PMID- 34782365
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20230106
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 28
IP  - 2
DP  - 2022 Jan 15
TI  - T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in 
      Experimental Gliomas.
PG  - 378-389
LID - 10.1158/1078-0432.CCR-21-1881 [doi]
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.
CI  - (c)2021 The Authors; Published by the American Association for Cancer Research.
FAU - Kilian, Michael
AU  - Kilian M
AUID- ORCID: 0000-0002-1946-3174
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Neurology, Mannheim Center for Translational Neuroscience (MCTN), 
      Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
FAU - Friedrich, Mirco
AU  - Friedrich M
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Neurology, Mannheim Center for Translational Neuroscience (MCTN), 
      Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
FAU - Sanghvi, Khwab
AU  - Sanghvi K
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Neurology, Mannheim Center for Translational Neuroscience (MCTN), 
      Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
FAU - Green, Edward
AU  - Green E
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
FAU - Pusch, Stefan
AU  - Pusch S
AUID- ORCID: 0000-0002-3407-4249
AD  - DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
AD  - Department of Neuropathology, Heidelberg University Hospital, University of 
      Heidelberg, Heidelberg, Germany.
FAU - Kawauchi, Daisuke
AU  - Kawauchi D
AUID- ORCID: 0000-0002-1254-9725
AD  - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
AD  - Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
FAU - Lower, Martin
AU  - Lower M
AD  - TRON - Translational Oncology at the University Medical Center of Johannes 
      Gutenberg University, Mainz, Germany.
FAU - Sonner, Jana K
AU  - Sonner JK
AUID- ORCID: 0000-0002-4700-272X
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
FAU - Kramer, Christopher
AU  - Kramer C
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
FAU - Zaman, Julia
AU  - Zaman J
AD  - Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
AD  - DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
FAU - Jung, Stefanie
AU  - Jung S
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
FAU - Breckwoldt, Michael O
AU  - Breckwoldt MO
AUID- ORCID: 0000-0002-9980-2390
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Neuroradiology at the Neurology Center, Heidelberg University 
      Hospital, Heidelberg, Germany.
FAU - Willimsky, Gerald
AU  - Willimsky G
AUID- ORCID: 0000-0002-9693-948X
AD  - Institute of Medical Immunology, Charite-Universitatsmedizin Berlin, corporate 
      member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, 
      Germany.
AD  - German Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.
FAU - Eichmuller, Stefan B
AU  - Eichmuller SB
AUID- ORCID: 0000-0002-3497-6904
AD  - Research Group GMP & T Cell Therapy, German Cancer Research Center (DKFZ), 
      Heidelberg, Germany.
FAU - von Deimling, Andreas
AU  - von Deimling A
AUID- ORCID: 0000-0002-5863-540X
AD  - DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
AD  - Department of Neuropathology, Heidelberg University Hospital, University of 
      Heidelberg, Heidelberg, Germany.
FAU - Wick, Wolfgang
AU  - Wick W
AUID- ORCID: 0000-0002-6171-634X
AD  - Department of Neuro-oncology and National Center for Tumor Diseases, Heidelberg 
      University Hospital, University of Heidelberg, Heidelberg, Germany.
AD  - DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
FAU - Sahm, Felix
AU  - Sahm F
AUID- ORCID: 0000-0001-5441-1962
AD  - DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center 
      (DKFZ), Heidelberg, Germany.
AD  - Department of Neuropathology, Heidelberg University Hospital, University of 
      Heidelberg, Heidelberg, Germany.
FAU - Platten, Michael
AU  - Platten M
AUID- ORCID: 0000-0002-4746-887X
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany.
AD  - Department of Neurology, Mannheim Center for Translational Neuroscience (MCTN), 
      Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
AD  - Helmholtz Institute for Translational Oncology (HI-TRON) Mainz, Mainz, Germany.
FAU - Bunse, Lukas
AU  - Bunse L
AUID- ORCID: 0000-0002-4490-7574
AD  - DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German 
      Cancer Research Center (DKFZ), Heidelberg, Germany. l.bunse@dkfz.de.
AD  - Department of Neurology, Mannheim Center for Translational Neuroscience (MCTN), 
      Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211115
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Receptors, Chimeric Antigen)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - *Glioma/genetics/therapy
MH  - Immunotherapy/methods
MH  - *Immunotherapy, Adoptive/methods
MH  - Mice
MH  - Neoplasm Recurrence, Local
MH  - *Receptors, Chimeric Antigen/therapeutic use
MH  - T-Lymphocytes
PMC - PMC9401455
EDAT- 2021/11/17 06:00
MHDA- 2022/04/08 06:00
PMCR- 2022/08/24
CRDT- 2021/11/16 06:11
PHST- 2021/05/23 00:00 [received]
PHST- 2021/09/15 00:00 [revised]
PHST- 2021/10/28 00:00 [accepted]
PHST- 2021/11/17 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2021/11/16 06:11 [entrez]
PHST- 2022/08/24 00:00 [pmc-release]
AID - 1078-0432.CCR-21-1881 [pii]
AID - CCR-21-1881 [pii]
AID - 10.1158/1078-0432.CCR-21-1881 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2022 Jan 15;28(2):378-389. doi: 10.1158/1078-0432.CCR-21-1881. 
      Epub 2021 Nov 15.