Orca-T Exhibits GVHD Preventive Potential in High-Risk Hematologic Malignancies

Everett H. Meyer, MD, PhD

Orca-T, a precision Treg-engineered donor product, demonstrated preventive potential for graft-versus-host disease (GVHD), with less immunosuppression, compared with the standard of care (SOC) in patients with high-risk hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT), according to early findings from a multicenter experience.

The rate of grade 2 or greater acute GVHD was reduced by 20% with the Orca-T protocol compared with SOC (Orca-T, 10%; SOC, 30%; P = .005). The rate of chronic GVHD dropped from 46% with SOC to 3% with Orca-T (P = .0002).

Additionally, treatment-related mortality fell from 11% with SOC to 0% with Orca-T (P = .04). In patients with grade 3 or greater GVHD, the relapse-free survival rate was 75% with Orca-T vs 31% with SOC (P = .001).

“Graft-versus-host disease remains a major complication that drives morbidity and non-relapse mortality in transplantation,” said lead study author Everett H. Meyer, MD, PhD, an assistant professor of medicine and pediatrics at Stanford University Medical Center, in a virtual presentation of the data. “Although the trial is still ongoing, we have seen what we think are promising graft-versus-tumor effects in the context of graft engineering.”

Acute GVHD is driven in part by heterogeneity in the donor-graft composition and the number of T cells in the grafts. T-cell depleted grafts can be used to reduce the risk of GVHD; however, T-cell reduced grafts and conventional grafts, where 1 million or more T cells are administered, are associated with a substantial risk of GVHD that single-agent prophylaxis cannot overcome.

Tregs, comprised of CD4+, CD25+, CD127-low T-regulatory cells, help control immune responses. Prior data have shown that adding donor-derived or third party–derived Tregs to the donor graft could prevent GVHD without compromising graft-versus-leukemia efficacy.

The SOC regimen comprises myeloablative conditioning from 10 to 2 days prior to HSCT, followed by tacrolimus, given 1 day prior to transplant. On day 0, patients receive an infusion of 10e8 to 10e9 T cells/kg of the apheresis product. Then, in the post-transplant setting, patients receive prophylactic methotrexate on days 1, 3, 6, and 11.

The Orca-T protocol consists of the same myeloablative condition 10 to 2 days before transplant. On the day of transplant, patients receive an infusion of 3e6 Treg/kg of hematopoietic stem and progenitor cells (HSPCs) and Treg. Then, patients are given a 3e6 T-cell/kg infusion of Tcon on day 2 and begin on single-agent tacrolimus at 4 to 6 ng/mL target doses from day 3 on.

Patients with high-risk, minimal residual disease–positive, active leukemia, lymphoma, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPNs), who are healthy enough for myeloablative transplant, are eligible for enrollment. Patients have to have a Karnofsky Performance Status of greater than 70, be under the age of 65, and have a human leukocyte antigen (HLA) matched, related or unrelated transplant donor.

Taken collectively, data from the phase 1b (NCT01660607) and ongoing phase 2 (NCT04013685) trials showed that the median age of patients in the Orca-T cohort (n = 50) was 47 (range, 20-65) vs 48 (range, 20-64) in the SOC cohort (n = 144). About half of patients in both cohorts (52% and 49%, respectively), were male.

Primary diseases in the Orca-T cohort included acute myeloid leukemia (42%), acute lymphoblastic leukemia (28%), chronic myeloid leukemia (4%), B-cell lymphoma (2%), MDS/myelofibrosis (16%), and other, comprising mixed phenotype acute leukemia (8%). Similar percentages were observed in the SOC control cohort (53%, 26%, 7%, 6%, 22%, and 2%, respectively).

Additionally, 62% of patients in the Orca-T cohort and 56% of patients in the SOC cohort had an HLA-matched sibling donor as their graft source. Unrelated donors served as the graft source for 38% and 44% of patients, respectively. 

At the time of transplant, 23% and 21% of patients had active leukemia in the Orca-T and SOC cohorts, respectively. The median follow-up times were 223 days (range, 30-1561) and 886 (range, 55-1783), respectively.

Scaling an approach such as Orca-T from single centers to multiple centers remains a challenge; however, in this study, manufacturing and logistics were carried out by Orca Bio. Over 12 clinical sites across the United States participated.

“In our experience, every patient has received a product with a vein-to-vein time of less than 72 hours with no product failures,” said Meyer.

Additionally, consistent dosing of at least 2 million CD34 HSPCs/kg and about 3 million Treg cells/kg with an average purity of 96% was observed.

Notably, patients treated with Orca-T vs SOC had shorter time to neutrophil engraftment (median 12 vs 14 days, respectively; P < .0001), time to platelet engraftment (median 11 vs 17 days, respectively; P < .0001), and time from day 0 hospital discharge (median 15 vs 17 days, respectively; P = .01).

Moreover, Orca-T appears to retain a graft-versus-tumor effect in patients at relapse or in those with at least 180 days of follow up.

In October 2020, the FDA granted Orca-T RMAT (Regenerative Medicine Advanced Therapy) and Orphan Drug Designation status for the treatment of patients eligible for HSCT.

The phase 2 trial is currently recruiting patients and further results are anticipated, concluded Meyer.

Reference

Meyer EH, Hoeg R, Moroz A, et al. Orca-T, a precision Treg-engineered donor product, prevents acute GvHD with less immunosuppression in an early multicenter experience with myeloablative HLA-matched transplants. Orca Bio. December 6, 2020. Accessed December 6, 2020. https://bit.ly/39URbD4.