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000301764 1001_ $$0P:(DE-He78)792fd96345efded9a78c902105479a68$$aVolkmar, Michael$$b0$$eFirst author$$udkfz
000301764 245__ $$aEnhanced mutanome analysis towards the induction of neoepitope-reactive T-cell responses for personalized immunotherapy of pancreatic cancer.
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000301764 520__ $$aPersonalized immunotherapy of pancreatic ductal adenocarcinoma (PDAC) through T-cell mediated targeting of tumor-specific, mutanome-encoded neoepitopes may offer new opportunities to combat this disease, in particular by countering recurrence after primary tumor resection. However, the sensitive and accurate calling of somatic mutations in PDAC tissue samples is compromised by the low tumor cell content. Moreover, the repertoire of immunogenic neoepitopes in PDAC is limited due to the low mutational load of the majority of these tumors.We developed a workflow involving the combined analysis of next-generation DNA and RNA sequencing data from matched pairs of primary tumor samples and patient-derived xenograft models towards the enhanced detection of driver mutations as well as single nucleotide variants encoding potentially immunogenic T-cell neoepitopes. Subsequently, we immunized HLA/human T-cell receptor (TCR) locus-transgenic mice with synthetic peptides representing candidate neoepitopes, and molecularly cloned the genes encoding TCRs targeting these epitopes.Application of our pipeline resulted in the identification of greater numbers of non-synonymous mutations encoding candidate neoepitopes with increased confidence. Furthermore, we provide proof of concept for the successful isolation of HLA-restricted TCRs from humanized mice immunized with different neoepitopes, several of which would not have been selected based on mutanome analysis of PDAC tissue samples alone. These TCRs mediate specific T-cell reactivity against the tumor cells in which the corresponding mutations were identified.Enhanced mutanome analysis and candidate neoepitope selection increase the likelihood of identifying therapeutically relevant neoepitopes, and thereby support the optimization of personalized immunotherapy for PDAC and other poorly immunogenic cancers.
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000301764 650_7 $$2Other$$aAdoptive cell therapy - ACT
000301764 650_7 $$2Other$$aGastrointestinal Cancer
000301764 650_7 $$2Other$$aImmunotherapy
000301764 650_7 $$2Other$$aT cell Receptor - TCR
000301764 650_7 $$2Other$$aVaccine
000301764 650_7 $$2NLM Chemicals$$aEpitopes, T-Lymphocyte
000301764 650_2 $$2MeSH$$aHumans
000301764 650_2 $$2MeSH$$aAnimals
000301764 650_2 $$2MeSH$$aPancreatic Neoplasms: genetics
000301764 650_2 $$2MeSH$$aPancreatic Neoplasms: immunology
000301764 650_2 $$2MeSH$$aPancreatic Neoplasms: therapy
000301764 650_2 $$2MeSH$$aMice
000301764 650_2 $$2MeSH$$aPrecision Medicine: methods
000301764 650_2 $$2MeSH$$aImmunotherapy: methods
000301764 650_2 $$2MeSH$$aMutation
000301764 650_2 $$2MeSH$$aT-Lymphocytes: immunology
000301764 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: immunology
000301764 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: genetics
000301764 650_2 $$2MeSH$$aCarcinoma, Pancreatic Ductal: therapy
000301764 650_2 $$2MeSH$$aMice, Transgenic
000301764 650_2 $$2MeSH$$aEpitopes, T-Lymphocyte: immunology
000301764 650_2 $$2MeSH$$aEpitopes, T-Lymphocyte: genetics
000301764 7001_ $$0P:(DE-He78)22a86d571d45ad8293cf94b9a7f523e5$$aHoser, Dana$$b1
000301764 7001_ $$0P:(DE-He78)67614eacdbe6fe4404a46d2f8d01ac52$$aLauenstein, Claudia$$b2$$udkfz
000301764 7001_ $$aRebmann, Janina$$b3
000301764 7001_ $$0P:(DE-He78)2f34b89d62d5e5c651aa1e683844b092$$aHotz-Wagenblatt, Agnes$$b4
000301764 7001_ $$0P:(DE-He78)e65cfa9d82609e7cca9ea92150af032c$$aRieger, Jan Hendrik$$b5
000301764 7001_ $$0P:(DE-He78)e9c55f46b4b06cf835834ee7e3e00db8$$aPoschke, Isabel$$b6$$udkfz
000301764 7001_ $$0P:(DE-He78)45aa4fa7b16296bd3454cc3b68c33fc1$$aBecker, Jonas$$b7$$udkfz
000301764 7001_ $$0P:(DE-He78)3743a1b712edca2ffa829b7096d7037e$$aRiemer, Angelika B$$b8$$udkfz
000301764 7001_ $$0P:(DE-He78)0f44fcb0b05507b0a20b175f7ba9ed1c$$aSprick, Martin$$b9$$udkfz
000301764 7001_ $$0P:(DE-He78)732f4fbcddb0042251aa759a2e74d3b2$$aTrumpp, Andreas$$b10$$udkfz
000301764 7001_ $$aStrobel, Oliver$$b11
000301764 7001_ $$aBlankenstein, Thomas$$b12
000301764 7001_ $$0P:(DE-He78)bc039c65f54568c14d4aca488c101452$$aWillimsky, Gerald$$b13$$udkfz
000301764 7001_ $$0P:(DE-He78)81ae96953d6149e4307057d71a190019$$aOffringa, Rienk$$b14$$eLast author$$udkfz
000301764 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2025-011802$$gVol. 13, no. 6, p. e011802 -$$n6$$pe011802$$tJournal for ImmunoTherapy of Cancer$$v13$$x2051-1426$$y2025
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