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Transient Inhibition of PI3Kδ Enhances the Therapeutic Effect of Intravenous Delivery of Oncolytic Vaccinia Virus.
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-02-28 , DOI: 10.1016/j.ymthe.2020.02.017 Mark S Ferguson 1 , Louisa S Chard Dunmall 1 , Rathi Gangeswaran 1 , Giulia Marelli 1 , James R Tysome 2 , Emily Burns 3 , Maria A Whitehead 4 , Ezra Aksoy 5 , Ghassan Alusi 6 , Crispin Hiley 1 , Jay Ahmed 1 , Bart Vanhaesebroeck 4 , Nicholas R Lemoine 7 , Yaohe Wang 7
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-02-28 , DOI: 10.1016/j.ymthe.2020.02.017 Mark S Ferguson 1 , Louisa S Chard Dunmall 1 , Rathi Gangeswaran 1 , Giulia Marelli 1 , James R Tysome 2 , Emily Burns 3 , Maria A Whitehead 4 , Ezra Aksoy 5 , Ghassan Alusi 6 , Crispin Hiley 1 , Jay Ahmed 1 , Bart Vanhaesebroeck 4 , Nicholas R Lemoine 7 , Yaohe Wang 7
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Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy.
中文翻译：
PI3Kδ 的瞬时抑制可增强溶瘤痘苗病毒静脉注射的治疗效果。
痘苗病毒（VV）等肿瘤靶向溶瘤病毒是有吸引力的癌症治疗剂，它们通过多种机制发挥作用，激发肿瘤溶解和抗肿瘤免疫反应。然而，这些药物的递送仍然仅限于肿瘤内给药，这阻碍了对难以接近和播散的肿瘤细胞的有效靶向。在本研究中，我们发现富含白细胞的磷酸肌醇 3-激酶 δ (PI3Kδ) 的短暂药理学抑制是一种增强溶瘤 VV 静脉内递送至肿瘤的新机制。在静脉注射亲肿瘤性 VV 之前，用 PI3Kδ 选择性抑制剂 IC87114 或临床批准的 idelalisib (CAL-101) 对免疫活性小鼠进行预处理，可显着改善病毒向肿瘤的递送。这是通过扰动涉及 RhoA/ROCK、AKT 和 Rac 的信号通路来抑制病毒附着到系统巨噬细胞而不是被系统巨噬细胞内化而发生的。与没有 PI3Kδ 抑制的递送相比，在静脉内递送 VV 之前使用 PI3Kδ 选择性抑制剂进行预处理可增强抗肿瘤功效并显着延长生存期。这些结果表明，有效静脉内递送溶瘤VV在临床上可能是可以实现的，并且可用于提高溶瘤病毒疗法的抗肿瘤功效。
更新日期：2020-02-28
中文翻译：
PI3Kδ 的瞬时抑制可增强溶瘤痘苗病毒静脉注射的治疗效果。
痘苗病毒（VV）等肿瘤靶向溶瘤病毒是有吸引力的癌症治疗剂，它们通过多种机制发挥作用，激发肿瘤溶解和抗肿瘤免疫反应。然而，这些药物的递送仍然仅限于肿瘤内给药，这阻碍了对难以接近和播散的肿瘤细胞的有效靶向。在本研究中，我们发现富含白细胞的磷酸肌醇 3-激酶 δ (PI3Kδ) 的短暂药理学抑制是一种增强溶瘤 VV 静脉内递送至肿瘤的新机制。在静脉注射亲肿瘤性 VV 之前，用 PI3Kδ 选择性抑制剂 IC87114 或临床批准的 idelalisib (CAL-101) 对免疫活性小鼠进行预处理，可显着改善病毒向肿瘤的递送。这是通过扰动涉及 RhoA/ROCK、AKT 和 Rac 的信号通路来抑制病毒附着到系统巨噬细胞而不是被系统巨噬细胞内化而发生的。与没有 PI3Kδ 抑制的递送相比，在静脉内递送 VV 之前使用 PI3Kδ 选择性抑制剂进行预处理可增强抗肿瘤功效并显着延长生存期。这些结果表明，有效静脉内递送溶瘤VV在临床上可能是可以实现的，并且可用于提高溶瘤病毒疗法的抗肿瘤功效。
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