Unbiased Identification of T-Cell Receptors Targeting Immunodominant Peptide–MHC Complexes for T-Cell Receptor Immunotherapy

Lorenz, Felix K.M.; Ellinger, Christian; Kieback, Elisa; Wilde, Susanne; Lietz, Maria; Schendel, Dolores J.; Uckert, Wolfgang

doi:10.1089/hum.2017.122

Cited by 12 publications

(12 citation statements)

References 50 publications

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“…However, in many cases, most of these peptides do not elicit strong antitumor immune responses because self–reactive T‐cells harboring TCR with high affinity to peptides undergo clonal deletion to maintain self–tolerance. Furthermore, given that different individuals have different TCR repertoires, peptide immunogenicity differs among individuals 33 . For these reasons, TCR‐dependent immunotherapeutic approaches have relied on a limited number of immunodominant peptides preferentially targeted by T‐cells in multiple individuals.…”

Section: Discussionmentioning

confidence: 99%

Development of a T‐cell receptor mimic antibody targeting a novel Wilms tumor 1‐derived peptide and analysis of its specificity

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Development of a T‐cell receptor mimic antibody targeting a novel Wilms tumor 1‐derived peptide and analysis of its specificity

et al. 2020

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“…Knowing which pMHC a TCR would bind is a key component toward understanding the mechanisms of T cell immunity. While this can be achieved experimentally, it is an expensive, time-consuming, and low-throughput procedure (23–26). Given this, it would be of great interest to develop means to predict the cognate pMHC target(s) of a TCR based on its sequence alone.…”

Section: Introductionmentioning

confidence: 99%

T-Cell Receptor Cognate Target Prediction Based on Paired α and β Chain Sequence and Structural CDR Loop Similarities

2019

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T-cell receptors (TCR) mediate immune responses recognizing peptides in complex with major histocompatibility complexes (pMHC) displayed on the surface of cells. Resolving the challenge of predicting the cognate pMHC target of a TCR would benefit many applications in the field of immunology, including vaccine design/discovery and the development of immunotherapies. Here, we developed a model for prediction of TCR targets based on similarity to a database of TCRs with known targets. Benchmarking the model on a large set of TCRs with known target, we demonstrated how the predictive performance is increased (i) by focusing on CDRs rather than the full length TCR protein sequences, (ii) by incorporating information from paired α and β chains, and (iii) integrating information for all 6 CDR loops rather than just CDR3. Finally, we show how integration of the structure of CDR loops, as obtained through homology modeling, boosts the predictive power of the model, in particular in situations where no high-similarity TCRs are available for the query. These findings demonstrate that TCRs that bind to the same target also share, to a very high degree, sequence, and structural features. This observation has profound impact for future development of prediction models for TCR-pMHC interactions and for the use of such models for the rational design of T cell based therapies.

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“…Human papillomavirus‐related HNSCCs have dramatically increased in the last two decades, and viral‐specific proteins have been explored as targets. T cells can recognize viral antigens in HPV‐related cancers, including HNSCC and cervical cancer, 43 and HPV‐related oncoproteins such as E6 and E7, can be targeted in these cancers 44 . A pilot study (NCT00257738) that treated recurrent HNSCC patients with HPV‐16‐derived peptides in conjunction with HIV‐derived “Penetrin” peptide showed T cell responses in PBMCs from vaccinated patients 45 .…”

Section: Vaccination Antigensmentioning

confidence: 99%

Personalized cancer vaccination in head and neck cancer

Shibata

Zhou

et al. 2021

Cancer Science

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Cancer is characterized by an accumulation of somatic mutations that represent a source of neoantigens for targeting by antigen‐specific T cells. Head and neck squamous cell carcinoma (HNSCC) has a relatively high mutation burden across all cancer types, and cellular immunity to neoantigens likely plays a key role in HNSCC clinical outcomes. Immune checkpoint inhibitors (CPIs) have brought new treatment options and hopes to patients with recurrent and/or metastatic HNSCC. However, many patients do not benefit from CPI therapies, highlighting the need for novel immunotherapy or combinatorial strategies. One such approach is personalized cancer vaccination targeting tumor‐associated antigens and tumor‐specific antigens, either as single agents or in combination with other therapies. Recent advances in next‐generation genomic sequencing technologies and computational algorithms have enabled efficient identification of somatic mutation‐derived neoantigens and are anticipated to facilitate the development of cancer vaccine strategies. Here, we review cancer vaccine approaches against HNSCC, including fundamental mechanisms of a cancer vaccine, considerations for selecting appropriate antigens, and combination therapies.

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Unbiased Identification of T-Cell Receptors Targeting Immunodominant Peptide–MHC Complexes for T-Cell Receptor Immunotherapy

Cited by 12 publications

References 50 publications

Development of a T‐cell receptor mimic antibody targeting a novel Wilms tumor 1‐derived peptide and analysis of its specificity

Development of a T‐cell receptor mimic antibody targeting a novel Wilms tumor 1‐derived peptide and analysis of its specificity

T-Cell Receptor Cognate Target Prediction Based on Paired α and β Chain Sequence and Structural CDR Loop Similarities

Personalized cancer vaccination in head and neck cancer

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