Orca-T Shows Preventative Potential for GVHS in High-Risk Blood Cancers


The precision Treg-engineered donor product Orca-T exhibited preventive potential for graft-versus-host disease in patients with high-risk hematologic malignancies who underwent hematopietic stem cell transplantation, with less immunosuppression compared with the standard of care.

Everett H. Meyer, MD, PhD

Everett H. Meyer, MD, PhD

The precision Treg-engineered donor product Orca-T exhibited preventive potential for graft-versus-host disease (GVHD) in patients with high-risk hematologic malignancies who underwent hematopietic stem cell transplantation (HSCT), with less immunosuppression compared with the standard of care (SOC) in a multicenter experience, according to the early findings presented during the 2020 ASH Annual Meeting.

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.


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.

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