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Overexpressing Bcl-2 enhances murine chimeric antigen receptor T cell therapy against solid tumor

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Abstract

Chimeric antigen receptor T (CART) cell therapy has demonstrated promising potential in the treatment of hematologic malignancies. However, its application to solid tumors is limited due to the restrictive nature of the tumor microenvironment, resulting in functional failure and poor persistence of CART cells. Overexpression of Bcl-2 in human CART cells (hCART) has been found to significantly enhance their anti-apoptotic effects both in vitro and in vivo. Nevertheless, the evaluation of hCART cells in preclinical studies has predominantly relied on immunodeficient mice xenograft tumor models, making it challenging to assess the impact of hCART cells on normal tissues and the immune system. We established a murine CART (mCART) that overexpresses Bcl-2 and targets the epidermal growth factor receptor variant III (EGFRvIII), named EGFRvIII·mCART-Bcl2. It demonstrated superior proliferation, cytotoxicity, and anti-apoptotic capabilities in vitro. In an immunocompetent mouse model of abdominal metastasis of colorectal cancer, EGFRvIII·mCART-Bcl2 exhibited improved survival of CART in the abdomen, increased tumor clearance, and significantly prolonged overall mouse survival. In summary, our study provides evidence that the introduction of Bcl-2 into mCART cells can enhance their therapeutic efficacy against solid tumors while ensuring safety.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article.

Abbreviations

CART:

Chimeric antigen receptor T cell

EGFRvIII:

Epidermal growth factor receptor variant III

Bcl-2:

B-cell lymphoma 2

ALL:

Acute lymphoblastic leukemia

Fluc:

Firefly luciferase

ConA:

Concanavalin

IL-2:

Interleukin 2

E:T:

Effector-to-target

ELISA:

Enzyme-linked immunosorbent assay

IFN-γ:

Interferon-γ

nATC:

None-transduced activated T cell

FACS:

Fluorescence activated cell sorting

HE:

Hematoxylin and eosin

TME:

Tumor microenvironment

GVHD:

Graft-versus-host disease

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Funding

This research was funded by by Suqian Sci & Tech Program Grant No. S202006 and K202014.

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Author notes

  1. Xiaoyan Wang, Guodong Liu and Xianggang Shi these authors have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Suqian First People’s Hospital, Suqian, 223800, Jiangsu, China

    Xiaoyan Wang, Yuxing Wang, Bo Jiang & Wei Liu

  2. Department of General Surgery, Suqian First People’s Hospital, Suqian, 223800, Jiangsu, China

    Guodong Liu

  3. School of Life Sciences, Jiangsu University, Zhenjiang, 212013, China

    Xianggang Shi, Anran Dai, Xiangzhi Zhang & Feng Yu

Authors
  1. Xiaoyan Wang
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  2. Guodong Liu
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  3. Xianggang Shi
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  4. Yuxing Wang
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  5. Bo Jiang
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  6. Wei Liu
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  8. Xiangzhi Zhang
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  9. Feng Yu
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Contributions

Feng Yu and Guodong Liu; methodology, Xiaoyan Wang and Yuxing Wang; validation, Yuxing Wang, Bo jiang; formal analysis, Anran Dai and Xiangzhi Zhang; investigation, Xianggang Shi, Anran Dai, Xiangzhi Zhang; resources, Yuxing Wang and Bo jiang; data curation, Bo jiang and Wei Liu; writing—original draft preparation, Guodong Liu, Xiaoyan Wang, Xianggang Shi; writing—major revision and reply, Xiaoyan Wang, Anran Dai, Xiangzhi Zhang; visualization, Guodong Liu and yuxing Wang; supervision, Feng Yu and Guodong Liu; project administration, Feng Yu; funding acquisition, supported by Suqian Sci&Tech Program Grant No. S202006 and Suqian Sci&Tech Program Grant No. K202014. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Xianggang Shi or Feng Yu.

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Cite this article

Wang, X., Liu, G., Shi, X. et al. Overexpressing Bcl-2 enhances murine chimeric antigen receptor T cell therapy against solid tumor. Human Cell (2024). https://doi.org/10.1007/s13577-024-01066-x

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  • DOI: https://doi.org/10.1007/s13577-024-01066-x

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