Targeting human melanoma neoantigens by T cell receptor gene therapy

Leisegang, Matthias; Kammertoens, Thomas; Uckert, Wolfgang; Blankenstein, Thomas

doi:10.1172/jci83465

Cited by 55 publications

(55 citation statements)

References 30 publications

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“…Currently, there is no published data on neoantigen‐specific TCR‐engineered T‐cell therapy in humans. However, preclinical studies have shown encouraging results where neoantigen‐specific TCR‐engineered T cells are also effective for large‐sized solid tumors …”

Section: Neoantigen‐based Personalized Immunotherapymentioning

confidence: 99%

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

2018

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Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, from which the majority of patients experienced no or minimum clinical benefit. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer‐specific immune targets. Highly tumor‐specific antigens, neoantigens, are generated by somatic mutations that are not present in normal cells. It is plausible that by targeting antigens with high tumor‐specificity, such as neoantigens, the likelihood of toxic effects is very limited. However, understanding the interaction between neoantigens and the host immune system remains a significant challenge. This review focuses on the potential use of neoantigen‐targeted immunotherapies in cancer treatment and the recent progress of different strategies in predicting, identifying, and validating neoantigens. Successful identification of highly tumor‐specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

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Section: Neoantigen‐based Personalized Immunotherapymentioning

confidence: 99%

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

2018

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“…Structural studies have revealed that two TCRs used in a clinical setting, DMF4 and DMF5, have to make structural compromises when interacting with the nonapeptide . In accordance, Blankenstein and colleagues recently showed that T cells, transduced with a clinically relevant TCR, induced rejection of tumors expressing the analog E L AGIGILTV, but not native AAGIGILTV, Melan A/MART‐1 epitope . Consequently, there is a need to understand the seemingly complex molecular rules that govern T‐cell antigen recognition in this system so that effective therapies can be developed.…”

Section: Introductionmentioning

confidence: 99%

TCR‐induced alteration of primary MHC peptide anchor residue

et al. 2019

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The HLA‐A*02:01‐restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T‐cells‐1 (MART‐1) protein, represents one of the best‐studied tumor associated T‐cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA‐A*02:01 and TCRs from clinically relevant T‐cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5‐HLA‐A*02:01‐AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well‐studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.

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“…Most of the neoantigen-targeting studies have been performed using melanoma samples, because melanoma has the highest somatic mutation burden among human cancers and hundreds of neoantigen candidates can be identified for each patient (34,(42)(43)(44)(45)(46). Only few studies have been performed in cancer types with a relatively lower number of somatic mutations, although a large body of evidence has suggested the importance of neoantigens.…”

Section: Discussionmentioning

confidence: 99%

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor–Engineered T Cells for Ovarian Cancer

Matsuda

Leisegang

Park

et al. 2018

Clinical Cancer Research

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To prepare Translational relevanceAdoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells is considered as a promising novel immunotherapy strategy. It takes four steps to prepare; (1) prediction of neoantigen epitopes, (2) neoantigen peptides synthesis, (3) identification of neoantigen-specific TCR and (4) production of virus vector to express TCR. Among them, the most challenging part is identification of neoantigen-specific TCRs. Our protocol required only two weeks from stimulation of T cells with peptides to the identification of neoantigen-specific TCRs. We conducted a pilot study to validate our time-efficient protocol in solid cancers with relatively lower mutational loads such as ovarian cancer. We successfully induced neoantigen-specific T cells against three neoantigens and established corresponding TCR-engineered T cells. One case of neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide. These results give an important insight into the clinical application of adoptive T cell therapy with neoantigen-specific TCR-engineered T cells.Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 2, 2018; DOI: 10.1158/1078-0432.CCR-18-0142 4 ABSTRACTPurpose: Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anti-cancer cytotoxic T cells. Adoptive T cell therapy with neoantigen-specific T cell receptor (TCR)-engineered T cells would be an attractive therapeutic option for advanced cancers where the host antitumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor. Our protocol required only two weeks from stimulation of T cells with neoantigen-loaded dendritic cells to the identification of neoantigen-specific TCRs. We conducted the pilot study to validate our protocol. Experimental Design: We used tumors from 7 ovarian cancer patients to validate our protocol.Results: We chose 14 candidate neoantigens from 7 ovarian tumors (1-3 candidates for each patient), and then successfully induced 3 neoantigen-specific T cells from one healthy donor and identified their TCR sequences. Moreover, we validated functional activity of the three identified TCRs by generating TCR-engineered T cells which recognized the corresponding neoantigens and showed cytotoxic activity in an antigendose-dependent manner. However, one case of neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide. Conclusion/discussions: This pilot study demonstrated the feasibility of our efficient process from identification of neoantigen to production of the neoantigen-targeting cytotoxic TCR-engineered T cells for ovarian cancer and revealed the importance of careful validati...

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Targeting human melanoma neoantigens by T cell receptor gene therapy

Cited by 55 publications

References 30 publications

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

TCR‐induced alteration of primary MHC peptide anchor residue

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor–Engineered T Cells for Ovarian Cancer

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