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Development of minimally invasive cancer immunotherapy using anti-disialoganglioside GD2 antibody-producing mesenchymal stem cells for a neuroblastoma mouse model

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Abstract

Purpose

Mouse IgG anti-disialoganglioside GD2 antibody-secreting mouse mesenchymal stem cells (anti-GD2-MSCs) were developed, and their anti-tumor effects were validated in an in vivo neuroblastoma mouse model.

Methods

Anti-GD2 antibody constructs were generated, incorporating FLAG-tagged single-chain fragment variables against GD2 fused to a linker sequence, and a fragment of a stationary portion was changed from human IgG to mouse IgG and GFP protein. The construct was lentivirally introduced into mouse MSCs. A syngeneic mouse model was established through the subcutaneous transplantation of a tumor tissue fragment from a TH-MYCN transgenic mouse, and the homing effects of anti-GD2-MSCs were validated by In vivo imaging system imaging. The syngeneic model was divided into three groups according to topical injection materials: anti-GD2-MSCs with IL-2, IL-2, and PBS. The tumors were removed, and natural killer (NK) cells were counted.

Results

Anti-GD2-MSCs showed homing effects in syngeneic models. The growth rate of subcutaneous tumors was significantly suppressed by anti-GD2-MSCs with IL-2 (p < 0.05). Subcutaneous tumor immunostaining showed an increased NK cell infiltration in the same group (p < 0.01).

Conclusion

Anti-GD2-MSCs using mouse IgG showed a homing effect and significant tumor growth suppression in syngeneic models. Anti-GD2-MSC-based cellular immunotherapy could be a novel therapeutic strategy for intractable neuroblastoma.

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Data availability statement

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to the member of the Department of Immunology, Kyoto Prefectural University of Medicine for useful comments. The English used in this manuscript was reviewed by enago.

Funding

This work was supported by a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT KAKENHI grant number 19H03719), and by the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED (grant number 20ck0106609h0001), and Funding for Research Projects, Children’s Cancer Association of Japan.

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Authors and Affiliations

  1. Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-Ku, Kyoto, 602-8566, Japan

    Kosuke Kambe, Masafumi Iguchi, Mayumi Higashi & Shigehisa Fumino

  2. Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Kosuke Kambe, Tsunao Kishida & Osam Mazda

  3. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Shigeki Yagyu

  4. Department of Pediatric Surgery, Reproductive and Developmental Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Tatsuro Tajiri

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  1. Kosuke Kambe
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Contributions

We are grateful to Dr. S. Yagyu for collaboration on many phases of this work. We thank M. Higashi and M. Iguchi for technical assistance with the experiments. Finally, we are grateful to the member of the Department of Immunology, Kyoto Prefectural University of Medicine for useful comments. All authors reviewed the manuscript.

Corresponding author

Correspondence to Kosuke Kambe.

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The authors declare no competing interests.

Conflict of interest

The authors declare no conflicts of interest in association with the present study.

Ethical approval

All experimental animal procedures and protocols conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Committee for Animal Research of Kyoto Prefectural University of Medicine.

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Kambe, K., Iguchi, M., Higashi, M. et al. Development of minimally invasive cancer immunotherapy using anti-disialoganglioside GD2 antibody-producing mesenchymal stem cells for a neuroblastoma mouse model. Pediatr Surg Int 39, 43 (2023). https://doi.org/10.1007/s00383-022-05310-z

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