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Exploratory study on the efficacy of bortezomib combining mitoxantrone or CD22-CAR T therapy targeting CD19-negative relapse after CD19-CAR T cell therapy with a simpler cell-line-based model

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Abstract

Target-negative relapse after CD19 chimeric antigen receptor engineered (CAR) T cell therapy for patients with B lineage acute lymphoblastic leukemia (B-ALL) presents limited treatment options with dismal outcomes. Although CD22-CAR T cells mediate similarly potent antineoplastic effects in patients with CD19dim or even CD19-negative relapse following CD19-directed immunotherapy, a high rate of relapse associated with diminished CD22 cell surface expression has also been observed. Therefore, it is unclear whether any other therapeutic options are available. Mitoxantrone has shown significant antineoplastic activity in patients with relapsed or refractory leukemia over the past decades, and in some cases, the addition of bortezomib to conventional chemotherapeutic agents has demonstrated improved response rates. However, whether this mitoxantrone and bortezomib combination therapy is effective for those patients who have relapsed B-ALL after receiving CD19-CAR T cell therapy remains to be elucidated. In this study, we established a cellular model system using a CD19-positive B-ALL cell line Nalm-6 to investigate the treatment options for CD19-negative relapsed B-ALL after CD19-CAR T cell therapy. In addition to CD22-CAR T therapy, we observed that the combination of bortezomib and mitoxantrone exhibited effective anti-leukemia activity in the CD19-negative Nalm-6 cell line by downregulating p-AKT and p-mTOR. These results suggest that this combination therapy is a possible option for target-negative refractory leukemia cells after CAR-T cell treatment.

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Funding

This work was supported in part by grants from the National Natural Science Foundation of China (grant nos. 81770202 and 81470304), Key Project from Science and Technology Department of Zhejiang Province (grant no:2019C03032), Pediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province (No. JBZX-201904). and the Zhejiang Medical and Health Science and Technology Plan Project (2022KY868).

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  1. Diandian Ba and Hongzhe Li contributed equally to this work.

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  1. Department/Center of Hematology-oncology, Pediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province, Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, #57 Zhuganxiang Road, Yan-an Street, Hangzhou, 310003, PR China

    Diandian Ba, Hongzhe Li, Rongrong Liu, Ping Zhang & Yongmin Tang

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Diandian Ba, Hongzhe Li, Rongrong Liu ,and Ping Zhang performed the experiments. Diandian Ba and Hongzhe Li analyzed the data. Diandian Ba and Yongmin Tang wrote and revised the manuscript. All authors have contributed to the manuscript, reviewed the manuscript and approved the submitted version.

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Correspondence to Yongmin Tang.

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Ba, D., Li, H., Liu, R. et al. Exploratory study on the efficacy of bortezomib combining mitoxantrone or CD22-CAR T therapy targeting CD19-negative relapse after CD19-CAR T cell therapy with a simpler cell-line-based model. Apoptosis 28, 1534–1545 (2023). https://doi.org/10.1007/s10495-023-01853-1

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