Targeting PD-1 + T cells with small-format immunocytokines enhances IL-12 antitumor activity.

Autor:	Silva-Pilipich N; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain; Nanogrow Biotech, Montevideo 11500, Uruguay. Electronic address: nsilva.1@alumni.unav.es., Beloki U; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain., Apaolaza P; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain., Igea A; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain., Salaberry L; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Nanogrow Biotech, Montevideo 11500, Uruguay., Prats-Mari L; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain., Rovira E; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain., Ondiviela M; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain., Gorraiz M; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain; Immunology and Immunotherapy Program, Cima Universidad de Navarra, 31008 Pamplona, Spain., Lasarte JJ; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain; Immunology and Immunotherapy Program, Cima Universidad de Navarra, 31008 Pamplona, Spain., Vanrell L; Nanogrow Biotech, Montevideo 11500, Uruguay. Electronic address: lvanrell@nanogrow.com., Smerdou C; DNA and RNA Medicine Division, Cima Universidad de Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdISNA) and CCUN, 31008 Pamplona, Spain. Electronic address: csmerdou@unav.es.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Nov 19. Date of Electronic Publication: 2024 Nov 19.
DOI:	10.1016/j.ymthe.2024.11.027
Abstrakt:	Immunostimulatory cytokines and immune checkpoint inhibitors hold promise as cancer therapeutics; however, their use is often limited by reduced efficacy and significant toxicity. In this study, we developed small-format immunocytokines (ICKs) based on interleukin-12 (IL-12) and blocking nanobodies (Nbs) targeting mouse and human programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1). Both PD-1- and PD-L1-targeted ICKs demonstrated similar in vitro performance, significantly increasing IL-12 tethering to immune cells and enhancing T cell cytotoxic activity compared with IL-12 alone. The antitumor efficacy of ICKs was evaluated by intratumoral delivery using self-amplifying RNA-based vectors or as recombinant proteins in mice. Despite effective PD-L1-mediated tumor anchoring and promising in vitro results, IL-12 antitumor activity was significantly enhanced only when specific targeting to intratumoral T cells was achieved via anti-PD-1 Nb. This effect was also observed when the PD-1 specific ICK was delivered by electroporation of a DNA/RNA layered vector. Our findings suggest that targeting the appropriate type of cell within the tumor microenvironment could outperform tumor-anchoring strategies in the context of IL-12 therapy. Human versions of these ICKs were also developed, which showed to be active in human immune cells, opening an opportunity for clinical translation. Competing Interests: Declaration of interests L.V. declares being a co-founder of Nanogrow Biotech, a startup that develops Nbs for pharmaceutical applications. L.S. and N.S.-P. are currently employees of Nanogrow Biotech. The following patent related to this work has been filed: WO2024083988A1. (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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