Orca-T Delivers Major Gains Beyond Conventional Prophylaxis in Hematologic Malignancies

Current data position Orca-T as a powerful platform for future advancements in allogeneic transplantation for patients with hematologic malignancies, given its superiority to conventional prophylaxis. However, David Miklos, MD, PhD, says questions remain regarding its long-term comparative standing against standard posttransplant cyclophosphamide (PTCy), according to David Miklos, MD, PhD.

Findings from the phase 3 component of the Precision-T trial (NCT05316701), presented at the SOHO 2025 Annual Meeting, showed that moderate to severe chronic graft-vs-host-disease (cGVHD)–free survival (cGFS) was significantly higher at 1 year with Orca-T plus tacrolimus vs conventional allograft plus tacrolimus and methotrexate (HR, 0.26; 95% CI, 0.14-0.47; log-rank P < .00001), meeting the trial’s primary end point.1 Moreover, at 1 year, treatment with Orca-T plus tacrolimus reduced the incidence of moderate to severe cGVHD (HR, 0.19; 95% CI, 0.08-0.43; Gray’s test P = .00002), increased GVHD-free relapse-free survival (GRFS; HR, 0.37; 95% CI, 0.23-0.60; log-rank P = .00003), and showed a positive trend in overall survival (OS) vs tacrolimus and methotrexate (HR, 0.49; 95% CI, 0.20-1.22; log-rank P = .11823).

“It seems a little early to be deciding what the preferred long-term regimen will be,” Miklos, a professor of medicine and chief of Stanford Medicine’s Blood and Marrow Transplantation and Cell Therapy Program, shared in an interview with OncLive®. “I think that graft engineering, and Orca-T, is going to be the superior long-term regimen [vs PTCy], but we’re all going to have to wait [for the data confirming it].”

In the interview, Miklos discussed efficacy outcomes with Orca-T from the Precision-T trial, the need for further comparative and long-term data to inform the roles of Orca-T vs PTCy in the current treatment paradigm, and the potential of graft engineering as a platform for future advancements in allogeneic transplantation.

OncLive: What did findings from the Precision-T trial indicate about Orca-T’s efficacy in preventing moderate to severe cGVHD and improving OS?

Miklos: [Prior findings from this trial were] presented at [the 51st Annual EBMT Meeting] and we are still waiting for the peer-review publication.2 What we do know is that the moderate to severe cGFS rate was 78% with Orca-T vs 38.4% with conventional tacrolimus-methotrexate prophylaxis. The other number to note is OS, which was 93.9% compared with 83.1%. Obviously, that represents a gold standard: a randomized, controlled trial publication with well-powered patient comparisons conducted at numerous sites. This is clear evidence that graft engineering with a T-regulatory component is superior to what has been done since the 1970s, which involved the use of methotrexate mixed with either tacrolimus or cyclosporine. There’s not much to discuss; it’s superior. Avoiding GVHD provides the quality of life [QOL] every patient hopes for. Avoiding cancer relapse is superior. OS is, obviously, the gold standard.

But the question remains: Is this the alternative treatment for the prevention of cGVHD, or has the world moved forward in the 5 years since the trial was conducted and analyzed? Of course, [using] PTCy instead of the antimetabolite methotrexate used in combination with mycophenolic acid and tacrolimus, is now the new standard. In fact, the National Marrow Donor Program tells us that everyone has a donor, and that mismatched and haploidentical transplants can be performed using this regimen, making allogeneic transplants available to the world.

Given the superiority of Orca-T vs tacrolimus-methotrexate in Precision-T, do these data position Orca-T as a viable alternative to PTCy as the new standard?

Now we are left in this perplexing situation. We know that PTCy comparison will be required in good faith…but what do we do with this information? We can look at retrospective data and perhaps the current publication of the phase 3 ALLG BM12 CAST trial (ACTRN12618000505202) from the Australian group. That study included 130 patients, it was much smaller than Precision-T, and we don’t have the data for a head-to-head propensity comparison. [However], it does provide a very good dataset for comparison. Visually, it looks very similar, with both GRFS and OS appearing similar. That would suggest that PTCy is still a contender, and perhaps it’s more accessible globally. Here’s the thing, though: How do we advance PTCy from here, and how can we begin to understand graft engineering as a platform to improve therapies? This would involve extending it to less intensive conditioning, older patient populations, and reducing relapse by utilizing antitumor benefits, which is another aspect of what Orca-T graft engineering offers.

The jury is [still] out and people have to decide for themselves. We don’t know anything about price, reimbursement, or long-term outcomes beyond 2 years. Similarly, for most PTCy treatments, we don’t know about outcomes beyond 1 year, specifically regarding non–relapse mortality [NRM], complications of infection, long-term effects, and whether there will be late relapses.

Beyond the initial transplant complications, what longer-term complications need to be monitored to assess Orca-T’s and PTCy’s true effect on survival outcomes?

OS is a process influenced by 3 things: toxicity from chemotherapy during the transplant, acute GVHD toxicity, and relapse or late toxicity. We’re past the initial window of concern for transplant GVHD complications, [which is typically] around day 30, day 90, or 1 year. Now we’re focused on immune reconstitution, protection from viruses, and drug protection from viruses. [We don’t know much] about concerns for bronchiolitis obliterans, organizing pneumonias, and other viral transformations not only for treatment with Orca-T graft engineering but also for PTCy. I’m a convert to the CAR [chimeric antigen receptor] T community. We track these patients for 5 and 15 years after these genetic modifications. Longer-term follow-up, as required, has shown us that the NRM in patients receiving these [CD19-directed CAR T-cell] therapies is [approximately] 16% at 5 years due to infectious complications. What will be the infectious complications after PTCy, where we have greatly reduced the numbers of surviving T cells, or in an Orca-T graft, where you’re putting in fewer T cells but providing a better environment with regulatory T cells where you’re not selecting against allogeneic cells to enable long-term antitumor benefit? We don’t know.

Given the need for FDA approval and the agency’s focus on response rates, having set this 1-year GRFS [rate], it seems that the [investigators] met the bar. I have great enthusiasm for the ability to engineer [this therapy]; however, OS [outcomes] will require longer follow-up.

How might Orca-T’s observed reductions in grade 3 or higher acute GVHD, serious infections, and rehospitalizations translate into improved patient QOL and a reduced health burden following transplant?

Readmission to a hospital due to ongoing GVHD, infectious complications, or recurrence of the cancer represents a cost that continually needs to be paid not only by an insurance company but also by the patient and their family, who are living through the burden of requiring additional management and medical care. What is that worth financially? We’re about to find out, because that type of QOL calculation is probably what agencies, insurance companies, and patients themselves will be trying to understand. It is worth a lot. CGVHD is the morbidity of allogeneic transplants. NRM due to recurrent infections is a common problem after these cell therapies. If graft engineering overcomes this, not only is it better today, but it also provides the platform and the path to future improvements.

Given that the Precision-T trial compared Orca-T plus tacrolimus to conventional tacrolimus-methotrexate rather than PTCy, how should these results be contextualized within the evolving GVHD prophylaxis paradigm?

The randomized, controlled Precision-T trial did not include PTCy. In the current environment, we see PTCy being compared with tacrolimus-methotrexate with the exact same intention of randomization. Neither of these [studies is] blinded. The end points of cGVHD are not entirely objective, so there are arguments that there is a subtle interpretation of what is going on with the patients. OS is a hard end point that is beneficial to patients, but OS without any type of moderate or severe cGVHD is also critical for QOL. We are going to have to conduct an analysis of side-by-side comparisons, because no randomized trial that can match PTCy is going to be conducted in the next 2 years. We’re going to have to move forward with the data we have.

[Outcomes with Orca-T vs PTy] are close, but there’s an obvious long-term benefit when you haven’t greatly reduced the repertoire of T cells surviving PTCy. Instead, an enriched immune system can be fostered with a T-regulatory environment. One is a very negative selection, and one is a positive growth going forward.

What insights can be gained from concurrent retrospective data with PTCy and clinical trial data with Orca-T? What do these preliminary comparisons suggest regarding Orca-T’s benefit and readiness for widespread adoption?

[We have] a bit of insight from a concurrent retrospective data collection on PTCy and the treatment arm of the Orca-T trial. There’s only the treatment arm of the Orca-T trial and some in-house Stanford data [available] for comparison due to the limited number of patients treated, whereas PTCy is being used by many centers across the country and can be extensively analyzed through [the Center for International Blood and Marrow Transplant Research] and other registries. The OS [outcomes with PTCy in a historical cohort] were inferior [to that of Orca-T per long-term follow-up data]. This [result] is a major concern for survival, and would indicate that the use of graft engineering is superior. However, there’s going to be a lot of arguing about trials that were never meant to be compared head-to-head: about the quality of a clinical trial vs retrospective studies done in a nontrial situation, and about the selection of patients onto a trial vs those receiving the standard of care at institutions. That probably will just lead to more discussion and no clear solution.

Despite these challenges, what significant advances in allogeneic transplantation have been achieved in the last 5 years and where do you see the field heading?

We are left with advances in allogeneic transplantation from the past 5 years, which we’ve all waited for. We shouldn’t be disappointed by these results. These are 2 fantastic ways to move forward: achieving OS in excess of 80% at 1 year in an acute myeloid leukemia population, and greatly reducing the risk of severe cGVHD or improving the combined GRFS/OS. NRM risk is less than 5% after a couple of years when using Orca-T. Those are end points we only dreamed of. This is not a problem; this is [providing] 2 opportunities to move forward. Science, fortunately, has a way of figuring things out. It may take a couple more trials, but I’m sure that we will make incremental improvements in the field of allogeneic transplantation, so that by the time I turn 80, a therapy will be able to provide me with new, healthy stem cells in a bone marrow failure situation, which will give me higher survival [benefit]. Isn’t that what we’re after?

What strategies are being explored to improve antitumor benefits and avoid relapse with both PTCy and Orca-T?

Instead of adding more intensity to chemotherapy, which [a patient] won’t be able to tolerate at 80 years of age, [we’re asking ourselves]: How about we use targeted therapies against early hematopoietic blasts or leukemic cells themselves? What if we were able to target CD33, CD117, or early tumor antigen surface proteins with either a monoclonal antibody added to a toxin such as gemtuzumab ozogamicin [Mylotarg] or a CAR T-cell product that could identify the target tumor antigens? This would allow for less intensification during treatment and lead to less relapse.

[With] Orca-T, we have a hematopoietic stem cell bag, a conventional T-cell bag, and a T-regulatory cell bag. What about a fourth bag that—in this case, a CD19/CD22 CAR T-cell product—that targets B cells within the host? The loss of CAR, with the recurrence of B-cell disease after autologous CAR T-cell treatment, is associated with disease relapse.

At Stanford, we’ve done this in the field of B-cell acute lymphoblastic leukemia. [Data from a phase 1 study (NCT05507827)] leveraging the Orca-T platform [presented during the 2024 ASH [American Society of Hematology] Annual Meeting and 2025 Transplant and Cellular Therapy Meetings showed] incredible tolerance to the [allogeneic CD19/CD20] CAR itself, [as it] is being inserted at the time of an allogeneic transplant. [Moreover], the persistence of the CAR made from the donor cells allowed for the extension of benefit beyond a year. Although the study is aging, the lead patients are out 3.5 years. In the analysis at ASH, the 10 patients beyond 1 year had B-cell aplasia, measurable CAR T cells, full donor engraftment, no cGVHD, and ongoing disease-free survival. In fact, all 17 patients treated on study are alive and are proceeding without those problems. [These results may show] that the combination of stem cells and nontargeted T cells can be greatly improved by adding a targeting agent, like a CAR T cell, into the graft made from donor cells. This is something we call an "allo-CAR transplant." This is a concept that you can build as a platform, not only off Orca-T but potentially off PTCy.

What are the logistical complexities involved in collecting donor cells for the Orca-T strategy?

Logistically, collecting donor T cells that are nonmobilized or non-GCSF mobilized, and then having that donor undergo GCSF and plerixafor mobilization to collect the stem cell product, is more complicated. Both products were necessary for this study. We’re still trying to understand if a separate collection for the cells used to make the CAR T cell was necessary; additional studies will be needed.

That trial stands on its own, especially when we compare the same CARs against CD19-targeted or CD19/CD22-targeted [CAR T-cell therapies] with the autologous studies that have been well done in this space and have shown an overall recurrence of [approximately] 50% by 6 months. These patients are out beyond a year and proceeding well. Long-term follow-up is always beneficial, but incremental studies are needed to see whether we do this after PTCy, if we need to use G-mobilization, or if we could have made the CAR from T cells that went through G-mobilization.

There are a lot of [unanswered] questions. One of the questions answered, though, was whether tacrolimus was necessary for the graft. Tacrolimus administration did not impede the expansion or benefits of the CAR T cell. Early concerns that tacrolimus or other immunosuppressive medicines would impede the benefit of a CAR T cell have been removed through this trial, as well as through studies where patients who have had prior CAR T cells are undergoing treatments.

Reference

1. Faramand R, Salhotra A, Gandhi A, et al. A randomized phase 3 trial in patients with hematologic malignancies demonstrates improved survival free of chronic GVHD with Orca-T compared to conventional allogeneic hematopoietic stem cell transplant. Clin Lymphoma Myeloma Leuk. 2025;25(suppl 1):S1008-S1009. doi:10.1016/S2152-2650(25)02766-1
2. Meyer EH, Salhotra A, Gandhi AP, et al. Orca-T demonstrates improved survival free of chronic GvHD compared to conventional allogeneic hematopoietic stem cell transplant: a randomized phase 3 trial in advanced hematologic malignancies. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract OS15-01.