In comparison with conventional transplant options, Orca-T may be more effective with a lower probability of infection in patients with hematologic malignancies.
The precision cellular therapy, Orca-T, demonstrated improvement in 1-year graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) compared with standard transplant following myeloablative conditioning (MAC) for hematological malignancies, according to findings from 2 studies.1
The findings were presented by Samer Srour, MBBS, assistant professor, Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, during the 10th Annual Meeting of the Society of Hematologic Oncology.
“The way conventional transplant is most commonly done across the world is you take the graft as it is with over 50 of the cells and you throw them in the patient. And then [you can] try to do some manipulation by giving some immunosuppressive medications, and try to mitigate the GVHD decrease the relapse,” Srour said during a presentation at the meeting. “With Orca-T, we thought, is there any better way to do this,” he added.
Srour explained that Orca-T optimizes allograft to improve results for allogeneic hematopoietic stem cell transplant. The newer therapy also has a higher precision compared with conventional transplant. After myeloablative therapy, conventional transplant may lead to imbalanced immune reconstitution, but Orca-T does the opposite.
Orca-T treatment is comprised of MAC with single-agent GVHD prophylaxis with tacrolimus. The normal approach to administer Orca-T is giving the patient MAC followed by hematopoietic stem progenitor cell (HSPC) and Treg infusion at a 3 x 106 Treg/kg cell dose. Patients then received a Tcons infusion at a 3 x 106 T cells/kg dose. In the post-transplant phase, patients received tacrolimus (5 ng/mL to 10 ng/mL target). Treatment is the same with standard transplant, with the exception of the transplant itself.
To demonstrate the efficacy of Orca-T vs conventional transplant, Srour compared a multicenter phase 1b study of 103 patients to single-center phase 1/2 study of 34 patients, and a control arm that included 375 patients from the Center for International Blood and Marrow Transplant Research. Patient ages across the cohorts ranged from 19 years to 65 years of age. Most patients evaluated were male and White. The primary disease was acute myeloid leukemia (AML) for most patients; however, a significant percentage had either acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS) as their primary disease. More patients received a Bulsufan-based myeloablative therapy than total-body irradiation-based myeloablative therapy. Most patients in the multicenter cohort and the single-center cohort had sibling donors, but most patients in the control group had HLA-matched unrelated donors.
“There was around 14% to 15% of patients with active disease in either arm. And for the [minimal residual disease] also positive at transplant, it was in 40% to 45% of patients,” Srour said.
Orca-T led to rapid engraftment, according to the results. The median time to neutrophil engraftment was 13 days, and the median time to platelet engraftment was 16 days. Orca-T showed robust immune reconstitution in T cell, T4 cells, TB cells, Tregs, B cells, and NK cells.
In the multicenter and single-center cohorts who had Orca-T, there was a lower rate of severe GVHD of 4% (95% CI, 0%-20%) compared with the control 16% (95% CI, 12%-19%). The rate of chronic GVHD at 1 year was 5% (95% CI, 0%-21%) vs 38% (95% CI, 33%-44%), showing a significant chronic GVHD reduction with Orca-T.
With a rate of 20% (95% CI, 8%-34%) in the Orca-T group compared with 35% (30%-40%) in the comparator group, Orca-T did not appear to increase relapse. Moreover, the GRFS observed with Orca-T was 71% (95% CI, 60%-78%) vs 21% (95% CI, 17%-25%) in the comparator arm.
The analysis signaled that Orca-T may improve overall survival (OS) without negatively impacting quality of life vs conventional transplant. The OS rate observed with the experimental transplant was 90% (95% CI, 82%-95%) compared with 68% (95% CI, 63%-73%) with the comparator. Findings also hinted that Orca-T may be further optimized by conditioning regimen choice. Specifically, Orca-T with either busulfan, fludarabine or thiotepa led to better disease control compared with other regimens.
For safety, grade 3 (severe) infection was less common. The rate of grade 3 infection observed in the study was 10% (95% CI, 2%-26%). Orca-T was well-tolerated.
Orca-T will be evaluated in a pivotal phase 3 clinical trial, which will include patents with AML, ALL, or MDS who are between the ages of 18 and 65 years old. The study will randomize patients to received either Orca-T or an unmanipulated allograft plus tacrolimus/methotrexate.
The primary end point of the ongoing study will be the rate of survival free of moderate-to-severe chronic GVHD with a secondary end point of RFS. Eighty-five patients with be included in each treatment arm, and the study will be completed when at least 57 events have occurred.
“Based on all this data, I believe this will be practice changing in a few years and hopefully get FDA approval, if we can prove it,” Srour said about the phase 3 trial.
Srour, Samer. Orca-T results in high GVHD-free and relapse-free survival following myeloablative conditioning for hematological malignancies: results of a single center phase 2 and a multicenter phase 1b study. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.