A novel and efficient CD22 CAR-T therapy induced a robust antitumor effect in relapsed/refractory leukemia patients when combined with CD19 CAR-T treatment as a sequential therapy.

Abstract

BACKGROUND:

CD19 chimeric antigen receptor (CAR) therapy has achieved impressive success in relapsed or refractory (R/R) B-cell malignancies, but relapse due to antigen escape is increasingly appearing reported. As the expression profile of CD22 is similar to that of CD19, CD22 has become a candidate target when CD19 CAR-T therapy fails.

METHODS:

A novel CD22 CAR incorporating scFv derived from an HIB22 hybridoma which bound the first and second Ig-like extracellular domains of CD22 antigen was constructed. Preclinical investigation of the CD22 CAR-T therapy against B-cell malignancies was evaluated by coculturing CD22 CAR-T cells with tumor cell lines or primary blasts from patients in vitro and using a xenograft mouse model in vivo. Further clinical study of CD22/CD19 CAR-T sequential therapy was conducted in 4 R/R adult B-cell acute lymphoblastic leukemia (B-ALL) patients.

RESULTS:

The novel CD22 CAR-T treatment had specific cytotoxicity to CD22 + target cells, and the survival time of mice in the CD22 CAR-T treatment group was significantly prolonged. Furthermore, it's validated that sequential CD22/CD19 CAR-T therapy was significantly superior than single CD19 or CD22 CAR-T treatment in a relapse xenograft model. All 4 patients achieved complete remission (CR) with negative minimal residual disease (MRD), including 3 patients who had received prior CD19-related immunotherapy. The proliferation of CD19 and CD22 CAR-T cells was observed respectively in vivo, and 3 of the 4 patients experienced cytokine release syndrome (CRS); 2 of these patients had grade 1 CRS and 1 had grade 3 CRS. Long term follow-up showed that 3 of the 4 (75%) patients had sustained CR for up to 1 year. Analysis of antigen expression in the relapsed patients demonstrated that loss or diminution of CD19 and CD22 expression might cause antigen escape from CAR-T surveillance.

CONCLUSIONS:

In summary, the novel CD22 CAR-T therapy was validated with antitumor effects both in vitro and in vivo. Furthermore, our study demonstrated the safety and robust efficacy of sequential CD22/CD19 CAR-T therapy in xenograft models and clinical trials, especially as the salvage treatment for R/R B-ALL patients with antigen loss or in whom anti-CD19 related immunotherapy failure failed.

TRIAL REGISTRATION:

Chinese Clinical Trial Registry (ChiCTR): ChiCTR1900025419, Supplementarily registered 26 August, 2019.

• Authors: Yu Zhang, Saisai Li, Ying Wang, Yang Lu, Yingxi Xu, Qing Rao, Huijun Wang, Haiyan Xing, Zheng Tian, Kejing Tang, Lulu Lv, Min Wang, Jianxiang Wang
• Journal: Experimental hematology & oncology (Exp Hematol Oncol) Vol. 11 Issue 1 Pg. 15 (Mar 22 2022) ISSN: 2162-3619 [Print] England
• PMID: 35317863 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).