment in resources and infrastructure is not, I wouldn't say, significant.
That's awesome. Thank you.
Our next question comes from the line of Peter Lawson with Barclays. Your line is now open. Please go ahead.
Great. Thank you. Thanks for the update. Appreciate all the details. I guess a question for Ran Reshef, just kind of when you're thinking about emerging therapies, especially in the transplant setting, kind of how many patients do you need to kind of see to feel that this is a real therapy moving forward? And then kind of if you could kind of also walk through how you think this could potentially change the number of patients that can be going on to transplant. Thank you.
Yes, good question. I'm not sure I have a very good answer. And obviously, as an investigator on the trial, I'm seeing these patients and I'm seeing their outcomes. And we've enrolled both TSC100, TSC101, and control patients. So we can clearly see the differences even with the fairly small patients. We had one or two TP53 patients in the control arm who really had a very rapid relapse and death as a result of relapse because they're so rarely salvageable.
And we've had high-risk patients on the experimental arm who are doing phenomenally well and have been actually asking me to share the abstract and the PowerPoint slides with them after they're presented publicly because even the patients are sharing some degree of enthusiasm because they're told that their relapse risk with this type of transplant will be 30%-50%.
They are alive and well and MRD negative, some of them even more than one year after transplant. So I don't know that I need to see many more patients than what was already presented now, at least in order to make the decision that this is appropriate for a registrational trial. Obviously, we need a registrational trial and we need a higher number of patients to convince not just the FDA, but the community, the oncology community at large. But I think these preliminary data are quite compelling to me already. I hope that answers your question, Peter.
Great. Thanks so much.
Our next question comes from the line of Gil Blum. We need him. Your line is now open. Please go ahead.
Hi, and good morning. And let me add my congratulations to the fascinating results here. Maybe as it relates to the matched control portion of the pivotal study, could you maybe help us understand a little bit how that matching is conducted? I mean, looking for a three-to-one ratio here, this is just very interesting. Thank you.
Yeah, so maybe I could turn this question to Dr. Crystal Louis, who's our Chief Medical Officer.
Thank you, Gavin. This is a great question that we are in the process of working with CIBMTR to answer, but holistically, what we're doing is taking the factors that we have historically known are very well associated with potential risk and/or relapse.
For example, how old is the patient? How old is the donor of the patient? Things of that nature, and saying, we've got certain parameters, want the patients to be matched with an age of this patient's 60, so within five years on the control arm, and CIBMTR will then take their associated database, look at all of the factors that we say are important to match, and then take three of their patients within their database that match exactly on those factors and use that as the comparator for a treatment-arm patient.
There are.
Thanks for taking our question. I'm sorry.
There are also fairly well-established risk factors associated with certain mutations in this patient population as well, so the overall risk factor for the patient is also another factor that would likely be required in the selection of patients on the control arm.
It's a nice piece, ultimately, what the registry is. It gives us the ability to look at a multitude of different factors. And in our mind, we actually think it has the ability to reduce the amount of potential bias that you'd be seeing because you have the ability to match on a multitude of factors when comparing the control arm to treatment-arm patients.
And then maybe I could follow up because there is an online question from David Nierengarten at Wedbush asking about what is the rationale for the three-to-one randomization. And so maybe I could have Dr. Shrikanta Chattopadhyay talk a little bit about the statistics behind why we would do a three-to-one or one to three, I should say: three patients on the control arm for every one patient on the treatment arm.
Yeah, thank you. So the rationale for choosing a three-to-one ratio is to really maximize the likelihood of finding these matches that Crystal just mentioned. Those could be baseline variables that are known to confer risks of relapses like disease status, the disease risk categories like ELN risk categories, pretransplant MRD status, and so on and so forth.
And so having a large pool of patients allows that better matching and a better representation of what the real-world outcomes would be for those patients. So as Gavin showed you in the pivotal trial design, we've done those statistical modeling for how many events would be required. And the number of events would be 184 relapse and death events that are distributed between the treatment arm and the control arm. And having the majority of the events on the control arm allows the treatment arm to be relatively smaller.
And we should be able to achieve that hazard ratio of 0.6 with about 140 patients, which would take about two years to perform. So those were the various thought processes that went into selecting those ratios. Obviously, it could also be a slightly lower ratio, which will achieve better matching. But we would still have the same number of subjects, better matched, but with a smaller matching ratio between the control arm and the treatment arm.
Okay. Our next question comes from Justin Zelin with BTIG. Your line is now open. Please go ahead.
Thanks for taking our questions and congrats on the compelling data here. I wanted to ask Dr. Reshef, based on the data we've seen thus far, what proportion of patients would you recommend usage of TSC101 if they're eligible for therapy? And my second question is, can you walk us through the thinking, the calculus of moving a patient from receiving standard myeloablative conditioning to reduced intensity conditioning with the TSC101 program, and what you'd like to see from the data in order to be comfortable doing so?
Of course. So maybe I'll start with your second question first. So reduced intensity regimens have been developed now about three decades ago with the idea of reducing non-relapse mortality. And they are, in fact, much better tolerated. So there has been a trend over the years in switching to reduced intensity transplant because they are much better tolerated and allowed us doing transplants even in patients well into their 70s, I would have to say, and potentially even older in the future.
There then has been a movement back realizing that reduced intensity transplants are not as effective in reducing disease relapse. And that ultimately, in a head-to-head trial, they failed to show a survival advantage. The desire to reduce transplant toxicity still exists. We just need to make reduced intensity transplants more effective in order for that to be appealing to patients.
In order to really move the needle, you need to make reduced-intensity transplants have a somewhat equivalent relapse risk to myeloablative transplant. You need to reduce it to somewhere in the range of 15%-20%, which is the current relapse risk in the myeloablative setting. I think the preliminary results of ALOHA are consistent with that.
If those could be reproduced on a larger scale, we will see a movement from myeloablative transplants to reduced-intensity transplants, which are sometimes transplants that can even be done outpatient. They can be done in older individuals, certainly improve the quality of life of patients, and shorten the time to recovery. From an ablative transplant, I tell patients that it takes 12 months to recover.
From a reduced intensity transplant, it's three to six months, and many patients would go back to work and would go back to normal life. So there is definitely an impetus in attempting to just create a more effective reduced intensity platform.
Thanks. And maybe just on the proportion of patients you'd recommend the program to based on the data you've seen thus far?
Oh, so you know that's easy. The platform is disease agnostic. So to me, if it's working in the most common diseases, acute leukemia and MDS, which was really designed to create a relatively homogeneous trial population, it should work for any disease and in any situation.
It's a way to remove residual recipient cells, which is, in essence, a way that would work in any type of disease in patients eligible for transplant. So to me, this is relevant for 100% of patients undergoing allogeneic transplant as a way to just improve achievement of complete donor chimerism. The challenge would be, of course, to generate data that is comprehensive enough that really covers as many diseases.
That may need to happen outside just one registrational trial, but I think could easily be extrapolated from a trial that is just focused on acute leukemia and MDS because of the disease-agnostic nature of the products.
Excellent. Thanks for taking our questions.
The next question will come from Tara Bancroft with TD Cowen. Your line is now open. Please go ahead.
Hi, good morning, and thanks for taking the questions. So I'm curious how your donor chimerism results influence your conviction and being able to potentially include that as an endpoint in the pivotal trial. I don't see that in your plan. So I'm curious if the FDA is still open to that based on ALOHA or on this. And then for the KOL, how meaningful would you find that as a biomarker in a pivotal trial based on these data today? Thank you.
Yeah, so maybe take the first part of.
No, go ahead.
I was going to say, I'll maybe take the first part of that, then hand Dr. Reshef the second part. So the inclusion of chimerism and the evaluation thereof will still be an exploratory endpoint. But from a practical perspective, since we'll ultimately be using a control arm through the CIBMTR registry as compared to having control arm patients that are enrolled on the study at our associated sites, we won't be able to obtain chimerism results because it still is an investigational assay.
So that's one where, again, we will continue to collect it on our patients that would be within the treatment arm, but we wouldn't necessarily be able to do a direct head-to-head comparison when moving into the pivotal because it's essentially an assay that wouldn't be available for control arm patients.
So that's why it'll remain an exploratory piece, but couldn't be moved up to any of the other key outcomes. And then Dr. Reshef, I'll pass to you the original question.
Sure. So I agree with Dr. Louis. This is a work in progress. And I think it is complementary to MRD testing. And MRD testing in AML and MDS has been notoriously challenging to standardize. However, chimerism testing that is disease-agnostic, and it's frequently used in transplant. And I think that's the point I would emphasize in response to your question.
This is a type of assay and a type of endpoint that we already are using clinically to determine clinical decisions. So the proof is in the pudding. We're already using this to make clinical decisions. So it is a compelling endpoint, and using it as an exploratory endpoint would help quite a bit.
Okay. Great. Thank you.
There are no further questions on the line. I'll turn the call over for the next section of the call.
Great. Thank you. So at this point, we want to shift gears and move to an update on our solid tumor program at TScan. So as many people are aware, we launched a phase 1 study, which we now call the PLEXITY study. There you go, in 2025. So we enrolled our first patient in May of this year.
And this study is really focused on trying to address what we believe is one of the biggest challenges in solid tumors. And that is that solid tumors are heterogeneous. Not every tumor cell behaves the same in a solid tumor. And in particular, not every target, not every tumor cell expresses a given target. So if you look at the histology diagram on the left, this is a sample from a non-small cell lung cancer.
And we have stained the sample in red for the target PRAME and in green for the target MAGE4. And what you can see is that these are distinct cell populations. Some of the cells are expressing PRAME. Some of the cells are expressing MAGE4. And surprisingly, very few cells are expressing both PRAME and MAGE4, which would show up as yellow in this image.
And so really, to address this type of heterogeneity, I mean, if you were to treat this tumor with just a single TCR for PRAME, for example, as shown diagrammatically on the right, you would end up addressing some of the cells. You might even see a partial response, but then that tumor would rapidly relapse.
If, on the other hand, you are able to treat that tumor with more than one TCR, in this case, PRAME and MAGE4, you have a much greater chance of addressing the heterogeneity of that cancer and potentially getting a long-term remission or even a cure. And so since the beginning, the strategy of our solid tumor program has to build, it was to build a collection of engineered T cell therapies that address different cancer-specific targets.
So the rows of this ImmunoBank are different cancer-specific proteins like PRAME and MAGE4, but then also address different HLA types. So each of these proteins will produce epitopes that are presented on different HLAs like HLA-A*02:01 or HLA-A*03:01, as we just discussed.
And so the idea is if we have enough TCRs in that ImmunoBank, then when a patient comes in, you could profile their tumor to see what targets are expressed in their tumor, what HLA genes are still intact in their tumor, and then choose the best two or three TCRs from that ImmunoBank to build a customized autologous multiplex therapy. And so based on that strategy, we have now successfully filed and cleared six INDs addressing six different TCRs in this program.
And those TCRs address MAGE-A1, HPV16, MAGE-C2, and PRAME, and four different HLA types are currently covered in the ImmunoBank. Largely, the HLA diversity is on MAGE-A1. And so the clinical trial design has been to first establish safety for each of these TCRs individually at two different dose levels.
And then once a TCR has cleared dose level two, which is about 2 billion cells infused into the patient, then that TCR becomes eligible to be combined with any other TCR that's cleared dose level two. So the update on this program is that since May, we have now dosed eight patients on this trial. So we've dosed patients across four different cohorts in the study: MAGE1, A*0201, HPV16, A*0201, PRAME, A*0201, and MAGEC2, B*07:02.
And then two of these TCRs have also been dosed at dose level two, the HPV and PRAME TCRs. And in fact, the PRAME TCR has cleared dose level two, and the HPV TCR is about to clear dose level two. We actually have a safety review committee meeting today to potentially clear this TCR through dose level two.
With the anticipated clearance of this HPV TCR, we've actually already enrolled our first patient that would qualify for multiplex therapy. This patient's tumor is positive for both HPV16 and PRAME. And we have already successfully manufactured product to administer multiplex therapy at dose level two. Now, we recognize that it's going to be important to compare the multiplex product to single-agent product at the same dose level.
And so we are in this study going to enroll some patients at dose level three that receive singleplex therapy. And to that end, we have also enrolled and are currently manufacturing product for a patient that is PRAME positive that would receive a singleplex infusion at dose level three of a PRAME TCR. So in essence, eight patients dosed to date, two pending. And we have now seen an uptick in interest in this trial.
Patient enrollment is going very well, and so we anticipate that as we move into 2025, we'll be in position to dose many more patients at that dose level three and multiplex therapy. So as a summary in terms of where we are to date, what we've shown is that since May, we've enrolled 10 patients and dosed eight patients. Sorry, I should say we've dosed eight patients. We've now manufactured product or are manufacturing product for patients nine and ten.
So we've shown that we can effectively enroll the study. We've shown that we can effectively manufacture for patients. This is a question as we went into the study. We are now dealing with T cells from patients with active disease, and so that is a little more challenging than what we've been seeing with the HEME program in which we're collecting T cells from healthy donors.
So it is encouraging to us that we are able to use our transposon-based manufacturing process successfully in the solid tumor program. We have shown that we've been able to move through dose escalation to the multiplex dose with PRAME and soon to be HPV as well and anticipate moving other products through dose level two in the very near future. And then finally, although we have not seen any radiologic responses at this point, it's still early.
We've just recently dosed some of these dose level two patients, and there's only three patients that have been dosed at dose level two. We have seen signs of anti-tumor activity. We've seen some evidence of tumor necrosis. So moving forward, as we move into 2025, we are now really trying to focus the program on areas that we think are areas with high unmet need.
So far, the initial patients in the study have been all comers. They've included patients with anal cancer, head and neck, melanoma, non-small cell lung, ovarian, sarcoma, and thyroid cancer. So obviously, a lot of heterogeneity in these first eight patients. But now that we've reached dose level two, sorry, dose level three enabling multiplex therapy, this is where we expect to be sort of our first efficacious dose level, either singleplex or multiplex treatment at dose level three.
Really, our goal moving into 2025 is to end the year with clearly interpretable data on multiplex therapy. To that end, we really want to focus on cancers that we believe have a high unmet need and are immune-rich cancers where we know the T cells will infiltrate successfully.
And so to that end, what we're choosing to do is as we get to dose level three, we're going to exclusively focus on patients. So if they're HPV positive patients, in other words, patients with head and neck cancer, cervical or anal cancer, that's one area of focus. What we're finding in our screening study is that a vast majority of patients that are HPV16 positive, their tumors are also PRAME positive.
So we anticipate that one very common multiplex therapy will be HPV plus PRAME. We see that in our first patient that we've manufactured product for now, that's in line to receive HPV plus PRAME. And then for HPV negative cancers, really focus exclusively on non-small cell lung, sarcoma, and head and neck cancers. These are all cancers where we have seen previous signals of clinical activity in other TCR-T cell trials.
There we anticipate that because PRAME is so prevalently expressed, most of these combinations will be with PRAME as the backbone in combination with one of the MAGE TCRs, either MAGE-A1, MAGE-C2, or MAGE-A4. And so to that end, we have now filed an IND for our first MAGE-A4 TCR. This is again an AO201 TCR. We filed that IND in November.
So anticipate that if there's no snags, that that would clear in December, and we'd be in position to start enrolling patients into the MAGE-A4 cohorts as early as Q1. Just a quick word on this MAGE-A4 TCR. So on the left, it also has very strong preclinical activity. It rapidly kills cells in vitro that are MAGE-A4 positive. And on the right, what I'm showing is the impact of adding MAGE-A4 to our immunobank.
Because a lot of patients with head and neck cancer and non-small cell lung cancer in particular are MAGE-A4 positive, then as we add this to the ImmunoBank, it substantially increases the percentage of patients that would qualify for multiplex therapy. Right now, with the current six TCRs in the ImmunoBank, if you look at the purple, you'll see that somewhere around 15, sorry, somewhere around 8% of patients qualify for some two-way combination of TCRs for non-small cell lung cancer.
As we add MAGE-A4, the percentage of patients that would qualify for multiplex therapy increases substantially to about 30% of patients. Because of that prevalence, there's just a higher probability that patients will be eligible to receive a multiplex therapy product in non-small cell lung cancer. We've now advanced this MAGE-A4 TCR through IND-enabling activities.
Once that clears, it will be in the phase 1 study, and at that point, we'll have seven TCRs from which to choose, so in summary, as I said, we've dosed eight patients to date. Two have advanced through dose level 2, assuming that the HPV TCR clears dose level 2 later today. We've shown that we can successfully manufacture product, including product for multiplex therapy.
We have some early evidence of dose-dependent T cell activation and expansion, and we've now recently filed this IND for MAGE-A4, so what we anticipate in terms of updated milestones is that 2025 will focus on trying to really dose as many patients with multiplex therapy in these key indications as possible, and we anticipate providing an update on both safety and response data for multiplex therapy by year-end. We're targeting a major medical conference in which to report those data.
So with that, I'm happy to open the floor to questions and answers as well.
As a reminder, if you'd like to ask a question, please press star five on your telephone keypad, and we'll pause for just a moment for the queue to assemble. Okay. Our first question comes from Peter Lawson with Barclays. Your line is now open. Please go ahead.
Great. Thank you. Thank you so much, Gavin, on the updates of the solid tumor program. I wonder if you kind of walked through the signals that you'll be looking for in the various solid tumor indications to gain confidence that there's a real signal to move forward?
Yeah. So obviously, the key for us is to really focus on response rates in this trial as well as duration of response. I think each of these indications obviously has a different sort of bar to meet in terms of what type of activity we would expect.
So it's kind of a nuanced question. Obviously, response rate in lung cancer is going to be different from what we would be looking to see in head and neck or sarcoma. But I think we'd have to obviously take a look at what the current standard of care is for each of those indications and look to substantially beat that to justify an autologous TCR-T cell product. I don't know if that sufficiently answered your question or.
No, it's definitely a nuanced question. I mean, I guess in each indication, you want to see at least one, at least one, at least two kind of responses in difficult-to-treat patients to make sure you're not fooled by N of 1s.
Yeah, no, absolutely. Yeah, and I would say that is why we're looking to first collect a substantial data set before we start reporting efficacy data on this program. You can fall into the trap that you treat your first patient, you get something exciting, you put it out there, and then that trend doesn't continue, so we want to have a reasonable number of patients so that we can have an interpretable data set before we really put that out at a medical conference.
Great. Thank you. And then kind of not to push you down an avenue of when you're going to present, but when would be an ideal time? Is this kind of a back half of 2025 when you think you'd potentially have enough data to feel comfortable to present this? Or what's the timeline we should be thinking about?
Yeah. I mean, I think obviously we're just eligible for a single pair of TCRs, hopefully by the end of today. But we want to advance other TCRs, the other MAGE TCRs, for example, through dose level two to unlock those T-Plex possibilities so that would still, excuse me, be ongoing through Q1 and Q2. So really, this is a year-end event that we'd be targeting to get enough patients treated with sufficient follow-up time to get radiological responses and confirmed radiological responses as well.
Great. Okay. Thank you so much. Really appreciate it.
Our next question will come from the line of Justin Zelin with BTIG. Your line is now open. Please go ahead.
Thanks for taking our questions and congrats on the update here. Just a question, Gavin. You mentioned you dosed with the multiplex already. I didn't hear you disclose if there was any CRS or safety profile with the combination. If you could kind of talk through what you've seen thus far or the expectation of additional CRS with the additional multiplex therapy. Thanks.
Yeah. So maybe I'll turn that over to Crystal for that question.
So the most straightforward way to answer that is we haven't dosed anybody with multiplex therapy yet. So being able to say what that safety profile is, it's just information that doesn't exist yet. But overarchingly, part of the reason why we wanted to do this in a staged manner is to be able to get those associated data sets moving forward.
I think holistically, it is one thing that we are always considering: what is the tox of each individual piece and then what the tox of the combinatorial piece will be. It is part of the reason why we are having patients remain in the hospital to be able to be evaluated, to be able to see how that's going. But the straightforward answer is at this point in time, we've not dosed a multiplex patient for me to be able to answer that question for you.
But it is part of the essential safety profile that we would be on the lookout for and have put parameters within the protocol to monitor for.
Understood. And if I could just ask, how do you think about the ratio when you're manufacturing the multiplex therapies? Does that depend on the different antigen presentation that the patient has?
When, oh, go ahead. I was going to say, I just want to make sure that I'm clear as to the associated question. Are you asking about ratios with respect to what are the doses?
With respect to two different TCRs?
Yeah, as far as multiplex.
Yeah. So as Gavin mentioned, the way that the protocol is currently written, you do have to have proceeded through two associated dose levels before moving into a T-Plex perspective. It is an ongoing discussion as to what the doses of T-Plex will be. We've written it for up to 4 billion and 4 billion, sort of 2 billion from each particular product.
But, to your point, would acknowledge that the protocol also gives us a little bit of flexibility to be able to say that based on what we're seeing from the two dose levels that have ultimately been cleared, it may be that it's not across the board for each combinatorial partner. There may be some partners where it's 1 billion and 2 billion. There may be some partners where it's 2 billion and 2 billion, things of that nature.
So the nice piece is the protocol gives us the flexibility to be able to look comprehensively at the data set to be able to decide how to move forward with the associated doses.
Great. Thanks for taking our questions.
The next question will come from Vikram Purohit with Morgan Stanley. Your line is now open. Please go ahead.
Hi. Thanks again for taking our questions. Apologies if you touched on this and I missed it, but how are you currently thinking about how many patients' worth of data across each tumor type you might need to see before determining a path towards a pivotal program? And what do you think a pivotal program could look like here? And how many tumor types do you hope to be able to scale into with a potential registrational program when the time comes?
All right, Vikram, we're going to charge you by the question. That was three questions. No. So these are challenging questions to answer at this stage of clinical development. I mean, obviously, it would be nice to have kind of a dozen patients with response data in defined areas to be able to get that early signal of efficacy. I think as with most companies in phase 1, you treat a substantial number of patients, you take a look at the data, and if you see a strong, compelling signal in one particular area, that's really what defines your pivotal path moving forward.
So if, for example, we were to see a nice, strong signal in patients with head and neck cancer that were HPV positive, and we saw that combination with PRAME was vastly outperforming what we would expect from standard of care, then that would be a potential path forward for a pivotal study.
Or if we saw something different with PRAME plus MAGE in lung cancer, that would be the signal that we would use to define a pivotal path. So I think, as I said, as with most companies, collect the data across a well-defined set of options and then follow the signal that we see, which hopefully we'll have some clarity on that signal by the end of next year, if not early 2026.
Understood. Thank you.
Our next question will come from Gil Blum. Wynita, your line is now open. Please go ahead.
Hey, good morning, and thanks for taking our question. The underlying biology, which could lead to dominance of specific pairings of antigens in certain tumors. Outside of the obvious HPV point here, it's just an interesting observation.
It's a little hard to hear the question, but I think what I was hearing is, is there sort of dominant pairs of antigens or particular expression patterns that would be observed maybe even for biological reasons? Do you want to take that question, Shree?
Sure. Yeah, and we've disclosed the results of our screening study earlier this year at ASCO. What we found is that PRAME is actually quite dominantly expressed in multiple tumors, not just in melanoma, but in head and neck cancer, for example. It's about 90%. In many other cancers, it's over 50%. Ovarian cancers as well, over 80%.
So PRAME is certainly one of those dominant antigens in addition to HPV16. It could serve as sort of a backbone for these combinations in non-HPV positive cancers. MAGE-A4 is well known in the literature. We've now included MAGE-A4 in our screening study. MAGE-A4 also is quite dominantly expressed in particularly squamous cell carcinomas of the head and neck and of the lung. So these are sort of the next in line in terms of these dominant antigens.
And so we anticipate seeing a lot of those combinations based on PRAME and MAGE4.
Thank you.
Our next question will come from Sam Slutsky with LifeSci Capital. Your line is now open. Please go ahead.
Hi, Anshul again here for Sam. You mentioned some hints of anti-tumor activity. I think you mentioned some necrosis potentially. I guess, is there anything else you can say in terms of what dose levels that was seen at? I mean, I guess if you're taking tumor samples, is that from patients who are already completed, or is that patients who are enrolling in ongoing treatment still? Just any more color on that would be useful.
Crystal, do you want to speak to that?
Coming off mute, yes, so as we would expect, the anti-tumor activity we've been seeing has been a little bit more pronounced on dose level two, and so for us, that ultimately is an encouraging piece that we are heading in a good direction with being able to move into higher dose levels and the ability to be able to multiplex coming forward.
Excellent. Looking forward to seeing more data next year. Thanks.
The next question will come from Tara Bancroft with TD Cowen. Your line is now open. Please go ahead.
Hi, again. So my question, I guess, is really in the indications that you're thinking about, what line of therapy do you see it being used in? And just in general, in practice, where would it be used?
Okay. Now, turn this to Crystal.
Yes, so that is a great question that, unfortunately, I'm going to have to hedge a little bit and say is a little bit too early for us to answer. As with any associated registrational program, especially when there are associated pieces where there's standard of care, you know that you're initially going to look into that relapse refractory setting.
The ability to move into earlier lines, I think, really then also becomes disease-dependent and what's in those associated earlier lines to be able to appreciate if it's one of those that post your first standard of care regimen, you're able to move on, or is it a more established disease where you potentially would have to get through two to three lines of therapy to be able to move on?
I'd almost say if we could put a pin in that question until we have more data on the associated disease we'd be looking for, I think I could give you a more straightforward answer then. Right now, without that, I'd be speculating, and I'd rather us be more data-driven and give you a more straightforward answer once we know the exact disease indications.
Of course, yes. That makes perfect sense. Thanks so much.
There are no further questions at this time. I'll now turn the call over to Gavin MacBeath for closing remarks.
Yeah. So thank you again, everyone, for joining us online. As I said, in summary, we are very encouraged by the data from the ALOHA study, and so look forward to initiating that trial next year, and then on the solid tumor program, again, look forward to collecting data on patients treated with multiplex therapy next year so that we can provide our first real update on safety and efficacy at year-end 2025, so I know everyone's been on this call for some time, so appreciate everyone for sticking through this and look forward to updating people on these programs moving forward. Thank you, everyone.