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ICOS Costimulation at the Tumor Site in Combination with CTLA-4 Blockade Therapy Elicits Strong Tumor Immunity.
Molecular Therapy ( IF 12.1 ) Pub Date : 2019-07-25 , DOI: 10.1016/j.ymthe.2019.07.013 Mario Martínez Soldevilla 1 , Helena Villanueva 1 , Daniel Meraviglia-Crivelli 1 , Ashwathi Puravankara Menon 1 , Marta Ruiz 2 , Javier Cebollero 1 , María Villalba 1 , Beatriz Moreno 1 , Teresa Lozano 2 , Diana Llopiz 2 , Álvaro Pejenaute 1 , Pablo Sarobe 2 , Fernando Pastor 1
Molecular Therapy ( IF 12.1 ) Pub Date : 2019-07-25 , DOI: 10.1016/j.ymthe.2019.07.013 Mario Martínez Soldevilla 1 , Helena Villanueva 1 , Daniel Meraviglia-Crivelli 1 , Ashwathi Puravankara Menon 1 , Marta Ruiz 2 , Javier Cebollero 1 , María Villalba 1 , Beatriz Moreno 1 , Teresa Lozano 2 , Diana Llopiz 2 , Álvaro Pejenaute 1 , Pablo Sarobe 2 , Fernando Pastor 1
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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.
中文翻译：
肿瘤部位的 ICOS 共刺激与 CTLA-4 阻断疗法相结合，可引发强大的肿瘤免疫。
细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 阻断疗法能够在一部分癌症患者中诱导持久的抗肿瘤反应。尽管如此，在寻求新的治疗组合方面仍有改进的余地。ICOS 共刺激已被强调为包含 CTLA-4 阻断治疗的可能目标。在此，我们描述了一种 ICOS 激动适体，当在不同肿瘤模型中结合抗 CTLA-4 抗体在肿瘤部位局部注射时，该适体可增强 T 细胞活化并诱导更强的抗肿瘤反应。此外，ICOS 激动适体被设计为双特异性肿瘤靶向适体，以在全身注射后到达任何播散的肿瘤病变。双特异性适体结合 CTLA-4 阻断剂治疗显示出强大的抗肿瘤免疫力，即使在黑色素瘤肿瘤模型中，单独使用 CTLA-4 治疗也没有显示出任何显着的治疗效果。因此，这项工作为开发涉及抗 CTLA-4 阻断剂和 ICOS 激动剂肿瘤靶向剂的组合疗法提供了强有力的支持。
更新日期：2019-07-25
中文翻译：
肿瘤部位的 ICOS 共刺激与 CTLA-4 阻断疗法相结合，可引发强大的肿瘤免疫。
细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 阻断疗法能够在一部分癌症患者中诱导持久的抗肿瘤反应。尽管如此，在寻求新的治疗组合方面仍有改进的余地。ICOS 共刺激已被强调为包含 CTLA-4 阻断治疗的可能目标。在此，我们描述了一种 ICOS 激动适体，当在不同肿瘤模型中结合抗 CTLA-4 抗体在肿瘤部位局部注射时，该适体可增强 T 细胞活化并诱导更强的抗肿瘤反应。此外，ICOS 激动适体被设计为双特异性肿瘤靶向适体，以在全身注射后到达任何播散的肿瘤病变。双特异性适体结合 CTLA-4 阻断剂治疗显示出强大的抗肿瘤免疫力，即使在黑色素瘤肿瘤模型中，单独使用 CTLA-4 治疗也没有显示出任何显着的治疗效果。因此，这项工作为开发涉及抗 CTLA-4 阻断剂和 ICOS 激动剂肿瘤靶向剂的组合疗法提供了强有力的支持。
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