Yongxian Hu; Yali Zhou; Mingming Zhang; Wengang Ge; Yi Li; Li Yang; Guoqing Wei; Lu Han; Hao Wang; Shuhui Yu; Yi Chen; Yanbin Wang; Xiaohong He; Xingwang Zhang; Ming Gao; Jingjing Yang; Xiuju Li; Jiangtao Ren; He Huang · 2021 · Clinical Cancer Research
Paper
Abstract Purpose: Autologous chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed/refractory acute lymphoblastic leukemia (r/r ALL). However, certain characteristics of autologous CAR-T cells can delay treatment availability. Relapse caused by antigen escape after single-targeted CAR-T therapy is another issue. Therefore, we aim to develop CRISPR-edited universal off-the-shelf CD19/CD22 dual-targeted CAR-T cells as a novel therapy for r/r ALL. Patients and Methods: In this open-label dose-escalation phase I study, universal CD19/CD22-targeting CAR-T cells (CTA101) with a CRISPR/Cas9-disrupted TRAC region and CD52 gene to avoid host immune-mediated rejection were infused in patients with r/r ALL. Safety, efficacy, and CTA101 cellular kinetics were evaluated. Results: CRISPR/Cas9 technology mediated highly efficient, high-fidelity gene editing and production of universal CAR-T cells. No gene editing–associated genotoxicity or chromosomal translocation was observed. Six patients received CTA101 infusions at doses of 1 (3 patients) and 3 (3 patients) × 106 CAR+ T cells/kg body weight. Cytokine release syndrome occurred in all patients. No dose-limiting toxicity, GvHD, neurotoxicity, or genome editing–associated adverse events have occurred to date. The complete remission (CR) rate was 83.3% on day 28 after CTA101 infusion. With a median follow-up of 4.3 months, 3 of the 5 patients who achieved CR or CR with incomplete hematologic recovery (CR/CRi) remained minimal residual disease (MRD) negative. Conclusions: CRISPR/Cas9-engineered universal CD19/CD22 CAR-T cells exhibited a manageable safety profile and prominent antileukemia activity. Universal dual-targeted CAR-T cell therapy may offer an alternative therapy for patients with r/r ALL.
Analysis
This study investigates the safety and efficacy of CRISPR/Cas9-engineered universal CD19/CD22 dual-targeted CAR-T cells (CTA101) for treating relapsed/refractory B-cell acute lymphoblastic leukemia (r/r ALL).
Discovery
Ortiz-Bueno M; Millán-López A; Labun K; Benabdellah K
Wu T; Lv B; Wang H; He G; Fu Y; Ji X; Zeng Y; Ni D; Qiu J; Hua K
Dmitry Sinelshchikov; Nikols Amaru Mora Millán; Miguel Perales-Patón; Juan Belmonte-Beitia; Matteo Italia
Xudong Wang; Jin Zhang
Deividas Pažėraitis; J. Kupčinskas
Chaurasiya S; Kim SI; Sah P; Zhang Z; Vashi Y; Wu H; Cillis J; Park A; Yang A; Woo Y; Xiong G; Liu J; Zhang H; Wang P; Liu C; Fong Y
Source record