Orca-T Shows Efficacy, Reduced GVHD Risk in Acute Leukemia, MDS: Caspian Oliai, MD

Allogeneic stem cell transplant (allo-HSCT) is part of the standard treatment paradigm for acute leukemia and myelodysplastic syndrome (MDS). But like most therapies for hematologic malignancies, it carries significant risks, with a main concern being chronic graft-vs-host disease (cGVHD).

Orca-T, an investigational allogeneic T-cell immunotherapy, improved cGVHD-free survival compared with allo-HSCT in patients with acute leukemia or MDS in the phase 3 Precision-T trial (NCT05316701). The results, presented at the 51st Annual Meeting of the EBMT, demonstrate Orca-T's potential to improve outcomes in this patient population.

"Simply stated, the unmet need in allotransplantation is to reduce the risk of graft-vs-host disease without increasing the risk of infections or relapse," Precision-T investigator Caspian Oliai, MD, MS, a medical oncologist and hematologist and medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center, told The American Journal of Managed Care®.

Here, Oliai discusses the treatment's mechanisms of action and the findings presented at the EBMT annual meeting, held March 30 to April 2, 2025, in Florence, Italy.

This transcript was lightly edited; captions were auto-generated.

Transcript

Can you tell us the main results of the Precision-T trial evaluating Orca-T that were presented at the 51st Annual Meeting of the EBMT?

Orca-T is a high-precision immunotherapy that's composed of stem cells and immune cells that are derived from an allogeneic donor, and it leverages a highly purified and polyclonal T-regulatory cell population that's capable of controlling alloreactive immune responses. We previously presented the phase 1b trial data, which showed that patients with acute leukemia and MDS who received myeloablatative conditioning with Orca-T had low rates of toxicity and low rates of relapse. Based on that promising data, the current phase 3 trial that was presented at EBMT this year enrolled patients with acute leukemia and MDS who received myeloablative conditioning and then randomized patients between Orca-T plus single-agent prophylaxis against graft-vs-host disease with tacrolimus only vs standard allotransplant with double-agent prophylaxis with tacrolimus and methotrexate.

The primary end point of subjects who were free of moderate to severe chronic graft-vs-host disease and alive at 1 year favored the Orca-T group—78% [in] Orca-T vs 38% in standard allotransplant. This corresponded to a hazard ratio of 0.26 and a P value that was statistically significant. When isolating out chronic graft-vs-host disease, 44% of subjects in the Orca-T arm did not experience moderate to severe graft-vs-host disease compared with only 13% of subjects receiving standard allotransplant were free of chronic graft-vs-host disease. Also, if we look at the rate of severe infections, that was approximately doubled in patients who received standard allotransplant compared to Orca-T. Also, 1-year overall survival was 94% in Orca-T and 83% with standard allotransplant. Really importantly, nonrelapse mortality—meaning that what percentage of patients died from a complication that was not associated with relapse—was only 3% in the Orca-T arm at 1 year vs 13% with standard allotransplant.

Based on these results that were presented at EBMT, Orca-T with tacrolimus appears to be safer than standard allotransplant using double-agent prophylaxis with tacrolimus and methotrexate, while still providing excellent disease control for a curative potential for patients with hematologic malignancies.

Discuss the mechanism of action in the mix of cells that make up the Orca-T. What is the clinical rationale for using these different cells together?

If we think about the standard allograft and standard allogeneic hematopoietic cell transplantation, it's composed of a variety of cell types that are typically administered together in a single infusion. However, the full benefits of this process could potentially be achieved by cellular selection, in which we purify for certain cell types that provide a therapeutic benefit while reducing or removing other cell types that pose a potential risk. The Orca-T strategy selects and separates into 3 distinct components. Number 1, the hematopoietic stem cells, they're given on day 0. Number 2, the purified T-regulatory cells, they're also given on day 0, but in a separate infusion. And then number 3, the conventional T cells, which are given at a relatively reduced dose compared to standard allotransplant, and they're given on day plus 2. So this separation allows for the regulatory T cells to migrate to the solid organs first so that by the time the conventional T cells arrive, an immune barrier is in place that mitigates graft-vs-host disease by preventing massive T-cell proliferation while still allowing for T-cell activation.

Reference

Meyer EH, Salhotra A, Gandhi AP, et al. OS15-01 Orca-T demonstrates improved survival free of chronic GVHD compared to conventional allogeneic hematopoietic stem cell transplant: a randomized phase 3 trial in advanced hematologic malignancies. Presented at: 51st Annual Meeting of the EBMT; March 30-April 2, 2025; Florence, Italy. Oral session 15-01. https://ebmt2025.abstractserver.com/program/#/details/presentations/989