ICOS Costimulation at the Tumor Site in Combination with CTLA-4 Blockade Therapy Elicits Strong Tumor Immunity
Mario Martínez Soldevilla, Helena Villanueva, Daniel Meraviglia-Crivelli, Ashwathi Puravankara Menon, Marta Ruiz, Javier Cebollero, María Villalba, Beatriz Moreno, Teresa Lozano, Diana Llopiz, Álvaro Pejenaute, Pablo Sarobe, Fernando Pastor
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) blockade therapy is able to induce long-lasting antitumor responses in a fraction of cancer patients. Nonetheless, there is still room for improvement in the quest for new therapeutic combinations. ICOS costimulation has been underscored as a possible target to include with CTLA-4 blocking treatment. Herein, we describe an ICOS agonistic aptamer that potentiates T cell activation and induces stronger antitumor responses when locally injected at the tumor site in combination with anti-CTLA-4 antibody in different tumor models.
Furthermore, ICOS agonistic aptamer was engineered as a bi-specific tumor-targeting aptamer to reach any disseminated tumor lesions after systemic injection. Treatment with the bi-specific aptamer in combination with CTLA-4 blockade showed strong antitumor immunity, even in a melanoma tumor model where CTLA-4 treatment alone did not display any significant therapeutic benefit. Thus, this work provides strong support for the development of combinatorial therapies involving anti-CTLA-4 blockade and ICOS agonist tumor-targeting agents.
CITATION Mol Ther. 2019 Nov 6;27(11):1878-1891. doi: 10.1016/j.ymthe.2019.07.013. Epub 2019 Jul 25.