Orca-T With Allogeneic CAR T-Cell Therapy Is Safe and Effective in High-Risk B-ALL

Orca-T plus allogeneic CD19/CD22-directed CAR T cell therapy was deemed safe and generated durable responses in adult patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to findings from a phase 1 trial (NCT05507827), which were presented at the 2026 Transplantation and Cellular Therapy Meetings.¹

Regarding safety, among 16 evaluable patients, the median time to platelet engraftment was 15 days (range, 12-33), and the median time to neutrophil engraftment was 13 days (range, 10-20). No patients experienced primary graft failure. Acute graft-vs-host disease (aGVHD) was reported in 1 patient; chronic GVHD (cGVHD) at mild and moderate levels was reported in 1 patient each. All 3 GVHD cases resolved. Grade 1 cytokine release syndrome (CRS) was observed in 13 patients, and grade 2 CRS was seen in 3 patients. One patient developed immune effector cell–associated neurotoxicity syndrome, and 1 patient had veno-occlusive disease but subsequently recovered their liver function.

In terms of efficacy, no patients relapsed. Additionally, at a median follow-up of 473 days (range, 214-1180), all patients remained alive.

“Twelve of our patients have follow-up beyond 1 year, and 2 patients have 3 years of follow-up,” Alfonso Molina, MD, MPH, said in a presentation of the data. “We believe that adoptive cell therapy is a rational approach that merits further investigation in high-risk B-cell malignancies.”

Molina is a hematology and medical oncology fellow at the Stanford University School of Medicine in Palo Alto, California.

What is the rationale for augmenting responses with CD19-directed CAR T-cell therapy in B-ALL?

Molina noted that autologous CD19-directed CAR T-cell therapy has yielded limited durable response rates in patients with B-ALL. For instance, in the single-arm, phase 1/2 ZUMA-3 trial (NCT02614066), findings from which supported the FDA approval of brexucabtagene autoleucel (brexu-cel; Tecartus) for the treatment of patients with relapsed/refractory B-ALL, the median duration of response (DOR) with brexu-cel among patients with complete response (CR)/CR with incomplete count recovery (CRi; n = 39) when censored at subsequent allogeneic stem cell transplant was 12.8 months (95% CI, 9.4-23.6).² In this trial, 42% of patients had received hematopoietic cell transplant (HCT) prior to brexu-cel, and 18% of patients received HCT following brexu-cel.

Additionally, in the phase 1b/2 FELIX trial (NCT04404660), data from which led to the FDA approval of obecabtagene autoleucel (obe-cel; Aucatzyl) for the treatment of adult patients with relapsed/refractory B-cell precursor ALL, at a median follow-up of 21.5 months (range, 8.6-41.4), 40% of patients who achieved CR or CRi with obe-cel (n = 99) were in ongoing remission without subsequent stem cell transplant or other therapy.³ In this trial, 44.1% of patients in the total population (n = 127) had received HCT prior to obe-cel, and 18% of patients received HCT following obe-cel.

“In these trials, we learned that overall, CAR T[-cell therapy] has good overall response rates [ORRs], and it’s good at clearing minimal residual disease [MRD],” Molina contextualized. “However…the DOR [was] only approximately 12 months [in ZUMA-3]. [Additionally], approximately 60% of [these] adult patients received an allogeneic transplant at some point during their treatment course.”

Molina added that the use of Orca-T engineered grafts in patients with hematologic malignancies is associated with relatively low rates of aGVHD and cGVHD. He also described the efficacy of an autologous CD19/CD22-directed bispecific CAR T-cell therapy, which, in a phase 1 trial (NCT03233854) in adult patients with relapsed/refractory B-cell malignancies, led to an ORR of 100%, including an 88% MRD-negative CR rate.⁴

“However, durable remission [with this CAR T-cell therapy] continues to be an issue,” according to Molina. “Based on these clinical outcomes and preclinical data, we questioned whether administering donor-derived allogeneic CAR T cells after Orca-T would enhance graft-vs-leukemia [effects] and prolong durable remission.”

What was the design of the phase 1 trial of Orca-T plus CAR T-cell therapy in B-ALL?

The current phase 1 trial enrolled patients at least 18 years of age with high-risk B-ALL who were eligible to receive myeloablative conditioning.¹ Eligible donor types included HLA 8/8 sibling or domestic unrelated donors.

Prior to receiving granulocyte colony–stimulating factor (G-CSF), donors underwent T-cell apheresis, which was used for CAR19-22 T-cell manufacturing at dose levels of 1 x 10⁶/kg, 2 x 10⁶/kg, or 3 x 10⁶/kg. On days –8 to –2, patients underwent myeloablative conditioning with total body irradiation (TBI) and cyclophosphamide, or busulfan, fludarabine, and thiotepa; donors received G-CSF and underwent mobilized hematopoietic progenitor cell apheresis; Orca-T manufacturing then commenced. On day 0, patients underwent hematopoietic stem cell transplant plus regulatory T-cell infusions. On day 2, patients received conventional T cells plus CAR T-cell infusions, followed by tacrolimus (Prograf) on day 3. The primary safety end point was evaluated on day 42.

In total, 16 patients received adoptive cell therapy in this trial. Eighteen patients were enrolled, 1 of whom discontinued the study due to infectious complications. Seventeen patients successfully manufactured Orca-T and donor CD19/CD22-directed CAR T-cell therapy, 1 of whom did not receive the CAR T-cell therapy due to an active infection. The remaining 16 patients received therapy as planned.

Among the 17 patients with successfully manufactured Orca-T and CAR T cells, the median age was 31 years (range, 21-58), and most were female (53%) and Hispanic (70%). High-risk features, of which patients could have more than 1, included Philadelphia chromosome (Ph)–positive disease (35%), Ph-like disease (18%), KMT2A or MLL rearrangements (12%), TP53 abnormalities (12%), complex karyotype (12%), MRD-positive disease post-induction (76%), and relapsed/refractory disease (47%). Prior therapies received included blinatumomab (Blincyto; 76%) and inotuzumab (Besponsa; 12%). ALL statuses at the time of HCT included CR with MRD-negative disease (53%), CR with MRD-positive disease (41%), and active disease (6%). Donor types included matched sibling (76%) and matched unrelated (24%). Conditioning regimens included fractionated TBI plus cyclophosphamide (88%) and fludarabine plus busulfan and thiotepa (12%).

What additional findings were seen with Orca-T plus CD19/CD22-directed CAR T-cell therapy in B-ALL?

The MRD negativity rate by flow cytometry and BCR-ABL1 reached 100%. Of the 2 patients who remained MRD-positive by clonoSEQ, the MRD negativity levels were decreasing as of the most recent trial assessment.

Allogeneic CAR T-cell persistence by PCR was also observed beyond 100 days.

“The CAR T[-cell] persistence was especially notable given that patients were on tacrolimus for a mean of 177 days,” Molina noted.

Additionally, patients maintained the target tacrolimus level of 5 to 7 ng/mL during the first 90 days of treatment, after which tacrolimus dosing was tapered off.

As of the data cutoff date, 13 of the 16 treated patients had persistent B-cell aplasia.

Although levels of T-cell subsets were low in the early days following adoptive cell therapy, which Molina noted was expected, significant immune reconstitution following Orca-T plus CAR T-cell therapy infusion occurred around day 90. Additionally, no patients experienced prolonged cytopenias, and the investigators observed prompt donor chimerism.

“Our next steps are performing correlative analyses to determine if outcome differences are linked to underlying immune differences there may be associated with the Orca-T graft,” Molina concluded.

Disclosures: Molina had no disclosures.

References

1. Molina A, Shiraz P, Kanegai A, et al. Mature outcomes from the phase I trial of Orca-T and allogeneic CD19/CD22 CAR-T cells for adults with high-risk B-ALL. Presented at: 2026 Transplantation & Cellular Therapy Meetings. February 4-7, 2026. Salt Lake City, Utah. Abstract 31.
2. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8
3. Jabbour E, Tholouli E, Sandhu KS, et al. Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study. J Clin Oncol. 2024;42(suppl 16):6504. doi:10.1200/JCO.2024.42.16_suppl.6504
4. Spiegel JY, Patel S, Muffly L, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021;27(8):1419-1431. doi:10.1038/s41591-021-01436-0