Introduction: The combination of Orca-T, an investigational allogeneic T-cell immunotherapy, with myeloablative conditioning (MAC) has demonstrated a significant reduction of graft versus host disease (GvHD) in a randomized Phase 3 trial (NCT05316701). The impact of combining Orca-T with reduced intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HSCT) for the treatment of hematological malignancies remains an open question.

Methods: This trial is a single-center, open-label, phase 1 feasibility and safety study with primary endpoints of incidence of grade III-IV GVHD, incidence of primary graft failure and donor T cell chimerism at day +60 and engraftment. Secondary endpoints include all grade acute GvHD, moderate to severe chronic GvHD, relapse free survival (RFS), non-relapse mortality (NRM), GvHD relapse free survival (GRFS) and overall survival (OS). The study has two independent trial arms depending on donor type [HLA matched related and unrelated, 8/8 HLA matched (n = 42) and 7/8 HLA mismatched (n = 7)]. The first eleven patients were conditioned with fludarabine 160 mg/m2, melphalan 50 mg/m2 and 4 Gy of total body irradiation (TBI). Fourteen subsequent patients received 10mg/kg of thiotepa instead of melphalan, with the same dosing of fludarabine and 4 Gy TBI. Conditioning was further reduced to thiotepa 5mg/kg, 3 Gy TBI with fludarabine kept at 160mg/m2where 24 patients were enrolled in this cohort. From this cohort patients, 8/8 HLA matched patients became eligible for outpatient treatment (n = 21). All patients received single agent tacrolimus with a target goal of 6-8 ng/ml.

Results: A total of 49 patients have been treated thus far with the final 58th patient scheduled to be treated within 45 days. The trial is now closed to additional accrual with primary endpoint to be completed by 10/31/2025. The median patient age was 68 years (range 60-75), with 63% males (n = 31) and 37% females (n = 18). Most patients were white, 80% (n = 39), with 20% (n = 10) other races. By disease, 59% had acute myeloid leukemia (n = 29), 29% had myelodysplastic syndrome (n = 14), 4% had acute lymphoblastic leukemia (n = 2), 6% had a myeloproliferative neoplasm (n = 3), and 2% had mixed phenotype leukemia (n = 1). Median Karnofsky performance status was 80% (range 70-100) and median HCT-CI of 1 (range 0-6). Median follow up thus far is 13.2 months (range 0.4–39), with no manufacturing failures.

All patients had successful neutrophil engraftment at a median of 15 days (range 9-39) and median CD3 donor chimerism at day+60 of 97% (range 43-100%). No patients experience primary or secondary graft failure. The 1-year estimated cumulative incidence (CI) of aGvHD is 14% (95% CI 6-27%), which was all grade II without any grade III-IV. The 1-year CI for moderate to severe cGvHD is 9% (95% CI 2-22%). The 1-year RFS and GRFS estimates are 81% (CI 95% 69-94%) and 72% (95% CI 59-88%) respectively. The 1-year OS is 85% (95% CI 75-97%). The CI estimate for 1-year NRM is 10% (95% CI 3-21%), with NRM attributed to infection (2/49) and sinusoidal obstruction syndrome (2/49). The CI for grade 3 infections is 6% by day+100 (95% CI 2-16%). The outpatient eligible RIC-HSCT conditioning cohort (n=21) had a CI NRM of 0%, CI grade 3 infection 0%, RFS 77% (95% CI 58-100%) and OS 93% (95% CI 82-100%) .

Conclusions: These early results demonstrate that Orca-T is a safe and feasible transplant strategy for RIC conditioning. The trial achieved the goal of identifying a lympho-depletive RIC conditioning regimen tolerated in the outpatient setting. Patients showed robust engraftment and donor T cell chimerism. The low incidence of acute and chronic GvHD with low rates of disease relapse suggest retention of graft versus leukemia effect. The results of this phase 1 study support a planned multicenter studies evaluatingGvHD-free and RFS post-transplant in the upcoming months.

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2025
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