With data from the phase 3 Precision-T trial (NCT04013685) displaying a chronic graft-vs-host-disease (GVHD)–free survival benefit with Orca-T and myeloablative conditioning compared with conventional allogeneic hematopoietic stem cell transplant (allo-HSCT) and myeloablative conditioning, other ongoing research using reduced-intensity conditioning approaches could help better characterize the potential for Orca-T in patients with advanced hematologic malignancies, according to Everett Meyer, MD.
“I see a large role for approaches like Orca-T, Orca-Q, or others out there outside of Orca, which are promising to change our field or even push us into the non-malignant space, for example, in the management of autoimmunity or neurodegenerative disorders,” Meyer said in an interview with OncLive®. “There is huge potential there.”
The FDA is currently reviewing data from Precision-T that supported priority review of a biologics license application seeking the approval of Orca-T for the treatment of select patients with hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia, and myelodysplastic syndromes (MDS).1 Following an extension of the review period from the regulatory agency, the current target action date under the Prescription Drug User Fee Act is July 6, 2026.2
Meanwhile, ongoing studies are looking at other approaches with Orca-T, such as the phase 2 SERENE-T trial (NCT07216443) evaluating the allogeneic T-cell immunotherapy following reduced-intensity or nonmyeloablative conditioning in patients with AML or MDS.3
In the interview, Meyer outlined how Orca-T’s design could help improve GVHD outcomes compared with conventional allo-HSCT, along with the ongoing investigation of reduced-intensity approaches incorporating Orca-T.
Meyer is an associate professor of medicine (blood & marrow transplantation), an associate professor of pediatrics (stem cell transplantation), and an associate professor of surgery (abdominal transplantation) at Stanford Medicine in California.
Key Things to Know About Orca-T in Hematologic Malignancies
- A biologics license application received FDA priority review, with the application seeking approval of Orca-T for the treatment of select patients with hematologic malignancies, including AML, acute lymphoblastic leukemia, and MDS.
- Following an extension of the review period by the FDA, the Prescription Drug User Fee Act target action date is July 6, 2026.
- Orca-T is also being evaluated in other trials and setting, including following reduced-intensity or nonmyeloablative conditioning for patients with AML or MDS in the phase 2 SERENE-T trial.
OncLive: What are some of the challenges with using conventional allo-HSCT approaches for patients with hematologic malignancies?
Meyer: Since its inception, conventional allo-HSCT has relied on taking a full apheresis product from the donor. [The] granulocyte colony-stimulating factor is mobilized, we collect all the blood cells, and then we give it to the recipient. The way we’ve controlled that immune reconstitution is to try to knock down all those cells. That originally was with tacrolimus/methotrexate, and more recently, post-transplant cyclophosphamide, abatacept [Orencia], and other approaches have been tested, but with the same concept. You take a large number of cells, shrink them down, and hopefully they expand well and [the patient does not develop] acute GVHD.
These newer approaches—post-transplant cyclophosphamide, abatacept, and others—are promising because they’re [associated with] a much lower incidence of acute GVHD, but a number of different complications [remain], including endothelial inflammation that drives, for example, cardiac toxicity and damage to the kidneys, and also problems with fighting infections. The big gorilla in the corner is relapse, because that is still a major problem. All these efforts are designed to try to facilitate graft-vs-leukemia effects.
In what ways could Orca-T help address some of these complications associated with allo-HSCT approaches?
Orca-T is an approach that takes the donor material and asks: What in the immune system reconstitutes itself in a more controlled fashion to try to prevent GVHD? We know a lot more about immunology than we did in the past, so with that immunology [knowledge], we know that regulatory T cells [Tregs] can control the immune system. When [a patient gets] an infection, [the Tregs] activate and bring down the infection, but they also participate in routine immune functions, including wound repair and other important factors. The rationale for Orca-T is to take those Tregs and relatively enrich them compared with the conventional T cells. [Then], when the precise donor graft goes into the recipient, there’s a lot less variability, and the patients can reconstitute more smoothly with less GVHD. That’s been proven now in clinical trials.
Across different clinical trials, we’ve seen Orca-T evaluated in different settings and with different conditioning approaches. What has been the rationale for exploring its potential role using these different approaches?
Orca-T has done phenomenally from phase 1 to phase 3 in showing [improvements] compared with the conventional tacrolimus/methotrexate, which is still the only proven way to prevent GVHD in the human leukocyte antigen–matched setting, because post-transplant cyclophosphamide has not shown superiority in that setting. Compared with [tacrolimus/methotrexate], Orca-T reduces GVHD enormously, and more importantly, reduces non-relapse mortality 3- or 4-fold. Therefore, it’s an incredible platform to build on.
The SERENE-T trial is evaluating the use of Orca-T following reduced-intensity or nonmyeloablative conditioning. What do you hope to learn from this study?
Most patients with severe hematological malignancies are older. For example, the peak of AML [cases] tends to be in older ages, where most patients could benefit from reduced-intensity chemotherapy conditioning. That’s always been a goal of the field, to use the immune system—not the chemotherapy necessarily. The question was: Does Orca-T work when you reduce the conditioning intensity? Because that opens the bone marrow niche, and there were questions about if a precise cell therapy from the donor graft could induce engraftment, because we didn’t know whether that was strong enough.
It turns out that in a phase 1 trial [NCT05088356] that we led at Stanford and that has [informed] a national phase 2 trial called SERENE-T, Orca-T was effective in the reduced-intensity conditioning setting in terms of myeloid engraftment, overall survival, and a low instance of GVHD. We’re very excited about that, because it could open the treatment to many more patients.
We’ve seen exceptional responses in MDS, for example. That’s where we still are under-treating some patients, because the larger hematology field has a dated view of how transplant is and how patients go through it. Therefore, we’re excited that there might be new methods that could be used for patients who are older and sicker.
References
- Orca Bio announces FDA acceptance and priority review of the biologics license application (BLA) for Orca-T to treat hematological malignancies. News release. Orca Bio. October 6, 2025. Accessed June 16, 2026. https://orcabio.com/orca-bio-announces-fda-acceptance-and-priority-review-of-the-biologics-license-application-bla-for-orca-t-to-treat-hematological-malignancies/
- Orca Bio announces FDA review extension of BLA for Orca-T for the treatment of hematologic malignancies. News release. Orca Bio. April 1, 2026. Accessed June 16, 2026. https://orcabio.com/orca-bio-announces-fda-review-extension-of-bla-for-orca-t-for-the-treatment-of-hematologic-malignancies/
- Trial of Orca-T following reduced intensity or nonmyeloablative conditioning in patients with acute myeloid leukemia or myelodysplastic syndrome. ClinicalTrials.gov. Updated April 15, 2026. Accessed June 16, 2026. https://clinicaltrials.gov/study/NCT07216443
