CT-524 Orca-T, A Precision Engineered Allograft, Results in High GVHD-Free and Relapse-Free Survival Following Myeloablative Conditioning for Hematological Malignancies

Background: Rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) following myeloablative allogeneic hematopoietic stem cell transplant (MA-alloHSCT) remain unacceptably high. Orca-T is a high-precision, allogeneic investigational cell therapy product comprised of stem and immune cells that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses, reducing the need for pharmacologic GVHD prophylaxis. Orca-T is produced in a central GMP facility and has been successfully scaled to clinical centers throughout the U.S. Aims: The aim of these studies was to evaluate the safety and efficacy of Orca-T in patients with hematologic malignancies. Methods: Data are reported for 138 patients with high-risk hematologic malignancies who received Orca-T in a single-center Phase 1/2 study (n=41) and a multicenter Phase 1b study (n=97) and had ≥ 100 days of follow-up as of 2/28/22. Orca-T was produced from G-CSF-mobilized peripheral blood (PB) from MRD (n=72), MUD (n=62), or MMUD (n=4). Median follow-up for recipients was 300 days (range: 27-1941). Median age was 49 years, and diagnoses included AML (43%), ALL (27%), MDS (10%), myelofibrosis (7%), and CML (6%). Patients received MAC (busulfan-based, n=109; TBI-based, n=27; BCNU, n=2) followed by GVHD prophylaxis with either single-agent tacrolimus (n=127), sirolimus (n=7), or tacrolimus plus mycophenolate (n=4, MMUD). A contemporaneous CIBMTR-based control arm was obtained that consisted of patients with similar diagnoses who received MA-alloHSCT from a PB source followed by tacrolimus/methotrexate prophylaxis. Results: Orca-T was successfully manufactured, distributed, and infused for all patients. Overall time from donor centers to recipient centers was under 60 hours in all cases. Median time to neutrophil engraftment was 13 days. Rates of grade ≥ 3 acute GVHD in the first 180 days and moderate to severe chronic GVHD through 1 year were low at 4% and 5%, respectively. NRM was infrequent at 4% through 1 year. Orca-T exhibited GVHD-free relapse-free survival (GRFS) of 71% & OS of 90% at 1 year. No formal comparison to CIBMTR cohort was performed. Conclusions: Results from patients treated with Orca-T, a high-precision Treg-engineered donor product, suggest a reduction in cGVHD, improved GRFS, and low toxicity relative to historic data. A multicenter randomized-control phase 3 trial comparing Orca-T to SOC is enrolling.