Orca-T significantly improved graft-vs-host disease–free relapse-free survival and time to engraftment, significantly reduced acute and chronic GVHD, and showed a trend toward improved overall survival vs standard of care in patients with serious hematologic malignancies
The high-precision allogeneic cellular therapy Orca-T significantly improved graft-vs-host disease (GVHD)–free relapse-free survival (RFS) and time to engraftment, significantly reduced acute and chronic GVHD, and showed a trend toward improved overall survival (OS) vs standard of care (SOC) in patients with serious hematologic malignancies, according to data from multicenter phase 1b and single-center trials presented during the 2021 ASH Annual Meeting.1
Orca-T was also found to be well tolerated with reduced non-relapse mortality rates, have robust immune reconstitution leading to low rates of severe posttransplant infections, and have vein-to-vein times of less than 72 hours across the United States.
“We have shown that the Orca-T approach appears to be scalable to multiple centers, appears to be reducing the rate of acute and chronic GVHD [with] single-agent tacrolimus, appears to result in reasonable engraftment and good chimerism levels, and the possibility of scaling graft engineering is very real and exciting for the field,” Everett H. Meyer, MD, senior study author and associate professor of medicine (blood and marrow transplantation and cellular therapy), of pediatrics (stem cell transplantation), and of surgery (abdominal transplantation) at Stanford University, said in a presentation during the meeting.
“Our clinical experience with Orca-T has grown significantly over the past year and we are pleased to present data on an expanded group of patients who now have 1 year of follow-up with Orca-T,” Ivan Dimov, PhD, cofounder and chief executive officer of Orca Bio, added in a press release ahead of the presentation.2
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. 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, which are comprised of CD4-positive, CD25-positive, and 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-vs-leukemia efficacy.
Orca-T is a high-precision cell therapy product that is designed to fit into traditional transplant center treatment protocols. The product has previously received Regenerative Medicine Advanced Therapy designation from the FDA and is being studied as a treatment across multiple hematologic malignancies.
Additionally, Meyer noted that Orca Bio has reliably manufactured to deliver consistent Treg dose and purity; the company has also delivered Orca-T at transplant centers across the United States. High purity Orca-T products have been delivered to more than 130 patients to date.
Orca-T treatment is comprised of myeloablative conditioning with single-agent posttreatment tacrolimus and no methotrexate. On day -10 to day-2, patients in both arms are treated with myeloablative conditioning; on day -1 on the standard arm, patients are given tacrolimus at 5 to 10 ng/mL target. On day 0, patients in the Orca-T arm receive an infusion of hematopoietic stem and progenitor cells and Treg at a cell dose of 3e6 Treg/kg; on day +2 posttransplant, they receive an infusion of Tcon at a cell dose of 3e6 T cells/kg, followed by day +3 with single-agent tacrolimus at 5 to 10 ng/mL target. No methotrexate, posttransplant cyclophosphamide, or other immunosuppressive therapies are given with Orca-T.
In day -10 to day-2 in the SOC arm, patients also undergo myeloablative conditioning. On day 0, patients are infused with apheresis product at a cell dose of 10e8 to 10e9 T cells/kg. Posttransplant, methotrexate prophylaxis was administered on days +1, +3, +6, +11.
In the single-center phase 2 trial (NCT04013685), patients needed to have acute leukemia, which could have been acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed phenotype; this included those who had active disease at time of transplant. The trial also included patients with myelodysplastic syndrome (MDS), myelofibrosis, non-Hodgkin lymphoma (NHL), or chronic myeloid leukemia (CML) in accelerated phase or blast crisis.
Additional eligibility criteria included having a 8/8 matched-related or -unrelated donor, hematopoietic cell transplantation-specific comorbidity index (HCT-CI) 4 or lower, Karnofsky performance score (KPS) of at least 70, being between the ages of 18 and 72 years, and having adequate organ function.
Twenty-nine patients were enrolled to the cohort, and they had a median age of 42 years (range, 19-71); 72% of patients were male. More than half of patients were White (52%), 1% were African American, 17% were Asian, and 28% had unspecified race. Forty-one percent of patients had AML, 6% had ALL, 2% had MDS/myelofibrosis, 4% had CML, 1% had NHL, and 4% had other primary disease. Moreover, 28% of patients had active leukemia at the time of transplant and 72% had graft source HLA-matched siblings. The median follow-up for this cohort was 617 days (range, 148-1809).
To enroll to the multicenter phase 1b trial (NCT01660607; n = 80), patients needed to have acute leukemia (AML, ALL, mixed phenotype), including those with active disease at time of transplant (≤ 10% bone marrow blast burden), MDS, myelofibrosis, blastic plasmacytoid dendritic cell neoplasm, or CML in accelerated phase or blast crisis. Additional requirements are 8/8 matched-related or -unrelated donor, a HCT-CI of 4 or lower, a KPS of at least 70, being between the ages of 18 and 72 years, and to have adequate organ function.
The median age in this cohort was 49 years (range, 22-65) and 51% of patients were male. Moreover, 67% of patients were White, 1% were African American, 13% were Asian, and 16% had unspecified race. Forty-five percent of patients had AML, 34% had ALL, 19% had MDS/myelofibrosis, 1% had CML, and 1% had other primary disease. Nineteen percent of patients had active leukemia at time of transplant and 53% had graft source HLA-matched siblings. The median follow-up for this group was 209 days (range, 27-704).
For comparison purposes, a SOC comparator cohort was identified with patients who were treated contemporaneously at Stanford University Hospital. Ninety-five consecutive patients received a peripheral blood stem cell–derived graft and Tac/MTX GVHD prophylaxis.
In the SOC cohort, the median age was 48 years (range, 20-64) and 49% of patients were male. Forty-four percent of patients were White, 2% were African American, 19% were Asian, and 30% had unspecified race. Thirty-nine percent of patients had AML, 26% had ALL, 19% had MDS/myelofibrosis, 6% had CML, 8% had NHL, and 2% had other primary disease. Twenty-one percent of patients had active leukemia at transplant and 56% had graft-source HLA-matched siblings. The median follow-up was 886 days (range, 55-1783).
All subjects reported have had at least 90 days of follow-up, or death prior to day +90.
Results showed that rapid engraftment was observed with Orca-T; neutrophil engraftment occurred at a median 13 days with Orca-T vs 14 days with SOC, and platelet engraftment occurred at 15 and 17 days, respectively.
One of 109 patients experienced graft failure with Orca-T; this was a patient with Philadelphia chromosome–positive ALL who experienced apparent graft rejection followed by rapid autologous recovery within weeks of total body irradiation/cyclophosphamide conditioning. An additional patient on Orca-T experienced poor graft function, which required a CD34 boost; the patient remains disease free more than 400 days posttransplant.
Additionally, immune reconstitution was found to be robust with Orca-T. Eighty percent of patients had more than 90% CD3-positive T cell donor chimerism at day +100 posttransplant; regarding CD19-positive B cells and CD56-positive natural killer (NK) cells, these rates were 100% and 98%, respectively.
Further findings showed that a low rate of infectious disease complications was observed with Orca-T. In the multicenter study, data were available for the first 52 patients who received treatment, and infections were graded per the BMT CTN Manual of Procedures and was independently assessed by external pathologist.
Grade 3 or higher acute GVHD occurred in 3% of patients on Orca-T compared with 20% of those on SOC in the phase 2 study; in the multicenter trial, this occurred in 5% of patients on Orca-T.
Chronic GVHD was also profoundly reduced with Orca-T; these rates were 3% and 43% with Orca-T and SOC, respectively, in the phase 2 trial. In the multicenter phase 1 study, the chronic GVHD rate was 5% with Orca-T.
Relapse was also not found to be increased with Orca-T. In the phase 2 study, relapse rates were 18% with Orca-T vs 19% with SOC; the relapse rate with Orca-T was 15% in the phase 1 trial.
Investigators noted that disease control with Orca-T may be further optimized depending on the choice of conditioning regimen. At 1-year posttransplant, the combined relapse rate—from both the phase 1 and 2 studies—was 0% with Orca-T and thiotepa/busulfan/fludarabine (n = 32), 16% with Orca-T and total body irradiation–based conditioning (n = 23), and 20% with Orca-T plus busulfan/cyclophosphamide or busulfan/fludarabine (n = 34).
In the Orca-T and thiotepa/busulfan/fludarabine group, the median follow-up was 172 days, with 7 patients having at least 1 year follow-up. This regimen was well tolerated, and no non-relapse mortality has been seen to date.
In a combined analysis of both data sets, GVHD-free RFS was markedly improved at 1 year with Orca-T (n = 109) vs SOC (n = 95) at 74% vs 34%, respectively. Orca-T plus single-agent GVHD prophylaxis was also well tolerated with low rates of non-relapse mortality at 6% vs 13% with SOC, respectively. Four non-relapse causes of death occurred with Orca-T, and these included mucormycosis, congestive heart failure, viral pneumonia, and COVID-19–related pneumonia.
A a trend toward improved overall survival was also observed with Orca-T. The OS rates at day 300+ posttransplant were 90% and 78% with Orca-T and SOC, respectively. Also, at this point in time, the chronic GVHD-free survival rates were 87% and 45%, respectively.
A phase 3 trial that will compare Orca-T with SOC allograft is expected to launch with its first enrolled patient in early 2022, investigators concluded.