Early Trial of Orca-T Produces 100% OS Rate in Hematologic Malignancies and 7/8 Mismatched Donors


In 8 patients with various hematologic malignancies who received an allogeneic hematopoietic stem cell transplant with 7/8 non-permissive HLA mismatched donors, Orca-T led to a 100% survival rate.

Findings from a single-center phase 2 trial (NCT01660607) of Orca-T showed a 100% overall survival (OS) rate in 8 patients with various hematologic malignancies, including acute leukemia, myeloproliferative neoplasms, and chronic myeloid, who received an allogeneic hematopoietic stem cell transplant (alloHSCT) with 7/8 non-permissive HLA mismatched donors, according to a presentation from the 2023 Transplantation & Cellular Therapy Meetings.

Orca-T is a high precision cell therapy. At a median follow-up of 426 days (range, 300-654), only 2 cases of relapse had been reported.

“In this early-phase 7/8 [mismatched donor] study, there was no non-relapse mortality [NRM] and 100% OS to date, consistent with the very low NRM and high OS seen with Orca-T in patients with fully matched [8/8] donors,” study author Everett H. Meyer, MD, PhD, Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford California, said in a presentation of the data.

Finding donors for transplant recipients can be difficult, especially those with mixed heritage or particular ethnic backgrounds, according to Meyer, who added that a promising way to open up transplant to all individuals is by using HLA mismatch.

“The Orca T high-precision cell therapy product relies on enriching T regulatory cells in the donor graft…to achieve a highly pure T regulatory population, which is administered to a conditioned patient with hematopoietic stem cells on day 0. Dose-matched conventional T cells are administered 2 days later. The idea is to provide an immune environment to help regulate and control reconstitution, and single-agent tacrolimus is used to prevent graft-versus-host-disease [GVHD],” Meyer added.

To be eligible for the study, patients between 18 and 72 years of age had to have acute leukemia in complete response, or active disease at the time of transplant with no more than 10% bone marrow blast burden; myelodysplastic syndrome; myelofibrosis; blastic plasmacytoid dendritic cell neoplasm; CML in accelerated phase or blast crisis; or non-Hodgkin lymphoma.

Patients also had to have an 8/8 or 7/8 matched related or unrelated donor; hematopoietic cell transplantation–specific comorbidity index of 4 or less; Karnofsky performance status of at least 70, and adequate organ function.

“The demographics of the individuals with mismatch on our trial [were] representative of our catchment area, but we have a lot of non-White, Asian, and mixed-heritage individuals who fall into this category,” Meyer said.

The protocol was designed such that patients with 8/8 fully matched donors would receive prophylactic tacrolimus, and patients with 7/8 mismatched donors would receive tacrolimus if they had host-vs-graft (HvG) mismatch or tacrolimus plus mycophenolate mofetil (MMF) if they had graft-vs-host and bidirectional mismatch (n = 7). However, the first two patients with HvG mismatch had complications, and both prophylactic agents were adopted for the remaining patients with HvG mismatch (n = 1).

The treatment schema was such that patients underwent myeloablative conditioning on day –10 to day –2 with total body irradiation/etoposide/cyclophosphamide, or busulfan, fludarabine, and thiotepa. Hematopoietic stem and progenitor cells and T regulatory cells were infused at a dose of 3 x 106 Treg/kg within 72 hours on day 0, and two days later, conventional T cells were administered at a dose of 3 x 106 T cells/kg. On day 3, patients began tacrolimus at a target dose of 6 to 8 ng/mL and mismatched patients received 1000 mg of MMF twice daily, which was tapered 500 mg per week after the first week.

Additional results showed “very good engraftment initially as we [saw] with our HLA matched patients on the trial,” Meyer noted, with a median engraftment of 12.5 days for neutrophils and 15.5 days for platelets. Moreover, whole blood chimerism and more than 90% donor T-cell chimerism was achieved by day 30 and day 90.

Additionally, mismatched patients experienced log-fold higher levels of IL-2 and lower levels of IL-10 in plasma on day 14 compared with matched patients.

“What was interesting is one of the early findings is that the early serum plasma levels look very different between our 7/8 matched individuals vs the 8/8 individuals,” Meyer said. “This really highlights that there is probably a lot more alloreactive activity in these patients. There’s always some discussion that [maybe] focused alloreactivity can enhance relapse. This was too small a population to know that, but it’s very interesting that we see signals of more alloreactivity.”

Regarding safety, only 1 case of grade 1/2 acute GVHD occurred, which was responsive to steroids, and only 1 grade 3 or greater infection was reported. No grade 3/4 acute GVHD or severe chronic GVHD occurred.

“Compared to currently available regimens for myeloablative alloHSCT with 7/8 mismatched donors, results from this small sample with Orca-T are encouraging. Additional study is warranted to further characterize the efficacy of Orca-T in this mismatched donor setting,” Meyer concluded.

Editor’s Note: Dr Meyer disclosed sponsored research support from Orca Biosystems Inc; role of cofounder and scientific advisor of GigaMune Inc; member of the scientific advisory board of Jura Bio; and consultant for TRACT Therapeutics, Indee Labs, and CTI Biopharma.

Pavlova A, Lowsky R, Muffly L, et al. Orca-T, a high-precision cell therapy, for the treatment of hematologic malignancies in patients with 7/8 mismatch donors. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 30
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