Orca-T

Myeloablative conditioning with cyclophosphamide and total body irradiation precede infusion of investigational Orca-T, which consists of infusions of HSPCs and Tregs on Day 0 and an infusion of T conventional (Tcon) cells on Day 2. Here, we report very promising initial feasibility, safety and efficacy of the combination of allogeneic CD19/CD22-CAR T cells with Orca-T in patients with high-risk B-ALL. This paradigm shifting combination of allogeneic CAR T and allo-HCT resulted in 100% MRD- CR with full donor chimerism but without GVHD or severe CAR-mediated toxicity. These data, which demonstrate antigen-specific anti-tumor benefit of allogeneic CAR T cells in combination with GVHD prophylaxis mediated by Tregs and tacrolimus, have potential implications that could benefit patients with other hematologic diseases.

P1, N=33, Recruiting, City of Hope Medical Center | Initiation date: Sep 2024 --> May 2024

P1, N=255, Active, not recruiting, Orca Biosystems, Inc. | Recruiting --> Active, not recruiting

P3, N=174, Active, not recruiting, Orca Biosystems, Inc. | Recruiting --> Active, not recruiting

P1, N=33, Recruiting, City of Hope Medical Center | Initiation date: Mar 2024 --> Sep 2024

P1, N=255, Recruiting, Orca Biosystems, Inc. | Trial completion date: Apr 2028 --> Jul 2026

P3, N=174, Recruiting, Orca Biosystems, Inc. | Trial completion date: Apr 2028 --> Apr 2027 | Trial primary completion date: Apr 2024 --> Apr 2025

P1/2, N=68, Completed, Everett Meyer | Active, not recruiting --> Completed

P1, N=33, Recruiting, City of Hope Medical Center

P1/2, N=68, Active, not recruiting, Everett Meyer | Trial primary completion date: Dec 2022 --> Dec 2023

RESULTS Orca-Q was successfully manufactured and delivered to all subjects with a vein-to-vein time (time between end of donor apheresis to start of recipient's Orca-T infusion) of < 72 hours...Sixteen patients received TBI-based MAC; 17 received busulfan-based MAC (Table)...With median follow-up of approximately 1 year, no patients experienced moderate or severe cGvHD, the low AE profile in the haplo setting remains favorable, and 1 year GvHD-free, relapse-free survival of 83% is very encouraging. This phase 1 study continues to enroll patients across the US.

Patients received a busulfan-based myeloablative chemotherapy regimen prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus. CONCLUSIONS Orca-T demonstrated promising results in this HR-MDS patient population, including high RFS, low incidence of GvHD, and very high OS at 1 year. A randomized controlled phase 3 multi-center trial comparing Orca-T to SOC in patients with MDS, AML, and ALL is currently enrolling across the US (NCT05316701).

Patients received a myeloablative regimen consisting of intravenous busulfan, fludarabine, and thiotepa (BFT) prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus, and had an 8/8 related or unrelated matched donor. Remarkably, non-relapse mortality was zero at 1 year with excellent overall survival , suggesting that this regimen could potentially improve outcomes for older patients. An ongoing Phase 3 trial evaluating Orca-T vs. standard of care is currently enrolling throughout the United States.

Orca-T patients exhibit early immune reconstitution of each of the major leukocyte and lymphocyte subsets hypothesized to control relapse and infection. Concomitantly, elevated Treg frequencies were also observed. This feature of immune reconstitution profiles of Orca-T recipients may be correlated to the reduced occurrence and severity of acute and chronic GVHD in these patients (Oliai et al., ASH 2022).

P1, N=18, Recruiting, Crystal Mackall, MD | Not yet recruiting --> Recruiting

P1, N=18, Not yet recruiting, Stanford University

P1/2, N=68, Active, not recruiting, Everett Meyer | Recruiting --> Active, not recruiting | N=24 --> 68

P3, N=174, Recruiting, Orca Biosystems, Inc. | Not yet recruiting --> Recruiting

P3, N=174, Not yet recruiting, Orca Biosystems, Inc.

Background GVHD and non-relapse mortality (NRM) remain frequent complications of HLA-matched HSCT despite the use of standard immunosuppression like tacrolimus and methotrexate. Alternative GVHD prophylaxis (PPX) strategies like T-cell depletion and post-transplant cyclophosphamide negatively impact relapse, infection, and organ toxicity, and no strategy has yet demonstrated a clear benefit for GVHD-free survival...Patients received a variety of myeloablative conditioning regimens (e.g., non-TBI, n=66; TBI-based, n=14) followed by single-agent PPX with either tacrolimus (n=73) or sirolimus (n=7)...Orca-T shows promise to improve GRFS and other transplant outcomes. Orca-T has been granted Regenerative Medicine Advanced Therapy status by the FDA, and a phase 3 prospectively, randomized study is planned.