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majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes<sup>1</sup>. However, most cancers have a modest mutational burden that is insufficient to generate responses using neoantigen-based therapies<sup>2,3</sup>. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks<sup>4</sup>. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins that are essential for tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric\u00a0CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric\u00a0CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.","bibjson":{"author":[{"initials":"M","lastname":"Yarmarkovich","name":"Yarmarkovich M"},{"initials":"QF","lastname":"Marshall","name":"Marshall QF"},{"initials":"JM","lastname":"Warrington","name":"Warrington JM"},{"initials":"R","lastname":"Premaratne","name":"Premaratne R"},{"initials":"A","lastname":"Farrel","name":"Farrel A"},{"initials":"D","lastname":"Groff","name":"Groff D"},{"initials":"W","lastname":"Li","name":"Li W"},{"initials":"M","lastname":"di Marco","name":"di Marco M"},{"initials":"E","lastname":"Runbeck","name":"Runbeck E"},{"initials":"H","lastname":"Truong","name":"Truong H"},{"initials":"JS","lastname":"Toor","name":"Toor JS"},{"initials":"S","lastname":"Tripathi","name":"Tripathi S"},{"initials":"S","lastname":"Nguyen","name":"Nguyen S"},{"initials":"H","lastname":"Shen","name":"Shen H"},{"initials":"T","lastname":"Noel","name":"Noel T"},{"initials":"NL","lastname":"Church","name":"Church NL"},{"initials":"A","lastname":"Weiner","name":"Weiner A"},{"initials":"N","lastname":"Kendsersky","name":"Kendsersky N"},{"initials":"D","lastname":"Martinez","name":"Martinez D"},{"initials":"R","lastname":"Weisberg","name":"Weisberg R"},{"initials":"M","lastname":"Christie","name":"Christie M"},{"initials":"L","lastname":"Eisenlohr","name":"Eisenlohr L"},{"initials":"KR","lastname":"Bosse","name":"Bosse KR"},{"initials":"DS","lastname":"Dimitrov","name":"Dimitrov DS"},{"initials":"S","lastname":"Stevanovic","name":"Stevanovic S"},{"initials":"NG","lastname":"Sgourakis","name":"Sgourakis NG"},{"initials":"BR","lastname":"Kiefel","name":"Kiefel BR"},{"initials":"JM","lastname":"Maris","name":"Maris JM"}],"identifier":[{"id":"10.1038/s41586-021-04061-6","type":"doi"},{"id":"34732890","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"Nature","name":""},"pages":[null],"title":"Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs.","type":"article","url":"https://www.nature.com/articles/s41586-021-04061-6","volume":[null],"year":[2021]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.69","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/7mja"},"rcsb":{"url":"https://www.rcsb.org/structure/7mja"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-A*24:02 binding \"QYNPIRTTF\" at 1.69&#8491; resolution","unique_chain_count":3}}