Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

Strønen, Erlend; Toebes, Mireille; Kelderman, Sander; Buuren, Marit M. van; Yang, Weiwen; Rooij, Nienke van; Donia, Marco; Böschen, Maxi Lu; Lund-Johansen, Fridtjof; Olweus, Johanna; Schumacher, Ton N.

doi:10.1126/science.aaf2288

Cited by 399 publications

(399 citation statements)

References 42 publications

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“…41,42 We used the peptide-MHC stability prediction tool NetMHCstabpan and could not confirm those previous reports since our results indicated that binding prediction alone performed better than both stability prediction alone and stability prediction in combination with binding.…”

Section: Discussionmentioning

confidence: 66%

“…41,42 To test the ability to utilize MHC-peptide stability predictions for neoepitope identification we used the prediction tool NetMHCstabpan. 43 Stability predictions alone and in combination with binding predictions, as recommended by the authors, 43 did not improve immunogenic neoepitope prediction performance when compared to binding prediction alone (Table 2).…”

Section: Resultsmentioning

confidence: 99%

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Predicting T cell recognition of MHC class I restricted neoepitopes

et al. 2018

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Epitopes that arise from a somatic mutation, also called neoepitopes, are now known to play a key role in cancer immunology and immunotherapy. Recent advances in high-throughput sequencing have made it possible to identify all mutations and thereby all potential neoepitope candidates in an individual cancer. However, most of these neoepitope candidates are not recognized by T cells of cancer patients when tested in vivo or in vitro, meaning they are not immunogenic. Especially in patients with a high mutational load, usually hundreds of potential neoepitopes are detected, highlighting the need to further narrow down this candidate list. In our study, we assembled a dataset of known, naturally processed, immunogenic neoepitopes to dissect the properties that make these neoepitopes immunogenic. The tools to use and thresholds to apply for prioritizing neoepitopes have so far been largely based on experience with epitope identification in other settings such as infectious disease and allergy. Here, we performed a detailed analysis on our dataset of curated immunogenic neoepitopes to establish the appropriate tools and thresholds in the cancer setting. To this end, we evaluated different predictors for parameters that play a role in a neoepitope’s immunogenicity and suggest that using binding predictions and length-rescaling yields the best performance in discriminating immunogenic neoepitopes from a background set of mutated peptides. We furthermore show that almost all neoepitopes had strong predicted binding affinities (as expected), but more surprisingly, the corresponding non-mutated peptides had nearly as high affinities. Our results provide a rational basis for parameters in neoepitope filtering approaches that are being commonly used.Abbreviations: SNV: single nucleotide variant; nsSNV: nonsynonymous single nucleotide variant; ROC: receiver operating characteristic; AUC: area under ROC curve; HLA: human leukocyte antigen; MHC: major histocompatibility complex; PD-1: Programmed cell death protein 1; PD-L1 or CTLA-4: cytotoxic T-lymphocyte associated protein 4

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Section: Discussionmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Predicting T cell recognition of MHC class I restricted neoepitopes

et al. 2018

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“…These approaches are now being adapted to create personalized therapeutic cancer vaccines. On the other hand, it might be difficult to select immunogenic epitopes eliciting active CTLs among candidate epitopes [59,60] . It takes time to assess the immunogenicity of candidate epitopes by in vitro experiments, though the vaccine should be delivered to patients quickly.…”

Section: Neoantigens As Novel Targets Of Cancer Peptide Vaccinesmentioning

confidence: 99%

Cancer vaccine therapy based on peptides

Katsuda

Yamaue

2017

Trends Immunother

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Following numerous unequivocal clinical failures, immunotherapy has become an attractive therapeutic modality. Peptide vaccines are cost-effective compared to other vaccine approaches, and effective epitopes eliciting strong immune response can be selected experimentally in silico and ex vivo. However, the clinical benefits of cancer peptides vaccine have been disappointing in most studies; therefore, we need to prove the clinical beneficial effects for cancer treatment following induction of more powerful cytotoxic T lymphocytes (CTLs). First, the choice of ideal target antigen is essential. Epitopes derived from tumor-associated antigens (TAAs), oncoantigens, vascular endothelial cells and neoantigens are then developed. In particular, wholeexome sequencing enables us to identify the epitopes of neoantigens. The choice of therapeutic objectives is also important and peptide vaccines might be better to be developed as preventative vaccines. Dendritic cells (DCs) vaccine pulsed with peptides is an approach to induce powerful CTLs and might overcome several disadvantages of peptide vaccines as monotherapy. Targeting vaccine therapy against DC subsets in vivo is under development.

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“…It was reported recently that neoantigen specific T cells that generated from healthy donors were able to recognize 11 of 57 predicted neoepitopes across three patients. This may broaden neoantigen-specific T cell reactivity, and provide a rationale for using "outsourced" T cells in curing tumor patients with dysfunctional immune system [34].…”

Section: Therapeutic Approaches Targeting Patient Specific Neoantigenmentioning

confidence: 99%

The Prediction and Function of Neoantigen in Oncobiology

Cui¹

2017

Proceedings of the 2017 International Conference on Material Science, Energy and Environmental Engineering (MSEEE 2017)

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Abstract.Recent clinical data clearly demonstrated that patient's own immune system has great potential in controlling the progression of many human cancers. Neoantigen is the foundation of tumor immunology for it is the "marker" for mature autologous T lymphocytes to distinguish tumor cells and normal cells. So identification of neoantigen is an important work in both fundamental studies and clinical immunotherapies. Neoantigen is patient-specific, it is derived from tumor genome somatic mutations in protein coding region. Identification of neoantigen is a laborious work before, but recent technological innovations have made this measurement easier and faster, though still not perfect. Now, numerous neoantigen based clinical trials are being carried out around the world by both academic institutes and companies, some have achieved exciting results.

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Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

Cited by 399 publications

References 42 publications

Predicting T cell recognition of MHC class I restricted neoepitopes

Predicting T cell recognition of MHC class I restricted neoepitopes

Cancer vaccine therapy based on peptides

The Prediction and Function of Neoantigen in Oncobiology

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