Sleeping Beauty Engineered CAR-T Therapy CARCIK-CD19 Demonstrates Safety and Anti-Leukemia Activity in R/R B-ALL

Chiara F. Magnani, PhD

CARCIK-CD19, an investigational allogeneic chimeric antigen-receptor T-cell (CAR-T) therapy, demonstrated safety and antileukemia activity in patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), according to recently presented study findings. The data, from 21 patients treated in the phase 1/2 CARCIK clinical trial (NCT03389035) and 6 patients treated in a compassionate-use study, were presented at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California.

CARCIK-CD19 consists of cytokine induced killer (CIK) cells that have been engineered with Sleeping Beauty transposon to target CD19. Among all the patients from CARCIK and the compassionate-use study included in the data analysis (n = 27), 18 patients (66.7%; 95% CI, 46.0-83.5) achieved a complete response (CR). Furthermore, among the 21 patients who received the 2 highest doses, 16 achieved a CR (76.2%; 95% CI, 52.8-91.8), with 81.3% being minimal-residual disease (MRD)-negative.

Among all patients, the overall survival was 71.4%(SE, 11.6) and the event-free survival was 41.5% (SE, 9.9) with a median follow-up of 2.8 years. For the 16 patients treated at the high dose who achieved a CR, the median duration of response (DOR) was 9.5 months. The DOR at 6 months was 54.4% (SE, 13.8).

“Robust CAR T-cell expansion was achieved in most patients and CAR T-cells were measurable for up to 27 months, in association with B-cell aplasia,” first author Chiara F. Magnani, PhD, an assistant professor in the Department of Medical Oncology and Hematology at the University of Zurich, and colleagues wrote. “Integration site analysis of the patient's peripheral blood demonstrated highly polyclonal marking. No signs of genotoxicity by transposon insertions could be observed.”

In terms of safety, 9 patients experienced cases of cytokine release syndrome (CRS) and 2 patients experienced cases of immune effector cell-associated neurotoxicity syndrome (ICANS). The CRS cases were grade 1 (n = 4) and grade 2 (n = 5) whereas both ICANS cases were grade 3. Four patients were administered tocilizumab. No cases of graft versus host disease (GvHD) were reported following treatment with CARCIK-CD19 despite the fact that 10 of the 27 patients had previously experienced GvHD following prior treatment with allogeneic hematopoietic stem cell transplantation (allo-SCT). Magnani and colleagues noted that 2 of 27 patients treated with CARCIK-CD19 experienced Grade 1 to 2 infections and 7 of 27 patients experienced Grade 3 or higher infections. In addition, 8 of 16 patients had cases of cytopenia that were persistent at 3 months post treatment.

The ages of the 27 treated patients ranged from 1 to 67 years (median, 38). The group included 4 children and 23 adults. Fourteen of the patients were female and 13 were male. The patient population was heavily pretreated, with the number of prior therapies ranging from 2 to 8 (median, 4). All patients had previously received at least 1 line of prior allo-SCT and 9 of the patients had received 2 prior lines of allo-SCT. Patients received lymphodepletion with fludarabine and cyclophosphamide prior to CARCIK-CD19 administration; bridging therapy was allowed. 

CARCIK-CD19 was administered to the first 9 patients in the trial at doses of 1x10⁶ cells/kg, 3x10⁶ cells/kg, and 7.5x10⁶ cells/kg. Because no dose-limiting toxicity was observed in the dose-escalation, the other 18 patients received 15x10⁶ cells/kg. Manufacturing of CARCIK-CD19 was successful for all 27 patients. The sources of the cells used in manufacturing included HLA-identical siblings, matched unrelated donors, and haploidentical donors. Magnani and colleagues noted that the donor type did not affect whether patients achieved a CR. They concluded that the nonviral manufacturing approach used for CARCIK-CD19 is “simple and effective” and that CARCIK-CD19 has an “excellent safety profile."

REFERENCE
1. Magnani CF, Lussana F, Gritti G, et al. Phase I/II trials with sleeping beauty engineered CAR T-cells of donor origin for B-cell acute lymphoblastic leukemia. Presented at: American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting. May 16-20, 2023; Los Angeles, CA. Poster #1206