Preliminary Safety and Efficacy of Myeloablative Orca-Q with No GvHD Prophylaxis for Treatment of Advanced Hematologic Malignancies

BACKGROUND

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative therapy for patients with advanced hematological malignancies. Conventional sources of stem cells contain T cells which promote graft versus leukemia (GvL) and graft versus infection (GvI), but also cause graft versus host disease (GvHD). Prevention of GvHD after alloHSCT routinely necessitates multi-agent immunosuppression consisting of either methotrexate or post-transplant cyclophosphamide (PTCy) combined with a calcineurin inhibitor and additional drugs. However, pharmacological immunosuppression results in poor immune reconstitution and increases the risks of organ damage, infection and disease relapse. Ex vivo pan T cell depletion (TCD) has been used to prevent GvHD without additional pharmacological control; however, the benefits are offset by increased infections and excess non-relapse mortality (NRM), as evidenced in BMT-CTN 1301. Orca-Q is a proprietary, precision engineered allogeneic T-cell immunotherapy designed to maximize GvL and GvI and to minimize GvHD. Here, we report the early clinical data using Orca-Q without any post-transplant pharmacological immunosuppression for GvHD prevention.

METHODS

Fourteen adult patients with high-risk hematologic malignancies eligible for myeloablative conditioning alloHSCT were enrolled on the HLA-identical donor dose expansion arm of a multicenter phase 1 study of Orca-Q (NCT03802695). HLA-identical donors were defined as related (n=7) or unrelated (n=7) donors with 8/8 match at HLA-A, -B, -C, and -DRB1 using high-resolution DNA typing. Orca-Q was centrally manufactured at the Orca Bio manufacturing site from G-CSF mobilized peripheral blood apheresis. Patients received no pharmacological GvHD prophylaxis. GvHD-free, relapse-free survival (GRFS) was defined as the time from transplant to the first occurrence of any of these events: grade 3-4 acute GvHD (aGvHD), moderate to severe chronic GvHD (cGvHD), disease relapse or death from any cause.

RESULTS

Orca-Q was successfully manufactured and administered to all recipients with a vein-to-vein time of less than 72 hours. As of July 11, 2024, a total of 14 patients with hematological malignancies had been treated (7 acute myeloid leukemia, 2 acute lymphocytic leukemia, 2 chronic myeloid leukemia, 3 myelofibrosis). Median age was 58.5 years (range 20-65 years), 54% of the patients were male and median follow-up was 21 months (range 1 -35 months). All patients received myeloablative conditioning, either busulfan/fludarabine/thiotepa (BFT; n=11) or total body irradiation-based (TBI; n=3).

All patients engrafted with donor cells and the median time for both neutrophil and platelet engraftment was 11 days (range 10-15 days and 10-19 days, respectively). One patient received TBI/etoposide and experienced grade 3 aGvHD that was treated to resolution. This patient subsequently developed secondary graft loss and, as of last follow-up, is still alive without disease relapse. Amongst the others, two had grade 2 aGvHD, one developed mild cGvHD, and none were reported with moderate or severe cGvHD. Two patients experienced a MOP grade 2 infection and one other experienced a MOP grade 3 infection. There were no instances of NRM among the study participants. Within the first year, 2 patients relapsed and died. At 1 year, the actuarial overall survival (OS) and RFS were both 85%, and GRFS was 77%.

BFT conditioning has shown promising disease control with Orca-T (Salhotra et al. 2023). Of the 11 Orca-Q patients who received BFT with no GvHD prophylaxis, only 2 had grade 2 aGvHD, none had grade 3 aGvHD, none had chronic GvHD (any grade), and one died from disease relapse at 1 year. The actuarial OS, RFS and GRFS were 90% at 1 year in the BFT subgroup.

CONCLUSIONS

The administration of Orca-Q without post-transplant pharmacological GvHD prophylaxis has shown promising clinical outcomes at the 1-year follow-up. Orca-Q offers similar benefits as TCD approaches, but without the compromises typically observed with TCD. Specifically, Orca-Q demonstrated low rates of GvHD and rare serious infections, and no NRM was reported. Orca-Q may provide a bridge to immunocompetency and also separate harmful GvHD alloreactivity from beneficial GvT alloreactivity. Disease control may be further augmented by BFT conditioning. The Orca-Q Phase 1 study continues to enroll patients across the US.