Orca-T Reduces GVHD, Mortalities in Hematologic Malignancies

Data presented during the 2021 Transplantation and Cellular Therapy Meetings showed that treatment with Orca-T, a first-generation precision cell therapy, achieved a significant reduction in cases of graft-versus-host disease (GVHD), an impressive GVHD relapse-free survival rate, and a lack of treatment-related mortalities while demonstrating scalability potential.¹

In the analysis that combined 2 trials, Orca-T–treated patients experienced improvements compared with a historical comparison to standard of care in median time to neutrophil engraftment (12 days vs 14 days; P < .0001), median time to platelet engraftment (11 days vs 17 days; P < .0001), and median time from day 0 to hospital discharge (15 days vs 17 days; P = .01)

Results showed that all patients engrafted, with signs of early engraftment among trial participants, explained lead study author Everett H. Meyer, MD, PhD, in a virtual presentation of the findings.

“Orca-T has good evidence for reduced GVHD, reduced chronic GVHD, a low nonrelapse mortality,” said Meyer, an assistant professor of medicine and pediatrics at Stanford University Medical Center in California. “In addition, the concept of going from a single center to multiple centers and scalability has been proven, with good vein-to-vein time of 72 hours across the continental United States. Due to this, Orca-T has achieved regenerative medicine advanced therapy status from the FDA, and we very much look forward to the clinical trial continuing.”

The data also showed that the GVHD-free relapse-free survival rate was 75% with Orca-T and 31% with the historical standard-control cohort.

Acute GVHD is driven partly 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. How-ever, T-cell–reduced grafts and conventionalgrafts (T cells administered ≥ 1 million) are associated with a substantial risk of GVHD that single-agent prophylaxis cannot overcome.

Regulatory T cells (Tregs), which are comprised of CD4+, CD25+, CD127-low T-regulatory cells, help control immune responses. Earlier findings have demonstrated that adding donor-derived or third party–derived Tregs to the donor graft could prevent GVHD without compromising graft-versus-leukemia efficacy.

“Highly purified T-regulatory cells are sorted and administered on day 0 with hematopoietic stem cells,” Meyer explained on the product’s protocol. “There is no immunosuppressive given, and the T-reg cells are allowed to expand to create the right microenvironment for the Tcons [conventional T cells], which are then administered on day 2 at a matching dose to the T-regulatory cells.”

Early findings of the multicenter trials, which were presented during the 2020 American Society of Hematology Annual Meeting and Exposition, also demonstrated that Orca-T prevented GVHD with less immunosuppression compared with a contemporaneous cohort of patients with high-risk hematologic malignancies who under-went standard-of-care hematopoietic stem cell transplantation (HSCT).²

The standard regimen is made up of myeloablative conditioning from 10 to 2 days prior to HSCT, followed by tacrolimus, which is given 1 day prior to transplant.³ On day 0, patients receive an infusion of 10E8 to 10E9 T cells/kg of the apheresis product. Patients are then given posttransplant prophylactic methotrexate on days 1, 3, 6, and 11.

In the Orca-T protocol, the same myeloablative conditioning is administered 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 and Treg. Patients then receive a 3e6 T-cell/kg infusion of Tcon on day 2; single-agent tacrolimus at 4 to 6 ng/mL target doses is administered from day 3 on.

The phase 1 dose-escalation portion of the trial has been completed.

“As part of our trial effort, we also had a phase 2, stage I portion...but we found that when we randomized patients to single-agent prophylaxis versus no prophylaxis, the patients with no prophylaxis showed GVHD [instantly], similar to standard of care, although [GVHD] was very responsive to steroids,” said Meyer.

To be eligible for the single-center, phase 1 trial (NCT04013685) out of Stanford University Medical Center and the multicenter phase 1b trial (NCT01660607) conducted by Orca Bio, patients must have had high-risk, minimal residual disease–positive active leukemia, lymphoma, myelodysplastic syndromes (MDS), or myeloproliferative neoplasms. Additional requirements were a Karnofsky Performance Status score of more than 70, younger than 65 years, and eligible for matched related or unrelated donor transplantation.

Data presented at the 2021 Transplantation and Cellular Therapy Meetings were from the combined cohorts.

In the Orca-T group of 50 patients, patient demographics were comparable to the standard-of-care control cohort (n = 144). The median age was 47 years (range, 20-65), and 52% of patients were male. Most were (60%) White, and the primary disease consisted of acute myeloid leukemia (42%), acute lymphoblastic leukemia (28%), chronic myeloid leukemia (4%), B-cell lymphoma (2%), MDS/myelofibrosis (16%), and other (8%; FIGURE).¹

Sixty-two percent of patients in the Orca-T cohort had human leukocyte antigen—matched siblings who served as the graft source; the rest (38%) had unrelated donors. Twenty-three per-cent of patients had active leukemia at the time of transplant, and the median follow-up was 223 days (range, 30-1561). Evaluated patients included those with at least 30 days of follow-up.

Regarding manufacturing, Meyer noted that the majority of it, along with logistics, is carried out by Orca Bio at a single location.

“Products are sent from donor centers to Orca [Bio] for processing, and then to recipient cen-ters, in collaboration with the National Marrow Donor Program,” Meyer said. “This has been highly successful with a vein-to-vein time of 72 hours, no manufacturing failures, and target dose or greater achieved for all of our patients.”

Further findings showed that patients treated with Orca-T experienced a reduction in grade 2 or higher acute GVHD compared with the standard control cohort, at 10% versus 30%, respectively. In the 4 patients who did have GVHD, 3 patients responded to steroids and 1 responded to secondary therapy, which was ruxolitinib (Jakafi).

One patient did experience initial engraftment followed by graft loss; this patient had autologous recovery and remains in remission, Meyer noted.

Orca-T was also found to retain graft-versus-leukemia immunity in patients at relapse or with at least 180 days of follow-up. Despite markedly reduced GVHD rates with Orca-T, early data suggested that the graft-versus-leukemia effect is preserved.

Regarding safety, Meyer said that Orca-T was found to be well tolerated overall. No reactivation due to cytomegalovirus occurred in 36 patients (72%), 8 (16%) with low-level viremia, and 6 patients (12%) required treatment. Additional infections included Epstein-Barr virus reactivation (n = 8; 1 patient required therapy), BK viruria/viremia (n = 4), rhinovirus (n = 1), Clostridioides difficile(n = 4), bacteriemia (n = 7), norovirus (n = 1), adenovirus (n = 3), and HHV-6 (n = 2).

Eighteen percent of patients (n = 9) experienced serious adverse events, all of which resolved, and 10% of patients had hepatic venoocclusive disease or sinusoidal obstruction syndrome and responded to therapy. At the time of the presentation, the treatment-related mortality rate was 0% with Orca-T versus 11% with standard therapy.

_REFERENCES

_{1. Meyer EH, Hoeg R, Moroz A, et al. Orca-T, a precision Treg-engineered donor product, in myeloproliferative HLA-matched transplantation pre-vents acute and chronic GVHD with less immunosuppression in an early multicenter experience. Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; virtual. Abstract 354. https://bit.ly/3rlZrCe}

_{2. 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. Blood. 2020;136(suppl 1):47-48. doi:10.1182/blood-2020-142974}

_{3. Meyer EH, Laport G, Xie BJ, et al. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recip-ients. JCI Insight. 2019;4(10):e127244. doi:10.1172/jci.insight.127244}