Orca-T, an engineered Treg donor product, as an aGvHD prophylaxis

Impaired development of regulatory T cells (Tregs) following hematopoietic stem cell transplant (HSCT) has been associated with enhanced graft-versus-host disease (GvHD), causing significant rates of morbidity and mortality. At the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Everett Meyer spoke about Orca-T, an engineered Treg donor product, as an agent for treating acute GvHD (aGvHD).¹ Orca-T was awarded regenerative medicine advanced therapy and orphan drug designation by the U.S. Food and Drug Administration (FDA) in 2019. See our interview with Meyer here and another interview with Barbara Fazekas de St Groth on why Treg reconstitution is important to prevent GvHD.

Orca-T is a CD34-selected Treg-engineered graft that has shown promising initial results but requires further testing. Compared with traditional HSCT, the donor cells in Orca-T are processed and the Tregs, hematopoietic stem cells, and progenitor cells are separated out from the conventional T cells and infused back into the patient according to the schema in Figure 1.

Figure 1. Protocol schema²

HSPCs, hematopoietic stem and progenitor cells; MA, myeloablative; Tcon, conventional T cell; Treg, regulatory T cell.

Study design

This analysis includes data from phase Ib (n = 11; NCT04013685) and phase I/II (n = 40; NCT01660607) trials.

Purification of Tregs was performed by immunomagnetic selection of CD25⁺ cells of granulocyte colony-stimulating factor-mobilized peripheral blood cells followed by flow cytometric cell sorting of CD4⁺CD127^lo cells. The infused target dose was 2–3 million Tregs/kg with a 1:1 ratio of conventional T cells and Tregs.

The primary objective of the studies was the rate of GvHD relapse-free survival (GRFS) at 1 year. Secondary objectives were dose limiting toxicity, overall survival, incidence and severity of chronic GvHD, and incidence of infections.

Results were compared with a historical standard of care (SoC) cohort treated at Stanford University Medical Center (N = 138) with both matched related (n = 79) and unrelated (n = 59) allo-HSCT consisting of unmanipulated peripheral blood stem cell products. Patients were treated with methotrexate plus tacrolimus for GvHD prophylaxis.

Eligibility criteria:

• Patients with high-risk, measurable residual disease-positive active disease (leukemia, lymphoma, myelodysplastic syndromes, or myeloproliferative neoplasms) and candidates for allo-HSCT with a matched related or unrelated donor.
• Patients aged < 65 years with a Karnofsky Performance Status score > 70 and adequate organ function.

Table 1. Baseline patient characteristics¹

Key points

• The study was carried out in > 12 clinical sites across the US.
• The products were sourced from matched related and matched unrelated donors and produced with a vein-to-vein time of < 72 hours without manufacturing nor logistic failures.
• Orca-T was found to result in significantly quicker engraftment and reduced hospital stays for patients compared with the current SoC.
• Furthermore, Orca-T significantly reduced the incidence of severe acute and chronic GvHD, and treatment-related mortality, while it improved relapse-free survival (Table 2).

Table 2. Engraftment length and hospital stay duration¹

Table 3 shows a doubling of the number of patients achieving a complete response with measurable residual disease-negativity at 90 days after treatment with Orca-T and this was maintained for 180 days. The response lasted for a year in 11 patients. This included four patients with active/refractory disease/partial response before Orca-T administration.

Table 3. Duration of response and variation over time¹

Conclusion

Orca-T was able to effectively reduce the incidence of acute and chronic GvHD compared with the current SoC. No treatment-related mortality was recorded in patients treated with Orca-T, and relapse-free survival was more than doubled compared with the SoC cohort. While further testing in larger clinical trials is required, these initial results are promising. Orca-T is currently being assessed in an ongoing multicenter trial.