Orca-T Offers Favorable Post-Transplant Outcomes in Advanced Hematologic Malignancies

Amandeep Salhotra, MD

Ongoing research with Orca-T cell therapy continues to indicate that the regulatory T-cell enriched donor cell therapy is safe and offers favorable outcomes without significantly increasing non–relapse mortality (NRM) rates vs unmanipulated graft in patients with hematologic malignancies undergoing allogeneic transplant and myeloablative conditioning; this is particularly promising for elderly patients, for whom myeloablative conditioning was traditionally considered too risky, according to Amandeep Salhotra, MD.

Findings from a retrospective analysis presented at the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation revealed superior 1-year relapse-free survival (RFS) rates, NRM rates, and overall survival rates with Orca-T vs post-transplant cyclophosphamide (PTCy)–based myeloablative conditioning and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute leukemia or myelodysplastic syndrome (MDS; TABLE).¹

Additional interim data from a phase 1 study(NCT05088356) reported at the same meeting showed a 12-month relapse-free survival rate of 77% (95% CI, 49%-91%) with Orca-T plus reduced-intensity conditioning and tacrolimus (n = 20), indicating that it is a viable alternative to conventional transplant for patients with advanced hematologic malignancies.²

“This is important because we normally do not offer a myeloablative conditioning regimen to older patients,” Salhotra, who is an associate professor in the Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, at City of Hope in Duarte, California, said in an interview with OncLive.

Further research is needed to compare Orca-T with other transplant approaches and optimize post-transplant therapies to prevent complications like chronic graft-vs-host disease (cGVHD), Salhotra added in the interview. Meanwhile, research exploring novel or standard therapies and investigating T-cell repertoire dynamics post-transplant with PTCy could help inform strategies to prevent post-transplant complications, especially cGVHD, he noted.

In the interview, Salhotra discussed the early-phase data showing the efficacy and safety of Orca-T in patients undergoing reduced-intensity allogeneic transplant, expanded on retrospective data comparing outcomes with Orca-T and PTCy-based approaches, and highlighted continued efforts to optimize transplant outcomes by leveraging other agents and enhancing oncologists’ understanding of GVHD mechanisms.

OncLive: What early clinical data have demonstrated the efficacy and safety of Orca-T in patients with hematologic malignancies undergoing reduced-intensity allogeneic transplant?

Salhotra: Orca-T is a manipulated product where patients receive fixed doses of CD34 stem cells in combination with regulatory T cells on day 0 followed by conventional T cells a couple of days later. [Pooled] data from phase 1b [NCT04013685] and phase 2 [NCT01660607] trialshave been previously reported.³ This is a large data set of 375 patients who got unmanipulated graft compared with 151 patients [who received] Orca-T graft. Investigators looked at outcomes like 1-year GVHD RFS [GRFS] and OS, and the GRFS rate favored Orca-T. The 1-year GRFS rate in patients who received the Orca-T graft was 70% compared with 21% in the patients who got the unmanipulated graft. The benefit of this superior GRFS is that patients have a better quality of life, they do not have GVHD, and they have a superior RFS. That translates into better outcomes and OS in this subgroup of patients.

Some subset analyses were performed in this large subset of 151 patients who got the Orca-T graft [in the phase 2 and phase 1b trials]. These subsets [included] patients who [underwent] BFT conditioning, which is a combination of [intravenous] busulfan, fludarabine, and thiotepa. Patients who [received] this conditioning along with the Orca-T graft had a superior 1-year RFS rate of 81% and a 1-year OS rate of 94%.

What unmet needs still exist for elderly patients with hematologic malignancies undergoing allogeneic transplantation, and how might the use of Orca-T address them?

Based on recent data from the Center for International Blood and Marrow Transplant Research [CIBMTR], we know that most patients who develop acute myeloid leukemia [AML] tend to be above the age of 60 to 65. The median age [of patients diagnosed with AML] is 67, and AML remains the number 1 indication for allogeneic stem cell transplantation. [The question is whether] there is a way we can improve the outcomes of patients who undergo an allogeneic transplant in this subset of patients. Since these are older patients, are we able to give them a myeloablative conditioning regimen? That was what we wanted to study in this [older] subset.

These data were [previously] presented by my colleague Caspian Oliai, MD, MS, of UCLA Health, at the 2023 ASH Annual Meeting and Exposition. [The phase 1b study (NCT04013685)) included] approximately 25 patients above the age of 55 who got an Orca-T graft. The median age [in this patient population] was approximately 60 years old. Importantly, patients who were older did not display any NRM at the 1-year mark, and their OS was comparable with patients who were under the age of 55. The 1-year OS rate was approximately [96%] in patients who were older.

The benefit of a myeloablative conditioning regimen, as shown in phase 3 studies, is that it reduces the relapse rate. [However], NRM [rates often] prevent our older patients from benefitting from them. We can potentially improve the outcomes of these AML patients by using a backbone of myeloablative conditioning with the manipulated Orca-T graft.

What prior research informed your retrospective analysis of survival outcomes with Orca-T vs PTCy–based allo-HSCT following myeloablative conditioning in patients with acute leukemia or MDS?

[One of] the 2 major platforms that are emerging for the prevention of GVHD is PTCy. This was first developed at Johns Hopkins, where patients who underwent the haploidentical transplant received cyclophosphamide on days 3 and 4 at 50 mg/kg in addition to tacrolimus and mycophenolate mofetil. [PTCy was] initially evaluated in the haploidentical setting, but as the results came out it has been increasingly adopted for matched unrelated donors and mismatched unrelated donors. It has been very successful in terms of reducing the incidence of cGVHD compared with our current standard, which is tacrolimus and methotrexate.

There was also the subsequent [phase 2] PROGRESS I study [(NCT02208037) conducted by the] Blood and Marrow Transplant [BMT] Clinical Trials Network [BMT CTN] of patients who received myeloablative conditioning and got PTCy. In that study, PTCy did not seem to have a superior cGVHD [rate] and RFS compared with the current standard of care [SOC].

What did findings from this retrospective analysis indicate about the feasibility and safety of using Orca-T plus tacrolimus vs the PTCy-based approach for patients with matched unrelated donors? What were the study’s main limitations?

In the BMT field, there is great interest in seeing how the data for Orca-T compare with [that of] PTCy. That was [what I] presented in the retrospective review. [The retrospective study included] approximately 85 patients who were propensity matched compared with the Orca-T patients from the CIBMTR dataset. Most of these patients were unrelated donors. In the Orca-T [arm], there were approximately 111 patients with a mix of match-related and matched-unrelated donors. Almost all the patients received busulfan-based conditioning across both groups.

RFS was superior in the Orca-T [arm, at] approximately 77% vs 62% in the PTCy arm. We also noticed that in patients older than age of 55 who received PTCy, the NRM goes up. There was a survival benefit in patients who received the Orca-T graft vs those who received PTCy.

The drawback was that this is a retrospective study. We did not have minimal residual disease data from most of the patients, and the median age of the patients who received the Orca-T graft was a little bit lower than in the PTCy arm, at 49 as opposed to 52. We need a head-to-head trial, where we can compare the outcomes in a similar patient population between PTCy and the Orca-T graft.

Could you expand on research exploring the use of novel or standard therapies to ensure safe transplantation? How can these studies improve oncologists’ understanding and ability to prevent post-transplant complications when treating patients with cGVHD?

[Performing] transplant safely is very important, and preventing post-transplant complications is another important goal of transplant physicians. [There was the] randomized phase 1/2 [AGAVE-201 (NCT04710576)] study presented at the meeting [evaluating] axatilimab [SNDX-6352]. Three 3 doses were studied: 0.3 mg/kg every 2 weeks, 1 mg/kg every 2 weeks, and 3 mg/kg every 4 weeks. The 0.3 mg [dose] every 2 weeks was the most efficacious in patients with established cGVHD. The overall response rate [ORR] was approximately 74%, and patients with fibrotic organ involvement had good responses to treatment. This is one of the newer approaches [leveraging] axatilimab antibodies, [which] target the monocyte macrophage pathway. It’s a pathway that is different from the conventional [ones] that we target when managing GVHD, which [involve] T cells or B cells. That’s another important [approach] for us to [potentially use when] treating patients with cGVHD.

Another study that I thought was important was [the phase 3 BMT CTN 1703 and 1801 study (NCT03959241)] documenting how PTCy works in patients. This [featured] retrospective biospecimen collection data in patients [receiving] reduced intensity [conditioning allogeneic transplantation] and compared PTCy with tacrolimus and methotrexate. Leslie S. Kean, MD, PhD, of Dana-Farber Cancer Institute and Boston Children’s Hospital presented these data. She had blood samples of patients collected posttransplant at different time points. She wanted to see how the T-cell repertoire develops in patients following transplant. She showed that there is rapid decline in the T-cell repertoire after patients get PTCy, which leads to a very significant reduction in the T-cell clones by day 30. These clones subsequently expand and repopulate the immune system or reconstitute the immune system 6 months and 1 year later. Using sophisticated T-cell receptor clonotypes by adaptive biotechnology, [researchers] showed that the repertoire of T cells is limited in patients who get PTCy. That might to some extent explain why patients had more infectious complications in the BMT CTN 1703 study, as the grade 2 to 4 infection rates were a bit higher compared with patients who received tacrolimus and methotrexate in the comparator arm.

What do results from BMT CTN 1703 suggest about the use of PTCy? Is any other research underway to further elucidate the viability of this strategy?

[That study] gives us a mechanism to understand why patients have infectious complications after PTCy. It’s a very important strategy for us to reduce the incidence of cGVHD, and it’s certainly better than what we’ve been using traditionally, which is tacrolimus and methotrexate. Further refinement of how we use PTCy is important.

There are some important studies underway where we can potentially reduce the dose of cyclophosphamide. There’s the phase 2 OPTIMIZE study [NCT06001385], where the primary end point is to look at safety and whether we can safely reduce the dose of cyclophosphamide without affecting the incidence of cGVHD. In that trial patients will get a reduced dose of cyclophosphamide at 37.5 mg/kg in 2 days and that can go down to 25 mg/kg, to find the lowest dose of cyclophosphamide that would still be effective. Hopefully this would reduce the T-cell repertoire at day 30, allowing for the expansion or repopulation of the immune system with a much more diverse clone of cells, and [ensuring that] the graft-vs-leukemia and the graft-vs-infection immunity is preserved in patients.

Would you like to spotlight any additional research within the GVHD space?

I [also] presented a retrospective review on cGVHD. We repurposed an old drug called leflunomide [Arava] which is approved in rheumatoid arthritis. It’s a pyrimidine biosynthesis inhibitor [and functions] similarly to other drugs like methotrexate. This is an investigator-initiated, single-center study. The goal of the study was to use leflunomide at the approved oral dose of 20 mg daily in patients with moderate to severe cGVHD. We treated approximately 18 patients in this study, and we looked at the safety, efficacy, and adverse effect profile of the patients with cGVHD. The primary end point was ORR at the 6-month mark. Approximately 50% of patients experienced a response with the drug. It was safe, well tolerated, and most patients were able to complete the 6-month study duration period. Also, few patients elected to go on study beyond that.

[Leflunomide is] an important adjunct that can be added [to treatment approaches] for patients who are not responding to standard treatments or who have plateaued on currently approved drugs [such as] ruxolitinib [Jakafi]. This can be used as an add-on therapy. [Notably,] we found high response rates [with leflunomide] in patients with mucosal involvement; those patients tend to respond well. It’s available for physicians to use at the 20 mg dose per day, and we should be sharing our data and outcomes in a manuscript that will be published soon.

References

1. Salhotra A, Arteaga AG, Oliai C, et al. A retrospective analysis comparing Orca-T to post-transplant cyclophosphamide based allogeneic hematopoietic stem cell transplant in patients with matched unrelated donors receiving myeloablative conditioning. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract A107.
2. Villar-Prados A, Sutherland K, Negrin R, et al. Phase 1 trial results for patients with advanced hematological malignancies treated with Orca-T cell therapy with reduced intensity conditioning and single agent tacrolimus. Presented at: EBMT 50th Annual Meeting; April 14-17, 2024. Glasgow, Scotland. Abstract A121.
3. Oliai C, Pavlova A, Muffly L, et al. Precision-engineered cell therapy Orca-T demonstrates high relapse-free survival at 1 year while reducing graft-versus-host disease and toxicity. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 54.