Orca-T Significantly Boosts Survival Over Cyclophosphamide in Transplant Study

A retrospective study found that Orca-T, an investigational T-cell immunotherapy, improved overall survival (OS) compared to post-transplant cyclophosphamide in allogeneic stem cell transplant patients. The phase 1b trial showed higher OS rates, lower graft-versus-host disease (GVHD) incidence, and reduced non-relapse mortality (NRM). The ongoing phase 3 Precision-T trial aims to further evaluate Orca-T’s efficacy against standard allo-HCT.

Orca-T Significantly Boosts Survival Over Cyclophosphamide in Transplant Study

A retrospective study has demonstrated that Orca-T, an investigational allogeneic T-cell immunotherapy, significantly improves overall survival (OS) compared to post-transplant cyclophosphamide in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HCT). The findings, initially presented at the 2024 American Society of Hematology (ASH) Annual Meeting, were revisited at the 2025 Transplantation & Cellular Therapy Meetings.

In the analysis, the OS rates at one, two, and three years for patients treated with Orca-T in a phase 1b trial (NCT04013685) were 96% (95% CI, 88%-99%), 88% (95% CI, 78%-94%), and 86% (95% CI, 73%-92%), respectively. These results were compared to patients from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry who received post-transplant cyclophosphamide following allo-HCT. In this group (n = 293), the OS rates at one, two, and three years were 82% (95% CI, 78%-87%), 73% (95% CI, 68%-79%), and 67% (95% CI, 61%-74%), respectively.

Further analysis of the entire cohort of patients who received Orca-T during the phase 1b study (n = 154) revealed one-, two-, and three-year OS rates of 88% (95% CI, 83%-94%), 80% (95% CI, 74%-87%), and 76% (95% CI, 69%-84%), respectively, over a median follow-up of 30 months (range, 0-54 months).

Orca-T demonstrated a lower incidence of graft-versus-host disease (GVHD) and infections while maintaining high survival rates. Lead study author Dr. Everett Meyer, associate professor of medicine, pediatrics, and surgery at Stanford Medicine, and his colleagues noted in their presentation that decreased non-relapse mortality (NRM) and increased relapse-free survival (RFS) could contribute to the improved OS observed in the Orca-T cohort.

GVHD remains a significant complication of allo-HCT, and while post-transplant cyclophosphamide is commonly used for GVHD prophylaxis, it may increase the risk of infections and organ toxicity. Orca-T is an investigational immunotherapy that incorporates highly precise donor regulatory T cells alongside single-agent tacrolimus as GVHD prophylaxis, potentially mitigating these risks.

The phase 1b study enrolled patients aged 18 to 75 with high-risk hematologic malignancies, including acute myeloid leukemia, acute lymphoblastic leukemia, high- or very high-risk myelodysplastic syndrome, and myelofibrosis. Participants were required to be eligible for myeloablative conditioning, have an HCT-specific comorbidity index of 4 or lower, a Karnofsky performance status of at least 70, and adequate organ function.

According to the study protocol, patients received myeloablative conditioning from day -10 to day -2 before receiving an infusion of hematopoietic stem and progenitor cells, along with regulatory T cells (Tregs) at a dose of 3 x 10^6 Treg/kg. On day 2, conventional T cells were administered at a dose of 3 x 10^6 T cells/kg, followed by single-agent tacrolimus on day 3 at a target dose range of 1 to 10 ng/mL.

The primary endpoints of the study were the incidence of dose-limiting toxicities and the rate of primary graft failure through day 28.

In terms of baseline characteristics, the median age of participants was 49 years (range, 39-58) in the Orca-T group and 48 years (range, 37-58) in the post-transplant cyclophosphamide group. The majority of patients in both groups were male (57%), had myeloid malignancies (Orca-T, 70%; cyclophosphamide, 72%), intermediate-risk disease (65%; 64%), were in their first complete remission (60%; 63%), and had matched unrelated donors (Orca-T, 52%; cyclophosphamide, 85%). The racial demographics showed that 68% of Orca-T patients and 84% of post-transplant cyclophosphamide patients were White, while 75% and 82%, respectively, were non-Hispanic/Latino.

The median follow-up period was 33 months (range, 5-54) for the phase 1b cohort and 24 months (range, 0-53) for the post-transplant cyclophosphamide cohort.

Additional findings highlighted that the one-year NRM rate was significantly lower in the Orca-T cohort (2% in the selected subgroup of 77 patients) compared to the post-transplant cyclophosphamide group (8% in 290 patients). The respective one-year RFS rates were 83% and 71%.

Examining the broader phase 1b cohort (n = 150), Meyer noted that primary graft failure occurred in only 2% of safety-evaluable patients treated with Orca-T, with no instances of secondary graft failure reported. Moderate-to-severe chronic GVHD was observed in 13% of patients, while 5% experienced grade 3 or higher acute GVHD.

Infection rates were also analyzed, with 28% of patients experiencing grade 1 to 3 infections, 5% developing grade 4 infections, and 1% encountering grade 5 infections. The overall NRM rate for the phase 1b cohort was 9%.

The ongoing phase 3 Precision-T trial (NCT05316701), which has completed patient enrollment, aims to further evaluate Orca-T against standard allo-HCT in patients with advanced hematologic malignancies.

Dr. Meyer disclosed that he has received research funding from Orca Biosystems, Inc., GigaGen, Indee Labs, and Triursus Therapeutics.

Orca-T Demonstrates Safety and Feasibility in Reduced-Intensity Stem Cell Transplant

Conference | Transplantation & Cellular Therapy Meetings

Findings from a phase 1 trial (NCT05088356) presented at the 2025 Transplantation & Cellular Therapy Meetings indicate that Orca-T, when used with reduced-intensity conditioning (RIC) in hematopoietic stem cell transplantation (HSCT), is a viable and safe alternative to conventional transplants for patients with advanced blood cancers

Study Findings

In an interim analysis with a median follow-up of 10.4 months (range, 1-32 months):

• Neutrophil engraftment occurred in a median of 15 days (range, 9-39).
• Platelet engraftment took a median of 19.5 days (range, 14-70).
• Donor chimerism for CD15 reached 100% at day 30 (range, 99%-100%) and remained at 100% at day 90 (range, 98%-100%).
• Donor chimerism for CD3 was 96% (range, 28%-100%) at day 30 and 99% (range, 76%-100%) at day 90.
• 12-month relapse-free survival (RFS) rate was 79% (95% CI, 65%-96%).

The study included 30 patients receiving transplants from either fully HLA-matched donors (n = 27) or 7/8 HLA-mismatched donors (n = 3).

Safety Data

• Acute graft-versus-host disease (GVHD): 4 patients (grade 2-4), none with grade 3-4.
• Chronic GVHD: Moderate cases in 2 patients, none classified as severe.
• Mortality rate: 20% over the study period, with causes including relapse (n = 2), infection (n = 2), and hepatic sinusoidal obstruction syndrome (n = 2).

Dr. Alejandro Villar-Prados and colleagues noted that Orca-T with RIC leads to strong engraftment, minimal GVHD, and a potent graft-versus-tumor effect.

Trial Design & Patient Characteristics

This dose-escalation study assessed the feasibility and tolerability of Orca-T’s engineered T-cell therapy in combination with RIC. It enrolled patients with leukemia (AML, ALL, mixed phenotype), myelodysplastic syndrome, or myelofibrosis.

• Median patient age: 68 years (range, 60-74)
• Median Karnofsky performance status: 90%
• Most common condition: Acute myeloid leukemia (AML) – 14 patients

Conclusion & Next Steps

The findings support the potential for Orca-T as a safer and effective alternative for HSCT with reduced-intensity conditioning. Researchers recommend larger, multicenter studies to confirm these results.