{"doi":"10.1093/neuonc/noaa050","title":"Treatment of an aggressive orthotopic murine glioblastoma model with combination checkpoint blockade and a multivalent neoantigen vaccine","abstract":"BACKGROUND: Although clinical trials testing immunotherapies in glioblastoma (GBM) have yielded mixed results, new strategies targeting tumor-specific somatic coding mutations, termed \"neoantigens,\" represent promising therapeutic approaches. We characterized the microenvironment and neoantigen landscape of the aggressive CT2A GBM model in order to develop a platform to test combination checkpoint blockade and neoantigen vaccination. METHODS: Flow cytometric analysis was performed on intracranial CT2A and GL261 tumor-infiltrating lymphocytes (TILs). Whole-exome DNA and RNA sequencing of the CT2A murine GBM was employed to identify expressed, somatic mutations. Predicted neoantigens were identified using the pVAC-seq software suite, and top-ranking candidates were screened for reactivity by interferon-gamma enzyme linked immunospot assays. Survival analysis was performed comparing neoantigen vaccination, anti-programmed cell death ligand 1 (αPD-L1), or combination therapy. RESULTS: Compared with the GL261 model, CT2A exhibited immunologic features consistent with human GBM including reduced αPD-L1 sensitivity and hypofunctional TILs. Of the 29 CT2A neoantigens screened, we identified neoantigen-specific CD8+ T-cell responses in the intracranial TIL and draining lymph nodes to two H2-Kb restricted (Epb4H471L and Pomgnt1R497L) and one H2-Db restricted neoantigen (Plin2G332R). Survival analysis showed that therapeutic neoantigen vaccination with Epb4H471L, Pomgnt1R497L, and Plin2G332R, in combination with αPD-L1 treatment was superior to αPD-L1 alone. CONCLUSIONS: We identified endogenous neoantigen specific CD8+ T cells within an αPD-L1 resistant murine GBM and show that neoantigen vaccination significantly augments survival benefit in combination with αPD-L1 treatment. These observations provide important preclinical correlates for GBM immunotherapy trials and support further investigation into the effects of multimodal immunotherapeutic interventions on antiglioma immunity. KEY POINTS: 1. Neoantigen vaccines combined with checkpoint blockade may be promising treatments.2. CT2A tumors exhibit features of human GBM microenvironments.3. Differential scanning fluorimetry assays may complement in silico neoantigen prediction tools.","journal":"Neuro-Oncology","year":2020,"id":57113,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":80,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":297952,"name":"Maximilian O. Schaettler","orcid":"0000-0001-7545-6342","position":1,"is_corresponding":false},{"id":300056,"name":"Dylan T. Blaha","orcid":null,"position":2,"is_corresponding":false},{"id":297953,"name":"Jay A. Bowman-Kirigin","orcid":"0000-0002-7687-3727","position":3,"is_corresponding":false},{"id":297954,"name":"Dale K. Kobayashi","orcid":"0000-0002-6370-2099","position":4,"is_corresponding":false},{"id":297955,"name":"Alexandra J. Livingstone","orcid":"0000-0001-5471-4576","position":5,"is_corresponding":false},{"id":225123,"name":"Diane E. Bender","orcid":"0000-0002-8311-4390","position":6,"is_corresponding":false},{"id":13814,"name":"Christopher A. Miller","orcid":"0000-0003-4266-6700","position":7,"is_corresponding":false},{"id":297956,"name":"David M. Kranz","orcid":"0000-0002-4931-126X","position":8,"is_corresponding":false},{"id":297957,"name":"Tanner M. Johanns","orcid":"0000-0003-1094-1528","position":9,"is_corresponding":false},{"id":231268,"name":"Gavin P. Dunn","orcid":"0000-0001-9302-4834","position":10,"is_corresponding":false},{"id":235664,"name":"Connor J. Liu","orcid":"0000-0002-2285-1928","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T21:06:31.136481Z","pmid":"32133512","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}