Noelia Silva-Pilipich, Uxue Beloki, Patricia Apaolaza, Ana Igea, Laura Salaberry, Laura Prats-Mari, Eric Rovira, Marina Ondiviela, Marta Gorraiz, Juan José Lasarte, Lucía Vanrell, Cristian Smerdou
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引用次数: 0
Abstract
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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.