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Kilian M, Friedrich M, Sanghvi K, et al. T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas. Clin Cancer Res. 2021;doi: 10.1158/1078-0432.CCR-21-1881.
Kilian, M., Friedrich, M., Sanghvi, K., Green, E., Pusch, S., Kawauchi, D., Löwer, M., Sonner, J. K., Krämer, C., Zaman, J., Jung, S., Breckwoldt, M. O., Willimksy, G., Eichmüller, S. B., von Deimling, A., Wick, W., Sahm, F., Platten, M., & Bunse, L. (2021). T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas. Clinical cancer research : an official journal of the American Association for Cancer Research, . https://doi.org/10.1158/1078-0432.CCR-21-1881
Kilian, Michael, et al. "T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas." Clinical cancer research : an official journal of the American Association for Cancer Research vol. (2021). doi: https://doi.org/10.1158/1078-0432.CCR-21-1881
Kilian M, Friedrich M, Sanghvi K, Green E, Pusch S, Kawauchi D, Löwer M, Sonner JK, Krämer C, Zaman J, Jung S, Breckwoldt MO, Willimksy G, Eichmüller SB, von Deimling A, Wick W, Sahm F, Platten M, Bunse L. T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas. Clin Cancer Res. 2021 Nov 15; doi: 10.1158/1078-0432.CCR-21-1881. Epub 2021 Nov 15. PMID: 34782365.
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Clin Cancer Res. 2021 Nov 15; doi: 10.1158/1078-0432.CCR-21-1881. Epub 2021 Nov 15.

T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas.

Clinical cancer research : an official journal of the American Association for Cancer Research

Michael Kilian, Mirco Friedrich, Khwab Sanghvi, Edward Green, Stefan Pusch, Daisuke Kawauchi, Martin Löwer, Jana K Sonner, Christopher Krämer, Julia Zaman, Stefanie Jung, Michael O Breckwoldt, Gerald Willimksy, Stefan B Eichmüller, Andreas von Deimling, Wolfgang Wick, Felix Sahm, Michael Platten, Lukas Bunse

Affiliations

  1. DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  2. Department of Neurology, Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  3. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  4. DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  5. Department of Neuropathology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany.
  6. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  7. Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  8. TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Mainz, Germany.
  9. Department of Neuroradiology at the Neurology Center, Heidelberg University Hospital, Heidelberg, Germany.
  10. Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  11. German Cancer Research Center (DKFZ), Heidelberg, Germany.
  12. German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
  13. Research Group GMP & T Cell Therapy, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  14. Department of Neuro-oncology and National Center for Tumor Diseases, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany.
  15. DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  16. Helmholtz Institute for Translational Oncology (HI-TRON) Mainz, Mainz, Germany.
  17. DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].

PMID: 34782365 DOI: 10.1158/1078-0432.CCR-21-1881

Abstract

PURPOSE: Gliomas are intrinsic brain tumors with a high degree of constitutive and acquired resistance to standard therapeutic modalities such as radiotherapy and alkylating chemotherapy. Glioma subtypes are recognized by characteristic mutations. Some of these characteristic mutations have shown to generate immunogenic neoepitopes suitable for targeted immunotherapy.

EXPERIMENTAL DESIGN: Using peptide-based ELISpot assays, we screened for potential recurrent glioma neoepitopes in MHC-humanized mice. Following vaccination, droplet-based single-cell T-cell receptor (TCR) sequencing from established T-cell lines was applied for neoepitope-specific TCR discovery. Efficacy of intraventricular TCR-transgenic T-cell therapy was assessed in a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor-targeting guide RNAs.

RESULTS: We identify recurrent capicua transcriptional repressor (CIC) inactivating hotspot mutations at position 215 CICR215W/Q as immunogenic MHC class II (MHCII)-restricted neoepitopes. Vaccination of MHC-humanized mice resulted in the generation of robust MHCII-restricted mutation-specific T-cell responses against CICR215W/Q. Adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert antitumor responses against CICR215W-expressing syngeneic gliomas.

CONCLUSIONS: The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of human leukocyte antigen (HLA)-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T-cell adoptive therapy.

©2021 The Authors; Published by the American Association for Cancer Research.

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