Orca-Q Elicits Compelling Data Among Patients Undergoing Haplo HSCT

Samer A. Srour, MD, MS

Positive clinical outcomes were observed when Orca-Q was administered with single-agent tacrolimus, without the use of posttransplant cyclophosphamide (PTCy) or mycophenolate mofetil, in patients who were undergoing haploidentical allogeneic hematopoietic stem cell transplantation (HSCT).¹

Orca-Q is a next-generation investigational cell therapy. In the haploidentical arm of a 3-arm, phase 1 trial (NCT03802695), the agent led to a reduction in rates of acute and chronic graft-vs-host disease (GVHD) and improved GVHD relapse-free survival (GRFS) in this patient population.

At 1-year, the GRFS rate with Orca-Q was 75%, which compared favorably with 46% in patients who underwent allogeneic HSCT with PTCy.

“This is extremely encouraging because historically, if you achieve 40%-50%, we would be happy with that, and in our cohort, it was 75%. Then the overall survival, which means any patients are alive at 1 year, also was the same as 75%,” Samer A. Srour, MD, MS told Targeted Oncology^TM, in an interview.

In the interview, Srour of The University of Texas MD Anderson Cancer Center, Houston, Texas, reviewed data from the dose-expansion phase of an ongoing phase 1 trial of Orca-Q in the HSCT setting for patients with high-risk hematologic malignancies.

Targeted Oncology: Can you discuss the background of the phase 1 trial of Orca-Q?

Srour: I presented data on Orca-Q in the phase 1 first-in-human, clinical trial. Orca-Q is an unmanipulated graft, and its impact on improving the outcomes of haploidentical stem cell transplantations. Historically, before 2009-2010, patients who don't have matched donors and these patients with high-risk hematologic malignancies who failed treatments, or even if did not fail treatments, are at very high-risk of dying from their disease, if they don't have matched donors to do stem cell transplant, which was the only way to cure them, they have limited options. We used to use transplants and some mismatch transplants which did not have very encouraging outcomes and had a high-risk of complications.

Since we introduced cyclophosphamide almost over 15 years ago, we were able to change the outcomes for the haploidentical transplants, which means those related patients who are not fully matched and who will not be 100% match, with the cyclophosphamide, we were able to do transplants from these not fully matched related donors. The reason behind the success is we improved our graph failure and graft-vs-host disease. Less patients had graft failure, and less patients had graft-vs-host disease. At the same time, we have improved our supportive treatments to treat infections and other complications. Pretty much every patient in need for transplant, has a donor. If not fully matched, they have a partially match-related donor. That was practice changing over 14 years ago and the haploidentical transplants just continue to increase.

With that being said, the outcomes are still a little different. If you look at the overall picture, patients who are alive and graft-vs-host disease free, doing well, and without complications at 1 year, it's only in the range of 40%-50%. Most of the patients are still either not cured or if they are cured, they are having big problems from the graft-vs-host disease, infections, and other problems. Because of that, we have been trying to improve the outcomes of the haploidentical stem cell transplantation.

Where does Orca-Q fit into this research?

Instead of giving drugs like cyclophosphamide, which again, can help a large proportion of patients but remains unpredictable how these patients who are these patients who will survive at one year without relapse and without a graft-vs-host disease, it also comes at the expense of many other complications early after transplant, like infections and increase delayed neutropenia, delayed thrombocytopenia, and increase the frequency of transfusions, among others.

Orca-Q, is a novel way where instead of doing that, what we call in vivo by giving cyclophosphamide and other drugs like cellcept and tacrolimus, [we ask,] can we do that ex vivo? Before we give the graft, which is the donor cells, can we purify those and keep the good cells because they are good for recipients. They can either decrease the graft-vs-host disease, decrease this infection, etc. Orca-Q, is a more purified graft, there's no engineering, so we keep the hematopoietic progenitor cells to reconstitute the port system, and we also keep certain amounts of iNKT cells to decrease the graft-vs-host disease. We also keep other subsets of the cells which were important to fight for infection and fight for the tumor. With Orca-Q, we are trying to eliminate the need for cyclophosphamide, and that's indeed what we did. Also, we eliminated the need of other immunosuppressive agents.

What were the findings from this phase 1 trial?

Findings from this study were compelling. Right now, we are still accruing patients across different centers in the United States. With the first 26 patients who were accrued in this haploidentical recipient arm, the patients who received haploidentical transplants, the results were very encouraging. The first outcome we looked at was, did all the patients engraft because 1 of the things in the in the mismatch and haplo transplants that we are concerned about, particularly when you manipulate the cells outside the recipient, is that there is also risk of graft failure when you give them back to the to the recipient. We didn't see any primary graft failure among all the patients who received the graft on this dose-expansion, or these 26 patients engrafted, which was very good to see. The second thing related to that is that they did not just engraft, they engrafted rapidly with the medium time to neutrophil engraftment of only 12 days. Likewise, the platelets, the time to engraftment was around 16-17 days. Most of the patients within 2-3 weeks were transfusion independent, so they don't require any transfusions. This is 1 of the first outcomes we looked at.

Next to that, we have seen very good immune reconstitution and relatively low-risk of severe infection. Only 19% of our patient population had what we call grade 3 infections, so that was also encouraging. One of the main outcomes in our study was graft-vs-host disease. The key always with the transplant, and more so in the haploidentical transplant, is, how can we decrease the graft-vs-host disease risk and the infections and the mortality without increasing the relapse? The graft-vs-host disease, if we talk about the acute graft-vs-host disease, was low. Indeed, only 5% had severe acute graft-vs-host disease in our patient population. That is encouraging compared with post-transplant, historical data. Then, we looked at the chronic graft-vs-host disease. The median follow-up was a little over 6 months in our patient cohort and we will still need more follow-up, but at least it's a decent follow-up to start with. We didn't see any moderate or severe GVHD cases, which was also encouraging.

One of the most important outcomes to look at is survival: are your patients alive? More important for me, are they alive and with no complications. There's an interesting outcome we look at in the transplant more and more these days called graft-vs-host disease relapse-free survival, which means your patients are alive and without active disease and are in remission. This is a good indicator of good quality-of-life. In our cohort, the graft-vs-host disease relapse-free survival was 75%. This is extremely encouraging because historically, if you achieve 40%-50%, we would be happy with that, and in our cohort, it was 75%. Then the overall survival, which means any patients are alive at 1 year, also was the same as 75%.

What kind of challenges need to be faced moving forward with this study?

The study is still ongoing. Since those 26 patients were treated, we have added more patients to this cohort, and we definitely need to add more patients and we need a little bit more time, maybe like 6 more months to make sure that these results are validated with higher sample size and longer follow-up, which I hope it will. The next step should be automatically to go to a randomized clinical trial where we say we have this new, novel, first-in-human Orca-Q. For me, the Q stands for quality-of-life. This is a good platform, not just to improve the outcomes of these applications, but also to improve their quality-of-life with less toxicity. We have to randomize patients to this compared with the conventional way of doing transplant, which is most commonly done with cyclophosphamide given after transplant. That will be my goal, to work with my colleagues and co-authors on this study to proceed with that randomized study as soon as possible so we can get the best answer in the coming couple of years or so and determine whether this should be a new standard of care for our patients.

Is there any other research in this space that interests you?

[At] the Tandem meetings, [experts] talked about upcoming studies, future directions, how we cure cancer, and how we can cure larger proportions of the patients who have hematologic malignancies. Because this meeting is mostly about hematologic malignancies, how can they cure them without compromising their quality-of-life? I understand the biggest goal from the patients is that they will want to be living. But also, if you ask all these patients how you're going to be living, they're going to have a good quality-of-life. In the Tandem meeting and in upcoming meetings, I hope we see more studies focusing on how we can cure more patients with good quality-of-life. For the patients who can cure right now with whatever results we have, how can we improve their quality-of-life with the data we have as well?

REFERENCE:

1. Salhotra A, Srour SA, Hoeg RT, et al. Orca-Q demonstrates favorable GvHD-and-relapse-free survival in haploidentical transplants without post-transplant cyclophosphamide. Blood. 2022;140(supp 1):1865-1866. doi:10.1182/blood-2022-170459