Orca-T in patients undergoing allo-HSCT for hematologic malignancies

Finding donors for transplant recipients can be challenging, particularly for those of mixed-race heritage and certain ethnic backgrounds.¹ The use of single allele human leukocyte antigen (HLA)-mismatched (7/8) donors is one promising strategy aimed to expand the donor pool and increase access to transplantation; however, historically outcomes following this method have proved less favorable, with reduced overall survival (OS) and increased incidence of graft-versus-host disease (GvHD).¹

Similarly, HLA-matched donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been associated with high rates of GvHD and relapse.² As such, new interventions are currently being explored to further improve outcomes for myeloablative allo-HSCT in both matched and mismatched settings.^1,2

Orca-T, a high-precision cellular therapy comprised of enriched regulatory T cells and conventional T cells alongside stem cells, is designed to improve immune reconstitution and prevent GvHD. This regimen has previously received both orphan drug designation and regenerative medicine advanced therapy by the U.S Food and Drug Administration (FDA). Here, we summarize recent data from two trials of Orca-T in patients with hematologic malignancies, both presented by Meyer^1,2 at the 2023 Tandem Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR. The first trial was in patients receiving stem cell transplants from 7/8 mismatched donors¹ and the other investigated relapse and GvHD outcomes of Orca-T in patients undergoing allo-HSCT with 8/8 matched donor cells.²

Orca-T in patients undergoing allo-HSCT with 7/8 mismatched donors¹

Study design

This single-center phase II trial (NCT01660607) included patients aged 18–72 years with a range of hematologic malignancies (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], mixed phenotype acute leukemia, and myelodysplastic syndromes [MDS]) using 8/8 or 7/8 matched related or unrelated donors and who were eligible for myeloablative conditioning (MAC).

Patients received MAC regimens prior to Orca-T, followed by GvHD prophylaxis with tacrolimus and mycophenolate mofetil in 7/8 matched donors and single-agent tacrolimus for 8/8 matched donors post-HSCT. Results for patients with 7/8 mismatched donors are reported below.

Results

The baseline demographics of patients with 7/8 mismatched donors (n = 8) encompassed non-white backgrounds, such as Asian and mixed-race heritage; some with high-risk diseases of measurable residual disease-positivity, as well as all non-permissive HLA-mismatches.

Initial results showed that neutrophil and platelet engraftment in transplant recipients occurred at a median of 12.5 days and 15.5 days, respectively. At Day 30 and Day 90 post-HSCT, full whole blood and donor T-cell chimerism >90% was observed across all patients. Moreover, analysis of serum plasma at Day 14 revealed higher log-fold levels of interleukin-2 and lower levels of interleukin-10 for 7/8 mismatched compared with the 8/8 matched cohort.

At a median follow-up of 426 days, clinical outcomes among the eight patients were as follows:

• One case of Grade 1–2 acute GvHD; no cases were Grade 3 or higher
• No severe chronic GvHD events, with one Grade 3+ infection observed
• Two events of disease relapse, with no non-relapse mortalities
• Overall survival (OS) rate of 100%

Orca-T in patients receiving allo-HSCT from 8/8 matched donors: 1-year relapse and GvHD outcomes²

Study design

This was an analysis of patients with 8/8 matched donors treated with Orca-T in a phase II single-center study (NCT01660607) and a multicenter phase Ib multicenter study (NCT04013685). Both trials included patients who were eligible for standard MAC and aged 18–65 years (phase Ib) or 18–72 years (phase II). The treatment schedule was similar to that above; using single-agent prophylaxis for 8/8 matched donors. For comparison purposes, a Center for International Blood & Marrow Transplant Research (CIBMTR)-based control cohort of patients receiving standard-of-care allo-HSCT with tacrolimus/methotrexate prophylaxis was used.

Results

At baseline, there were similar proportions of primary diseases (ALL, AML, and MDS), HLA-matched donors (unrelated and related), and conditioning regimens between the Orca-T cohort who had >100 days of follow-up (n = 151) and the CIBMTR control cohort (n = 375).

Compared with the CIBMTR cohort, patients treated with Orca-T demonstrated more favorable outcomes overall, with higher GvHD relapse-free survival (RFS) rates (70% vs 21%), lower non-relapse mortality (4% vs 10%), and higher overall survival (88% vs 68%). All patients within the Orca‑T cohort experienced engraftment, with a median time to neutrophil and platelet engraftment of 13 days and 19 days, respectively.

Moreover, treatment with the thiotepa, busulfan, and fludarabine (TBF) conditioning regimen was shown to further enhance clinical outcomes with Orca-T. There was a lower incidence of ALL in the Orca-T TBF cohort (n = 71) compared with the Orca-T cohort, but baseline characteristics overall (including very high-risk subgroups of patients with measurable residual disease positivity and active disease) were similar between the two arms.

Among the Orca-T TBF cohort, the efficacy and safety outcomes at a median follow-up of 413 days post-allo-HSCT were as follows:

• 1-year RFS of 87% and 1-year non-relapse mortalities of 0%
• Low incidence of severe (Grade 3+) infections (9%)
• Low incidence of Grade ≥3 acute (1.5%) and chronic GvHD (5%)
• 1-year GvHD RFS of 81% and 1-year OS rate of 94%

Conclusion

The early phase II trial of Orca-T in patients with 7/8 mismatched donors demonstrated encouraging results with no non-relapse mortality and high overall survival rates consistent with that seen in 8/8 matched donors. As such, it remains a promising regimen compared with current standards for myeloablative allo-HSCT with 7/8 mismatched donors, particularly for minority and disadvantaged groups; though further investigations are needed to establish its clinical efficacy in this setting.

The 1-year+ outcomes of Orca-T from the combined phase Ib multicenter and phase II single-center Orca-T trials showed graft-versus-leukemia and graft-versus-infection effects, low incidence of GvHD, and reduced treatment-related mortality and relapse in patients with matched donors for hematologic malignancies (acute leukemias and high-risk MDS), including those treated with TBF regimens. These data led to the initiation of the randomized controlled phase III trial comparing Orca-T with standard of care (NCT05316701).