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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
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.
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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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