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Orca-T plus allogeneic CAR T-cell therapy may represent a rational treatment approach in high-risk B-cell malignancies.
A treatment strategy comprising allogeneic CAR T-cell therapy and hematopoietic stem cell transplant (HSCT) using Orca-T and CD19- and CD22-directed CAR T-cell therapy may represent an approach for patients with high-risk B-cell malignancies, according to data from a phase 1 trial (NCT05507827) presented at the
Findings demonstrated that in patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) who were candidates for myeloablative conditioning (n = 16), no disease-free survival (DFS) or overall survival (OS) events were reported at a median follow-up of 473 days (range, 214-1180).
Regarding safety, grade 1 acute graft-vs-host disease (GVHD) occurred in 6% of patients (n = 1), and mild chronic GVHD and moderate chronic GVHD were each reported in 6% of patients (n = 1 each). The rates of grade 1 and grade 2 cytokine release syndrome were 81% and 19%, respectively, and 6% of patients experienced grade 1 immune effector cell–associated neurotoxicity syndrome. Veno-occlusive disease was reported in 6% of patients.
“[Allogeneic CAR T-cell therapy and HSCT] is a rational approach that merits further investigation in high-risk B-cell malignancies,” lead study author Alfonso Molina, MD, MPH, said in a presentation of the data.
Molina is a hematology and medical oncology fellow at Stanford University in California.
Molina explained that patients with high-risk, relapsed/refractory B-ALL often require HSCT as consolidative treatment following CAR T-cell therapy in order to achieve long-term remission, and investigators have explored an all-in-one approach combining the modalities.
In a prior phase 1 trial (NCT03233854), an autologous CD19/22-directed CAR T-cell therapy was evaluated in adult patients with relapsed/refractory B-ALL and large B-cell lymphoma.2 Data from this study showed that patients with B-ALL (n = 17) experienced an overall response rate of 100% and a minimal residual disease (MRD)–negative complete response (CR) rate of 88%.
In the phase 1 trial presented at ASH 2025, investigators combined Orca-T with an allogenic CAR T-cell therapy.1 Orca-T is an allogeneic T-cell immunotherapy, and a biologics license application seeking the approval of the agent for patients with patients with hematologic malignancies, including acute myeloid leukemia, ALL, and myelodysplastic syndromes,
Investigators enrolled patients at least 18 years of age with high-risk B-ALL who were candidates for myeloablative conditioning.1 Patients needed to have 8/8 HLA matched donors who were siblings or domestic unrelated donors.
Apheresis was conducted on donor T-cells to manufacture the CD19/22 CAR T-cell therapy, which was given at doses of 1 x 106 KG, 2 x 106 KG, or 3 x 106 kg. From day –8 to –2, patients underwent myeloablative conditioning with total body irradiation (TBI) plus cyclophosphamide, or busulfan plus fludarabine and thiotepa (BFT). During this time, donors underwent granulate colony stimulating factor mobilization and hematopoietic stem and progenitor cell (HSPC) apheresis for the manufacturing of Orca-T. Patients were then infused with HSPCs and regulatory T cells on day 0; conventional T cells and CAR T-cell therapy on day 2; and tacrolimus on day 3.
The study’s primary end point was safety at day 42.
Investigators enrolled 18 patients, and successful Orca-T and donor CD19/22 CAR T-cell therapy manufacturing was complete for 17 patients; 1 patient discontinued the study due to infectious complications. Sixteen patients ultimately received Orca-T and CAR T-cell therapy, with 1 patient not receiving CAR T-cell therapy due to an active infection.
The 17-patient population had a median age of 31 years (range, 21-58), 53% of patients were female, and 70% of patients were Hispanic. High-risk features in this population including Philadelphia chromosome (Ph)–positive disease (35%), Ph-like disease (18%), KMT2A or MLL rearrangements (12%), TP53 mutations (12%), complex karyotype (12%), MRD-positive disease after induction therapy (76%), and relapsed/refractory disease (47%). Prior therapies included blinatumomab (Blincyto; 76%) and inotuzumab ozogamicin (Besponsa).
At the time of HSCT, 53% of patients were in MRD-negative CR, 41% were in MRD-positive CR, and 6% had active disease. Seventy-six percent of patients had a matched sibling donor, and 24% had matched unrelated donors. Myeloablative conditioning regimens included TBI plus cyclophosphamide (88%) and BFT (12%).
During the presentation, Molina also shared data comparing CAR T-cell persistence between the allogenic CAR T-cell therapy in this phase 1 trial vs the autologous agent utilized in the prior phase 1 study.
He explained that the autologous and allogeneic product yielded CAR T-cell expansion, although the allogenic product was associated with longer mean persistence. He also noted that safety outcomes between the 2 approaches were similar.
“Our next steps include performing correlative analyses to determine if outcomes differences may link to underlying immune differences associated with the Orca-T product,” Molina concluded.
Disclosures: Molina did not report any financial conflicts of interest.
