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T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas
Michael Kilian1,2,3, Mirco Friedrich1,2, Khwab Sanghvi1,2,3
1DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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.
Insights
Researchers identified specific mutations in gliomas that create targets for immunotherapy. These findings pave the way for new T-cell therapies against brain tumors.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Genomics
Background:
- Gliomas are aggressive brain tumors known for resistance to conventional treatments like radiation and chemotherapy.
- Specific genetic mutations in gliomas can lead to the creation of neoepitopes, which are potential targets for immunotherapy.
- Developing targeted therapies is crucial for improving outcomes in glioma patients.
Purpose of the Study:
- To identify immunogenic neoepitopes in gliomas suitable for targeted immunotherapy.
- To investigate the potential of T-cell receptor (TCR)-transgenic T-cell therapy for glioma treatment.
- To establish immunocompetent preclinical models for glioma neoepitope discovery and therapy assessment.
Main Methods:
- Utilized peptide-based ELISpot assays in MHC-humanized mice to screen for recurrent glioma neoepitopes.
- Employed droplet-based single-cell TCR sequencing for neoepitope-specific TCR discovery after vaccination.
- Developed a novel glioma model in MHC-humanized mice for assessing intraventricular TCR-transgenic T-cell therapy efficacy.
Main Results:
- Identified recurrent capicua transcriptional repressor (CIC) inactivating hotspot mutations (CICR215W/Q) as immunogenic MHC class II (MHCII)-restricted neoepitopes.
- Demonstrated that vaccination in MHC-humanized mice elicits robust MHCII-restricted, mutation-specific T-cell responses against CICR215W/Q.
- Showed that adoptive transfer of CICR215W-specific TCR-transgenic T cells effectively targets CICR215W-expressing gliomas in a preclinical model.
Conclusions:
- The study highlights the successful integration of immunocompetent MHC-humanized glioma models for discovering shared immunogenic neoepitopes.
- Facilitates the identification and preclinical validation of human leukocyte antigen (HLA)-restricted neoepitope-specific TCRs.
- Supports the potential of locoregional TCR-transgenic T-cell adoptive therapy as a viable strategy for glioma treatment.
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