Orca-T With Reduced Intensity Conditioning Is Safe and Feasible in Hematologic Malignancies

The use of the allogeneic immunotherapy Orca-T following reduced intensity conditioning (RIC) led to robust myeloid and T-cell engraftment, along with low rates of acute graft-vs-host disease (GVHD) and moderate-to-severe chronic GVHD, in patients with hematologic malignancies, according to data from a phase 1 trial (NCT05088356).¹

Findings presented at the 2025 ASH Annual Meeting and Exposition showed that no patients (n = 53) experienced primary graft failure or loss. Grade 2 to 4 acute and late-onset GVHD occurred at a rate of 12.3% (95% CI, 5%-23%). Notably, no grade 3 or 4 acute GVHD events were reported, and all patients with acute GVHD responded to systemic steroids. Any-grade chronic GVHD occurred in 27% (95% CI, 14%-42%) of patients; however, moderate-to-severe GVHD was reported in 9.6% (95% CI, 3%-21%).

“Orca-T is safe and feasible to be used in the RIC allogeneic hematopoietic stem cell transplant [allo-HCT] setting, where we observed robust myeloid and T-cell engraftment despite early T-cell mixed chimerism,” lead study author Alejandro Villar-Prados, MD, PhD, said in a presentation of the data.

Villar-Prados is a resident in the Translational Investigator Program at Stanford Medicine in California.

What was the rationale of the phase 1 trial evaluating Orca-T with RIC?

The FDA is currently reviewing a biologics license application (BLA) seeking the approval of Orca-T for the treatment of select patients with hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndromes (MDS).² The BLA, which received priority review, was based on data from the phase 3 Precision-T trial (NCT04013685), which showed that Orca-T generated a statistically significant improvement in moderate-to-severe chronic GVHD–free survival compared with conventional allo-HCT.

The phase 1 trial sought to evaluate the use of Orca-T in the context of RIC.¹ The study included patients 18 to 75 years of age with high-risk acute leukemia who were in first complete remission (CR1), were beyond CR1, or had minimal residual disease (MRD) positivity; those with chronic myelogenous leukemia in accelerated, blast, or second chronic phase; and those with MDS or myeloproliferative neoplasms (MPNs).

Enrolled patients underwent RIC from days –7 to –2. They then received infusion of hematopoietic stem and progenitor cells, plus regulatory T cells (Tregs), at 3 x 10⁶ Tregs/kg on day 0; conventional T cells at 3 x 10⁶ on day 2; and tacrolimus at 5 to 10 ng/mL on day 3. Patients with mismatched donors were also given ruxolitinib (Jakafi) at 5 mg twice per day or mycophenolate mofetil at 1000 mg twice per day on day 4.

For patients with 8/8 HLA matched donors, conditioning regimens comprised fludarabine at 160 mg/m², melphalan at 50 mg/m², and total body irradiation (TBI) at 4 Gy, plus tacrolimus as GVHD prophylaxis (n = 11); fludarabine at 160 mg/m², thiotepa at 10 mg/kg, and TBI at 4 Gy, plus tacrolimus as GVHD prophylaxis (n = 12); and fludarabine at 160 mg/m², thiotepa at 5 mg/kg, and TBI at 3 Gy, plus tacrolimus as GVHD prophylaxis (n = 23). In the final group, outpatient administration per physician discretion was given to 6 patients.

For patients with 7/8 HLA matched donors, conditioning regimens were fludarabine at 160 mg/m², thiotepa at 10 mg/kg, and TBI at 4 Gy, plus tacrolimus and mycophenolate mofetil as GVHD prophylaxis (n = 2); or fludarabine at 160 mg/m², thiotepa at 5 mg/kg, and TBI at 3 Gy, plus tacrolimus in combination with mycophenolate mofetil or ruxolitinib as GVHD prophylaxis (n = 5).

The study’s primary end points were engraftment time and donor chimerism by day 60; and the incidence of grade 3/4 acute GVHD. Secondary end points comprised GVHD- and relapse-free survival (GRFS) after allo-HCT, overall survival (OS) after allo-HCT, and the incidence and severity of acute/chronic GVHD.

The median follow-up time for the overall population was 16.7 months. Patients had a median age of 68 years (range, 60-75), and most patients were male (62%) and While (79%). The median Karnofsky performance status was 80 (range, 70-100), and the median HCT comorbidity index was 1 (range, 0-6). Malignancy subtypes included AML (58%), MDS (30%), ALL (4%), mixed phenotype leukemia (2%), and MPNs (6%). Notably, 75% of patients were in CR prior to transplant.

For patients with AML, 2022 European Leukemia Network risk stratifications included favorable risk (19%), intermediate risk (39%), and adverse risk (42%). Sixty-five percent of patients with AML had MRD-positive disease. For those with MDS, risk stratification per Revised International Prognostic Staging System criteria included very high risk (13%), high risk (31%), and intermediate risk (56%).

Thirty-one percent of patients had matched related donors, 62% had matched unrelated donors, and 13% had mismatched donors.

What other data were reported at ASH 2025?

Findings also showed that the cumulative incidence of grade 2 to 3 infections was 32% (95% CI, 20%-44%); however, the rate of grade 3 infections was 6% (95% CI, 1.5%-14%).

Relapses occurred in 8.1% (95% CI, 3%-18%) of patients, including 3 patients with AML and 2 patients with MDS. The non-relapse mortality rate was 10% (95% CI, 4%-20%).

The OS and GRFS rates at 1 years following transplant were 88% (95% CI, 79%-98%) and 72% (95% CI, 60%-87%), respectively. In patients who were eligible to receive the outpatient RIC regimen, the 1-year OS and GRFS rates were 95% (95% CI, 87%-100%) and 80% (95% CI, 65%-100%), respectively.

An ongoing phase 2 trial (NCT07216443) is further investigating the use of Orca-T with RIC or nonmyeloablative conditioning in patients with AML or MDS.3

Disclosures: Villar-Prados did not report any financial conflicts of interest.

References

1. Villar-Prados A, Kim P, Sutherland K, et al. Allogeneic HSC and regulatory T cell (Orca-T) engineered cell therapy following reduced intensity conditioning: Results of a single center Phase 1 study. Blood. 2025;146(suppl 1):111. doi:10.1182/blood-2025-111
2. 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 December 22, 2025. https://orcabio.com/orca-bio-announces-fda-acceptance-and-priority-review-of-the-biologics-license-application-bla-for-orca-t-to-treat-hematological-malignancies/
3. Trial of Orca-T following reduced intensity or nonmyeloablative conditioning in patients with acute myeloid leukemia or myelodysplastic syndrome. ClinicalTrials.gov. Updated December 18, 2025. Accessed December 22, 2025. https://clinicaltrials.gov/study/NCT07216443