Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß 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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Detalles Bibliográficos
Autores: Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790, Bolaños-Mateo, E. (Elixabet)|||/items/073a1977-5579-4bd1-8604-98b3ccfd4361, Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d, Di-Trani, C.A. (Claudia Augusta)|||/items/5d899126-779d-4c97-8232-95bfe18f9f26, Olivera-Valle, I. (Irene)|||/items/c3d06db0-d277-4fe8-9b33-59005441fec1, Gomis-Cobos, G. (Gabriel)|||/items/c756710a-4f47-4acf-a13a-b47c739cef8c, Pinci, B. (Beatrice)|||/items/319d608a-6b4d-4209-9582-8cdabd7f017c, Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713, Sánchez-Gregorio, S. (Sandra)|||/items/0e87cc21-b1fc-49eb-891c-c1a9e6183b5e, Azpilikueta, A. (Arantza)|||/items/8cb8f9c3-bb52-41cc-a19d-03de632308e9, Eguren-Santamaría, I. (Iñaki)|||/items/a597d707-9f63-46ab-8da1-e99ed05e644e, Valencia, K. (Karmele)|||/items/bf771eab-81c1-4221-80f5-87713ad5e51f, Palencia-Coto, B. (Belén)|||/items/c439a2a6-fad9-4a0b-8309-ceca8c25edf2, Álvarez-Rodríguez, M. (Maite)|||/items/e298edcf-2e7f-4001-a5e2-244efa1a7781, Ochoa-Nieto, M.C. (María del Carmen)|||/items/a26293bb-e79a-42a3-be52-dbf5208f3f89, Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30, Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91, Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e, González-Vaz, J. (Javier)|||/items/9d321bb0-f713-4608-8d35-15b1c9588b76
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/67856
Acceso en línea:https://hdl.handle.net/10171/67856
Access Level:acceso abierto
Palabra clave:4-1BB
CD137
IL-12
MT: Delivery Strategies
TGF-β
Local immunotherapy
mRNA
Descripción
Sumario: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 b (TGF-b) and CD137 (4-1BB). Several neutralizing TGF- b agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-beta 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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