Preliminary safety and efficacy of myeloablative orca-q with tacrolimus or without graft-versus-host disease prophylaxis for treatment of advanced hematologic malignancies

Abstract

Abstract BACKGROUND Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only potentially curative option for several high-risk blood cancers and benign blood disorders. Conventional stem cell sources include high doses of T cells that contribute to graft-versus-leukemia (GVL) and graft-versus-infection (GVI) effects, but they also mediate graft-versus-host disease (GVHD). Preventing GVHD following alloHSCT typically requires multi-agent immunosuppression, commonly involving methotrexate or post-transplant cyclophosphamide (PTCy) in combination with a calcineurin inhibitor and other agents. However, pharmacologic immunosuppression impairs immune reconstitution and heightens the risk of organ toxicity, infection, and disease relapse. Orca-Q is a proprietary, investigational precision engineered allogeneic T-cell immunotherapy designed to promote GVL and GVI and minimize GVHD. Here, we report data from Orca-Q patients with 8/8 HLA matched related donors. Patients recieved either single agent tacrolimus (Arm A) or no immune suppression (Arm C) in a multicenter Phase 1 clinical study (NCT03802695). METHODS Adult patients with high-risk hematologic malignancies eligible for myeloablative conditioning alloHSCT with 8/8 HLA-matched donor were first enrolled on the dose expansion Arm A (with single agent tacrolimus for GVHD prevention; n=18). Due to a low incidence of GVHD, Arm C (with no immunosuppression; n=26) was opened and Arm A closed to enrollment of patients with 8/8 HLA matched donors. Orca-Q was centrally manufactured at an Orca Bio GMP facility (Sacramento, CA) from G-CSF mobilized peripheral blood apheresis. Patients were followed for adverse events for one year post-transplant and for survival thereafter. GVHD-free, relapse-free survival (GRFS) was defined as the time from transplant to the first occurrence of any of these events: grade 3-4 acute GVHD (aGVHD), moderate to severe chronic GVHD (cGVHD), disease relapse, or death from any cause. RESULTS Orca-Q was successfully manufactured and administered to all recipients with a vein-to-vein time of less than 72 hours. As of July 14, 2025, a total of 44 patients with hematological malignancies had been treated, including acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, myelofibrosis, myelodysplastic syndrome, and mixed phenotype leukemia. On Arm A, 14 donors were related and 4 unrelated, compared to Arm B where 12 were related and 14 unrelated. Other patient baseline characteristics were as follows: Arm A: Median age 41 years (range 27-55), 56% male and median follow-up 1531 days (range 66-1825), and Arm C: Median age 60 years (range 20-70), 50% male and median follow-up 234 days (range 5-1418). All patients received myeloablative conditioning. Orca-Q was well tolerated. Overall clinical outcomes were:All patients engrafted neutrophils by day +20 (median 12 days)Overall survival and 1 and 2 years: 90% at 1 year and 86% at 2 yearsRelapse-free survival at 1-year: 87%Moderate-to-severe cGVHD-free survival at 1-year: 85%GRFS at 1-year: 78%Non-relapse mortality at 1-year: 3.4%Relapse incidence at 1-year: 12.7%Grade 3-4 aGVHD at Day +180: 7.1% (6% for Arm A and 8% for Arm C)Moderate-to-severe chronic GVHD at 1 year: 5.9% (12% for Arm A and 0% for Arm C) Orca-Q patients treated without pharmacological prophylaxis (Arm C) demonstrated more rapid immune reconstitution and improved control of infections. Specifically, BMT CTN Grade 2+ infections at 1-year: 33% for Arm A and 17% for Arm C;BMT CTN Grade 3 infection at 1-year: 6% for Arm A and 0% for Arm CMedian absolute CD4 / CD8 cell counts per µL at Day +28: 97 / 94 for Arm A and 102 / 245 for Arm C CONCLUSIONS Orca-Q demonstrates promising efficacy and safety as a precision-engineered T-cell immunotherapy for alloHSCT in patients with high-risk hematologic malignancies. The therapy achieved rapid neutrophil recovery, while maintaining low rates of severe acute GVHD, relapse, and non-relapse mortality across both treatment arms. The low infection rates observed suggest that the cellular composition of Orca-Q can control GVHD and accelerate immune reconstitution even without pharmacological immunosuppression. The Phase 1 study continues to enroll patients to further confirm these results.