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Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists
Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462790/ https://www.ncbi.nlm.nih.gov/pubmed/37650116 http://dx.doi.org/10.1016/j.omtn.2023.07.026 |
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author | Cirella, Assunta Bolaños, Elixabet Luri-Rey, Carlos Di Trani, Claudia Augusta Olivera, Irene Gomis, Gabriel Glez-Vaz, Javier Pinci, Beatrice Garasa, Saray Sánchez-Gregorio, Sandra Azpilikueta, Arantza Eguren-Santamaria, Iñaki Valencia, Karmele Palencia, Belén Alvarez, Maite Ochoa, Maria C. Teijeira, Álvaro Berraondo, Pedro Melero, Ignacio |
author_facet | Cirella, Assunta Bolaños, Elixabet Luri-Rey, Carlos Di Trani, Claudia Augusta Olivera, Irene Gomis, Gabriel Glez-Vaz, Javier Pinci, Beatrice Garasa, Saray Sánchez-Gregorio, Sandra Azpilikueta, Arantza Eguren-Santamaria, Iñaki Valencia, Karmele Palencia, Belén Alvarez, Maite Ochoa, Maria C. Teijeira, Álvaro Berraondo, Pedro Melero, Ignacio |
author_sort | Cirella, Assunta |
collection | PubMed |
description | Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor β (TGF-β) and CD137 (4-1BB). Several neutralizing TGF-β agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-β and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8(+) T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade. |
format | Online Article Text |
id | pubmed-10462790 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-104627902023-08-30 Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists Cirella, Assunta Bolaños, Elixabet Luri-Rey, Carlos Di Trani, Claudia Augusta Olivera, Irene Gomis, Gabriel Glez-Vaz, Javier Pinci, Beatrice Garasa, Saray Sánchez-Gregorio, Sandra Azpilikueta, Arantza Eguren-Santamaria, Iñaki Valencia, Karmele Palencia, Belén Alvarez, Maite Ochoa, Maria C. Teijeira, Álvaro Berraondo, Pedro Melero, Ignacio Mol Ther Nucleic Acids Original Article Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor β (TGF-β) and CD137 (4-1BB). Several neutralizing TGF-β agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-β and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8(+) T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade. American Society of Gene & Cell Therapy 2023-07-28 /pmc/articles/PMC10462790/ /pubmed/37650116 http://dx.doi.org/10.1016/j.omtn.2023.07.026 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Cirella, Assunta Bolaños, Elixabet Luri-Rey, Carlos Di Trani, Claudia Augusta Olivera, Irene Gomis, Gabriel Glez-Vaz, Javier Pinci, Beatrice Garasa, Saray Sánchez-Gregorio, Sandra Azpilikueta, Arantza Eguren-Santamaria, Iñaki Valencia, Karmele Palencia, Belén Alvarez, Maite Ochoa, Maria C. Teijeira, Álvaro Berraondo, Pedro Melero, Ignacio Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists |
title | Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists |
title_full | Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists |
title_fullStr | Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists |
title_full_unstemmed | Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists |
title_short | Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists |
title_sort | intratumoral immunotherapy with mrnas encoding chimeric protein constructs encompassing il-12, cd137 agonists, and tgf-β antagonists |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462790/ https://www.ncbi.nlm.nih.gov/pubmed/37650116 http://dx.doi.org/10.1016/j.omtn.2023.07.026 |
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