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Fourth-generation chimeric antigen receptor T cells targeting folate receptor alpha antigen expressed on breast cancer cells for adoptive T cell therapy

  • Preclinical study
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Abstract

Purpose

Treatment of breast cancer (BC) by standard methods is effective in the early stage, but ineffective in the advanced stage of disease. To develop an adoptive T cell therapy for advanced and severe BC, we generated fourth-generation chimeric antigen receptor (CAR) T cells targeting folate receptor alpha antigen (FRα) expressed on BC cells, and preclinically evaluated their anti-BC activities.

Methods

The fourth-generation FRα-CAR T cells containing extracellular FRα-specific single-chain variable fragment (scFv) and three intracellular costimulatory domains (CD28, 4-1BB, and CD27) linked to CD3ζ were generated using a lentiviral system, and then were evaluated for their anti-BC activities in two-dimensional and three-dimensional (spheroid) cultures.

Results

When our fourth-generation FRα-CAR T cells were cocultured with FRα-expressing MDA-MB-231 BC cell line at an effector to target ratio of 20:1, these CAR T cells specifically lysed 88.7 ± 10.6% of the target cells. Interestingly, the cytotoxic lysis of FRα-CAR T cells was more pronounced in target cells with higher surface FRα expression. This specific cytotoxicity of the CAR T cells was not observed when cocultured with FRα-negative MCF10A normal breast-like cell line at the same ratio (34.3 ± 4.7%). When they were cocultured with MDA-MD-231 spheroid, the FRα-CAR T cells exhibited antitumor activity marked with spheroid size reduction and breakage.

Conclusion

This proof-of-concept study thus shows the feasibility of using these fourth-generation FRα-CAR T cells for adoptive T cell therapy in BC.

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Data availability

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

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Acknowledgements

We thank Miss Wannasiri Chiraphabpiboon and Miss Pucharee Songprakon for technical assistance; Professor Dr. Lung-Ji Chang, University of Florida, USA for insightful comments and suggestions; Professor Dr. Peter Hokland, Aarhus University, Denmark for critical reading of and providing comments on our manuscript; and, Kevin Jones for reading and editing the final version of the manuscript.

Funding

This work was financially supported by research grants from the Thailand Research Fund (TRF) (grant numbers: IRN58W0001 and IRN5801PHDW01), the Siriraj Research Fund, Faculty of Medicine Siriraj Hospital, Mahidol University (grant number: R016333030 and R016034008), and the Center of Excellence on Medical Biotechnology (CEMB), The S&T Postgraduate Education and Research Development Office (PERDO), The Commission on Higher Education (CHE), Thailand (grant number: CB-61–006-01). MJ, CT, and PY were also supported by Chalermphrakiat Grants from the Faculty of Medicine Siriraj Hospital, Mahidol University.

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Authors and Affiliations

  1. Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand

    Piriya Luangwattananun, Mutita Junking, Jatuporn Sujjitjoon, Yupanun Wutti-in, Chanitra Thuwajit & Pa-thai Yenchitsomanus

  2. Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol, University, Bangkok, 10700, Thailand

    Piriya Luangwattananun, Mutita Junking, Jatuporn Sujjitjoon & Pa-thai Yenchitsomanus

  3. Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand

    Yupanun Wutti-in

  4. Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand

    Naravat Poungvarin

  5. Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand

    Chanitra Thuwajit

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  1. Piriya Luangwattananun
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Contributions

PL conducted experiments, performed data collection and analysis, interpreted the results, and drafted the manuscript. YW partly assisted with experimental studies and data analysis. PL, MJ, JS, CT, and PY conceptualized, designed, and planned the experimental studies, interpreted data, and revised and edited the manuscript.

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Correspondence to Mutita Junking or Pa-thai Yenchitsomanus.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethical approval of this study was granted by Siriraj Institutional Review Board (SIRB) of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (COA no. Si 267/2020).

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Luangwattananun, P., Junking, M., Sujjitjoon, J. et al. Fourth-generation chimeric antigen receptor T cells targeting folate receptor alpha antigen expressed on breast cancer cells for adoptive T cell therapy. Breast Cancer Res Treat 186, 25–36 (2021). https://doi.org/10.1007/s10549-020-06032-3

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