Orca-Q Delivers Early Evidence of GVHD Risk Mitigation in Hematologic Malignancies

Orca-Q, an allogeneic T-cell immunotherapy, has been associated with rapid immune reconstitution and minimized graft-vs-host disease (GVHD) risk for patients with high-risk hematologic malignancies who underwent myeloablative conditioning for allogeneic hematopoietic stem cell transplant (allo-HSCT) prior to receiving Orca-Q with no GVHD prophylaxis. However, confirmatory studies are needed to expand on these findings, according to Amandeep Salhotra, MD.

An ongoing phase 1 trial (NCT03802695) is evaluating the efficacy and safety of the Orca-Q donor graft following receipt in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), or mixed phenotype acute leukemia.1

Early data from arm C of the trial, which were presented at the 2025 Transplant and Cellular Therapy Meetings, showed that among patients with high-risk hematologic malignancies who received myeloablative conditioning followed by Orca-Q (n = 14), the 1-year overall survival (OS) rate was 85% (95% CI, 52%-98%).2 This rate was 90% (95% CI, 47%-99%) among patients who received busulfan/fludarabine/thiotepa (BFT) conditioning (n = 11). The GVHD relapse-free survival (GRFS) rates in the overall population and the BFT subgroup were 77% and 90%, respectively.

“[Orca-Q is] a promising strategy going forward in patients, but a larger sample size needs to be tested, and studies are currently ongoing,” Salhotra said in an interview with OncLive®.

In the interview, Salhotra discussed the importance of developing graft manipulation strategies for GVHD prevention in patients with hematologic malignancies; the benefits and challenges associated with the use of standard post-transplant cyclophosphamide in this setting; early data that have demonstrated the anti-GVHD activity of post-transplant Orca-Q; and future goals for Orca-Q research.

Salhotra is an associate professor in the Division of Leukemia in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

OncLive: What are the benefits and limitations of the GVHD prevention strategies currently available for patients who do not receive immunosuppression following transplantation?

Salhotra: GVHD is a major complication post-allogeneic stem cell transplantation. With conventional pharmacological-based GVHD prophylaxis, approximately 40% of patients will develop acute GVHD, and the incidence of chronic GVHD is between 50% and 70%, based on the type of graft used, the type of GVHD prophylaxis, and the type of doner. Acute and chronic GVHD are associated with a lot of comorbidities in patients who undergo transplantation.

[We have a few] different platforms to prevent GVHD. The conventional standard of care [SOC] has been the combination of calcineurin inhibitors and methotrexate. Rapidly emerging—especially in the reduced-intensity setting—is post-transplant cyclophosphamide–based prophylaxis, which uses cyclophosphamide at 50 mg/kg on days 3 and 4, in combination with tacrolimus and mycophenolate mofetil starting on day 5 [following transplant]. In the phase 3 BMT CTN 1703 study [NCT03959241], patients who received GVHD prophylaxis with post-transplant cyclophosphamide [plus tacrolimus and mycophenolate mofetil] had a superior 1-year GRFS rate compared with patients who received tacrolimus plus methotrexate [with a GRFS] difference of 17.8%.3

[Post-transplant cyclophosphamide is] now becoming a SOC. However, with post-transplant cyclophosphamide–based prophylaxis, we worry about infections in patients. Patients who have cardiac dysfunction or a poor performance status tend to have difficulties with this regimen. Additionally, it’s hard to give older patients a full dose of cyclophosphamide. Delayed count recovery is also challenging. In the myeloablative setting, which was [the focus of] the phase 3 Progress II trial [NCT02345850], the post-transplant cyclophosphamide approach did not generate an improvement in OS compared with the current SOC.

What was the rationale for the development of Orca-Q?

Orca-Q is a balanced graft that reduces the T-cell subsets associated with chronic GVHD and preserves the cells responsible for graft-vs-leukemia and graft-vs-infection [effects]. The graft was developed to improve upon the pure CD34-selected graft that was used in the Progress II study. The ongoing Orca-Q trial is in [8] institutions. It is a multicenter, United States [US]–based study and involves the collection of peripheral blood stem cells from the donor. The graft is sent for processing at the Orca Bio facility in Sacramento, California, where it is manufactured and sent back to the transplant center. All patients who are eligible for this type of graft should receive pretransplant myeloablative conditioning, either with BFT or radiation-based transplant using fractionated total body irradiation [TBI].

What data have been seen with Orca-Q thus far?

In presentations at the 2024 ASH Annual Meeting by Mehrdad Abedi, MD, [of the University of California Davis Comprehensive Cancer Center in Sacramento] and by me at the 2025 Transplantation and Cellular Therapy Meetings. We reported on a subset of 14 patients who received myeloablative conditioning followed by the Orca-Q graft.2 Importantly, these patients did not receive GVHD prophylaxis after infusion of the graft. We have mature follow-up data of 1 year in these patients.

On long-term follow-up, there is no evidence of chronic GVHD of moderate-to-severe intensity in these patients. In the 3 patients who received TBI-based myeloablative conditioning, [1 experienced grade 3 acute] GVHD. However, in the patients who received chemotherapy/BFT-based conditioning, no [grade 3] acute GVHD was noted. One patient developed [secondary] graft failure in the radiation arm, and in the BFT arm, all the patients engrafted on time. The median neutrophil and platelet [engraftment times were both] 11 days [neutrophils, range, 10-15; platelets, range, 10-19].

What are the next steps for this study and research on Orca-Q?

The trial is currently ongoing and is continuing to accrue patients. It’s a 3-arm study. Arm A is a matched donor cohort in which [patients with] HLA-matched and [1-allele mismatched] related and unrelated donors were enrolled, and that arm is close to accrual. Arm B is equally exciting because it includes haploidentical patients, and we are excited that [Orca-Q allows the use] of a haploidentical graft without the use of post-transplant cyclophosphamide. If we can avoid the use of cyclophosphamide, get good engraftment, and [see] low acute and chronic GVHD, that would be a major advance in the field.

[Presented data from arm C include] a small set of 14 patients, so we need to expand those results in more patients, but hopefully we’ll get a larger sample size as the study completes. We’ll probably have more data from all 3 arms that will be presented at the next few meetings.

[Orca-Q] is a promising modality for the prevention of GVHD, and patients who are eligible for myeloablative conditioning are eligible for this type of transplant. The next step would be to [study] the safety and efficacy of the Orca-Q graft in the reduced-intensity or even the nonmyeloablative settings. Currently, the graft is available for patients with malignant diseases like AML, ALL, and high-risk MDS, but we’d like to try it in patients with nonmalignant conditions like thalassemia, sickle cell anemia, and aplastic anemia because these are the patients who tend to have higher [rates of] GVHD. We want to reduce the mortality and morbidity from GVHD in nonmalignant conditions.

Currently, [this study is] limited to patients who have a sibling donor, a haploidentical donor, or an unrelated donor within the US; international donors currently cannot participate in this study. We look forward to the continued enrollment of patients [to the Orca-Q trial], and we’ll share the results of the ongoing studies with the community. There’s more to come.

References

1. A phase 1 study of Orca-Q in recipients undergoing allogeneic transplantation for hematologic malignancies. ClinicalTrials.gov. Updated April 3, 2024. Accessed February 25, 2025. https://clinicaltrials.gov/study/NCT03802695
2. Salhotra A, Abedi M, Srour SA, et al. Preliminary safety and efficacy of myeloablative Orca-Q with no GvHD prophylaxis for treatment of advanced hematologic malignancies. Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract 136.
3. Bolaños-Meade J, Hamadani M, Wu J, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388(25):2338-2348. doi:10.1056/NEJMoa2215943