Personalized neoantigen viro-immunotherapy platform for triple-negative breast cancer
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ..
BACKGROUND: Triple-negative breast cancer (TNBC) corresponds to approximately 20% of all breast tumors, with a high propensity for metastasis and a poor prognosis. Because TNBC displays a high mutational load compared with other breast cancer types, a neoantigen-based immunotherapy strategy could be effective. One major bottleneck in the development of a neoantigen-based vaccine for TNBC is the selection of the best targets, that is, tumor-specific neoantigens which are presented at the surface of tumor cells and capable of eliciting robust immune responses. In this study, we aimed to set up a platform for identification and delivery of immunogenic neoantigens in a vaccine regimen for TNBC using oncolytic vaccinia virus (VV).
METHODS: We used bioinformatic tools and cell-based assays to identify immunogenic neoantigens in TNBC patients' samples, human and murine cell lines. Immunogenicity of the neoantigens was tested in vitro (human) and ex vivo (murine) in T-cell assays. To assess the efficacy of our regimen, we used a preclinical model of TNBC where we treated tumor-bearing mice with neoantigens together with oncolytic VV and evaluated the effect on induction of neoantigen-specific CD8+T cells, tumor growth and survival.
RESULTS: We successfully identified immunogenic neoantigens and generated neoantigen-specific CD8+T cells capable of recognizing a human TNBC cell line expressing the mutated gene. Using a preclinical model of TNBC, we showed that our tumor-specific oncolytic VV was able to change the tumor microenvironment, attracting and maintaining mature cross-presenting CD8α+dendritic cells and effector T-cells. Moreover, when delivered in a prime/boost regimen together with oncolytic VV, long peptides encompassing neoantigens were able to induce neoantigen-specific CD8+T cells, slow tumor growth and increase survival.
CONCLUSIONS: Our study provides a promising approach for the development of neoantigen-based immunotherapies for TNBC. By identifying immunogenic neoantigens and developing a delivery system through tumor-specific oncolytic VV, we have demonstrated that neoantigen-based vaccines could be effective in inducing neoantigen-specific CD8+T cells response with significant impact on tumor growth. Further studies are needed to determine the safety and efficacy of this approach in clinical trials.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 11(2023), 8 vom: 26. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Brito Baleeiro, Renato [VerfasserIn] |
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| Links: |
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| Themen: |
Breast Neoplasms |
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| Anmerkungen: |
Date Completed 18.08.2023 Date Revised 28.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2023-007336 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM360859658 |
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| 245 | 1 | 0 | |a Personalized neoantigen viro-immunotherapy platform for triple-negative breast cancer |
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| 500 | |a Date Revised 28.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. | ||
| 520 | |a BACKGROUND: Triple-negative breast cancer (TNBC) corresponds to approximately 20% of all breast tumors, with a high propensity for metastasis and a poor prognosis. Because TNBC displays a high mutational load compared with other breast cancer types, a neoantigen-based immunotherapy strategy could be effective. One major bottleneck in the development of a neoantigen-based vaccine for TNBC is the selection of the best targets, that is, tumor-specific neoantigens which are presented at the surface of tumor cells and capable of eliciting robust immune responses. In this study, we aimed to set up a platform for identification and delivery of immunogenic neoantigens in a vaccine regimen for TNBC using oncolytic vaccinia virus (VV) | ||
| 520 | |a METHODS: We used bioinformatic tools and cell-based assays to identify immunogenic neoantigens in TNBC patients' samples, human and murine cell lines. Immunogenicity of the neoantigens was tested in vitro (human) and ex vivo (murine) in T-cell assays. To assess the efficacy of our regimen, we used a preclinical model of TNBC where we treated tumor-bearing mice with neoantigens together with oncolytic VV and evaluated the effect on induction of neoantigen-specific CD8+T cells, tumor growth and survival | ||
| 520 | |a RESULTS: We successfully identified immunogenic neoantigens and generated neoantigen-specific CD8+T cells capable of recognizing a human TNBC cell line expressing the mutated gene. Using a preclinical model of TNBC, we showed that our tumor-specific oncolytic VV was able to change the tumor microenvironment, attracting and maintaining mature cross-presenting CD8α+dendritic cells and effector T-cells. Moreover, when delivered in a prime/boost regimen together with oncolytic VV, long peptides encompassing neoantigens were able to induce neoantigen-specific CD8+T cells, slow tumor growth and increase survival | ||
| 520 | |a CONCLUSIONS: Our study provides a promising approach for the development of neoantigen-based immunotherapies for TNBC. By identifying immunogenic neoantigens and developing a delivery system through tumor-specific oncolytic VV, we have demonstrated that neoantigen-based vaccines could be effective in inducing neoantigen-specific CD8+T cells response with significant impact on tumor growth. Further studies are needed to determine the safety and efficacy of this approach in clinical trials | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Breast Neoplasms | |
| 650 | 4 | |a Immunogenicity, Vaccine | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Oncolytic Virotherapy | |
| 700 | 1 | |a Liu, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Chard Dunmall, Louisa S |e verfasserin |4 aut | |
| 700 | 1 | |a Di Gioia, Carmela |e verfasserin |4 aut | |
| 700 | 1 | |a Nagano, Ai |e verfasserin |4 aut | |
| 700 | 1 | |a Cutmore, Lauren |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Chelala, Claude |e verfasserin |4 aut | |
| 700 | 1 | |a Nyambura, Lydon Wainaina |e verfasserin |4 aut | |
| 700 | 1 | |a Walden, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Lemoine, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yaohe |e verfasserin |4 aut | |
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