Dr Salhotra Details Orca-T’s Performance in Phase 3 Precision-T Trial
Orca-T shows significant promise in reducing chronic graft-vs-host disease and improving survival rates in allogeneic transplant patients with hematologic malignancies.
Microscopic image of bone marrow cells - Generated with Google Gemini AI
In a promising development for allogeneic transplant recipients with advanced hematologic malignancies, Orca-T, a precision-engineered allogeneic graft, has shown substantial improvements in graft-vs-host disease (GVHD) outcomes, according to Amandeep Salhotra, MD.
The phase 3 Precision-T trial (NCT05316701) and data presented at the 51st Annual EBMT Meeting demonstrated that patients treated with Orca-T (n = 93) experienced a 1-year chronic graft-vs-host disease (cGVHD)-free survival (cGFS) rate of 78.0% (95% CI, 65.0%-86.6%) vs 38.4% (95% CI, 26.2%-50.5%) in patients who underwent allogeneic hematopoietic stem cell transplant (allo-HSCT; n = 94; HR, 0.26; 95% CI, 0.14-0.47; log-rank P <.00001). In the Orca-T arm, the incidence of moderate-to-severe cGVHD was 12.6% (95% CI, 5.3%-23.1%) compared with 44.0% (95% CI, 31.3%-56.1%) in the allo-HSCT arm (HR, 0.19; 95% CI, 0.08-0.43; Gray’s test P =.00002).
“[Overall], the study met its primary end point of chronic GVHD-free survival at 1 year. While overall survival was not significantly different yet, 94% of patients on the Orca-T arm were alive at 1 year, and there was a trend toward improved survival,” added Salhotra, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, in a press release.
In an interview with Targeted OncologyTM, Salhotra further discussed Orca-T and data from the phase 3 Precision-T trial (NCT05316701) in patients with advanced hematologic malignancies.
Targeted OncologyTM: Can you provide a brief overview of Orca-T, including its mechanism of action and how it's been studied?
Salhotra: Orca-T is a precision-engineered graft. It involves infusion of hematopoietic stem cells and regulatory T cells on day 0, followed by infusion of conventional T cells 48 hours after the hematopoietic stem cells are given. The idea is to administer precisely controlled doses of both stem cells and conventional T cells in order to create an immune barrier—unlike the standard stem cell transplant, where the apheresis product contains a mix of more than 50 different cell types. Some of these are helpful—such as memory T cells and [natural killer] cells, which help prevent relapse—but many naive T cells can cause graft-vs-host disease. So, it's a mixed bag. By giving cells as part of an engineered graft, we can precisely dose these subsets to enhance graft-vs-leukemia activity while minimizing GVHD.
What patient subgroups benefited most from the GRFS improvement?
GRFS—graft-vs-host disease-free, relapse-free survival—is a composite end point in transplant patients that captures those who remain free from both acute or chronic GVHD and relapse at the 1-year mark. In the Precision-T trial, patients receiving the Orca-T graft had significantly improved outcomes compared with those who received the standard [tacrolimus]/methotrexate regimen. GRFS at 1 year was 63% in the Orca-T arm vs 31% in the standard-of-care group, a statistically significant difference.
Most patients enrolled had myeloid malignancies—about 65% had [acute myeloid leukemia (AML)] or [myelodysplastic syndromes (MDS)]. Around 10% had acute lymphoblastic leukemia [ALL]. We do not yet have detailed subgroup analyses, but given the makeup of the cohort, it’s reasonable to conclude that patients with high-risk AML and MDS likely benefited most.
Looking at this agent, how does reduced rehospitalization impact patient quality of life?
There was a significant reduction in rehospitalization among patients randomized to the Orca-T arm at around 40% compared with about 55% in the standard-of-care group. This decrease impacts quality of life by reducing the burden of hospital stays, whether due to infections or GVHD—both more common in the standard-of-care arm. It also reduces economic costs. Ultimately, fewer rehospitalizations may contribute to the trend toward improved overall survival.
What are the key mechanistic differences between Orca-T and standard allogeneic HSCT?
In traditional allogeneic hematopoietic stem cell transplantation, we collect an unmanipulated apheresis graft from the donor and infuse it into the recipient postconditioning. With the standard approach, we typically see acute GVHD rates of 40% to 45% and substantial chronic GVHD. The engineered Orca-T graft differs significantly. On day 0, we infuse hematopoietic stem cells along with regulatory T cells. These regulatory T cells expand in vivo and migrate to GVHD target organs—the [gastrointestinal (GI)] tract, skin, and liver—forming an “immune barrier.”
Conventional T cells are then infused at a lower dose than in standard grafts. This delayed and controlled dosing prevents the inflammatory cascade that leads to GVHD while preserving [graft-vs-leukemia] activity. In the trial, relapse-free survival was comparable between arms, suggesting that splitting the cell doses maintains antileukemic activity while reducing GVHD.
What significant adverse events were avoided with Orca-T?
The main [adverse events] we worry about posttransplant are grade ≥3 infections. These were reduced to 8.6% in the Orca-T arm, compared with 16% in the standard-of-care arm. Rates of grade ≥2 acute GVHD were also significantly lower. The primary end point—moderate to severe chronic GVHD-free survival at 1 year—was met, with 78% in the Orca-T group vs 38% in the control group. So across common transplant outcomes, [including] rates of infection, acute GVHD, and chronic GVHD, patients receiving Orca-T consistently did better.
How does Orca-T impact minimal residual disease (MRD) management?
We need more data. The study enrolled approximately 190 patients—about 94 to 95 in each arm—but we do not yet have detailed MRD subgroup analysis. The trial stratified patients using disease risk index, and most had intermediate-risk disease.
In the future, I would be interested in how higher-risk groups—like ELN-adverse risk or MRD-positive patients, including those with TP53 mutations—respond to Orca-T vs standard grafts. That is something the transplant community is keen to understand.
What are the practical considerations for transplant centers looking to adopt Orca-T?
The practical considerations would be regarding collection of the stem cells. Currently, the graft has to be manufactured at a specialized facility, so the donors need to be either match-related donors, or if it is an unrelated donor, they have to be domestic. International donors are currently excluded due to logistics of collection and delivery.
The other practical consideration is that the patients need to be eligible for a myeloablative conditioning regimen. It has been tested in patients who are eligible for either busulfan-based or [total body irradiation]-based conditioning regimens. Trials in reduced-intensity settings are underway—we’re looking forward to those results.
At our center, we enrolled several patients. Apheresis was done in a single day, targeting 5 to 8 million CD34-positive cells/kg. We consistently received the grafts on time. Notably, there were no cases of graft failure, and all patients engrafted as expected. So, while there are logistical and manufacturing considerations, the safety and feasibility are promising.
Are there any long-term follow-up data available yet?
The current data are mature up to the 1-year mark. We're waiting to see if the relapse rate remains stable into year 2 and whether immune reconstitution continues to improve. We also want to see if there are any late-onset chronic GVHD or unexpected complications. Patients are being closely monitored for immune reconstitution and late effects, and we look forward to those data as they emerge.
In your opinion, how will Orca-T fit into the future of allogeneic transplantation?
Having [treated patients in the study], I can say the transplant course has [been safer]—less acute and chronic GVHD. If Orca-T receives approval, I envision it being used for patients eligible for myeloablative conditioning with high-risk AML, ALL, or MDS.
The transplant workflow would be the next challenge and reimbursements and those kinds of things are also going to come into place. That is certainly something that transplant centers would have to take into consideration, looking at the upfront costs of the cellular therapy and balancing it against the late costs that are associated with development of chronic graft-vs-host disease so at least there's an investment made in patients’ well-being upfront, so that the incidence of chronic GVHD and the late effects and the financial toxicity of that can be covered by this immunotherapy.
[Overall], the study met its primary end point of chronic GVHD-free survival at 1 year. While overall survival was not significantly different yet, 94% of patients on the Orca-T arm were alive at 1 year, and there was a trend toward improved survival. It will be important to see if those curves separate at the 2- or 3-year mark. Future studies using the Orca-T product in the reduced intensity setting would be of interest to transplant physicians like [me].
