T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas
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T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas. / Kilian, Michael; Friedrich, Mirco; Sanghvi, Khwab; Green, Edward; Pusch, Stefan; Kawauchi, Daisuke; Löwer, Martin; Sonner, Jana K; Krämer, Christopher; Zaman, Julia; Jung, Stefanie; Breckwoldt, Michael O; Willimksy, Gerald; Eichmüller, Stefan B; von Deimling, Andreas; Wick, Wolfgang; Sahm, Felix; Platten, Michael; Bunse, Lukas.
in: CLIN CANCER RES, Jahrgang 28, Nr. 2, 15.01.2022, S. 378-389.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas
AU - Kilian, Michael
AU - Friedrich, Mirco
AU - Sanghvi, Khwab
AU - Green, Edward
AU - Pusch, Stefan
AU - Kawauchi, Daisuke
AU - Löwer, Martin
AU - Sonner, Jana K
AU - Krämer, Christopher
AU - Zaman, Julia
AU - Jung, Stefanie
AU - Breckwoldt, Michael O
AU - Willimksy, Gerald
AU - Eichmüller, Stefan B
AU - von Deimling, Andreas
AU - Wick, Wolfgang
AU - Sahm, Felix
AU - Platten, Michael
AU - Bunse, Lukas
PY - 2022/1/15
Y1 - 2022/1/15
N2 - 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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-21-1881
DO - 10.1158/1078-0432.CCR-21-1881
M3 - SCORING: Journal article
C2 - 34782365
VL - 28
SP - 378
EP - 389
JO - CLIN CANCER RES
JF - CLIN CANCER RES
SN - 1078-0432
IS - 2
ER -