CRISPR/Cas9-Engineered Universal CD19/CD22 Dual-Targeted CAR-T Cell Therapy for Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia.

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 10 Pg. 2764-2772 (05 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33627493 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antigens, CD19
• CD22 protein, human
• Receptors, Chimeric Antigen
• Sialic Acid Binding Ig-like Lectin 2

Topics

• Adult
• Antigens, CD19 (immunology)
• CRISPR-Cas Systems
• Drug Resistance, Neoplasm
• Female
• Gene Editing
• Genetic Engineering
• Humans
• Immunotherapy, Adoptive (methods)
• Male
• Middle Aged
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (diagnosis, etiology, metabolism, therapy)
• Receptors, Chimeric Antigen (genetics, immunology)
• Recurrence
• Sialic Acid Binding Ig-like Lectin 2 (immunology)
• T-Lymphocytes (immunology, metabolism)
• Treatment Outcome