Tumor-Localized Secretion of Soluble PD1 Enhances Oncolytic Virotherapy.
Tumor-Localized Secretion of Soluble PD1 Enhances Oncolytic Virotherapy.
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DOI：
10.1158/0008-5472.can-16-1638
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Bartee E
中科院分区：
文献类型：
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作者：
Bartee MY;Dunlap KM;Bartee E
溶瘤病毒疗法代表了治疗各种侵袭性或难治性肿瘤的有吸引力的选择。虽然这种疗法在快速减积直接注射的肿瘤块方面是有效的，但实现完全根除已建立的疾病已被证明是困难的。克服这一挑战的一种方法是使用溶瘤病毒来诱导二次抗肿瘤免疫应答。不幸的是，虽然这些免疫应答的初始诱导通常是稳健的，但它们随后的功效通常通过多种免疫调节机制（包括PD 1/PDL 1 T细胞检查点途径）被抑制。为了克服这种抑制，我们产生了一种新的重组粘液瘤病毒（vPD 1），它通过从感染细胞分泌可溶形式的PD 1来特异性抑制肿瘤微环境中的PD 1/PDL 1通路。这种病毒在直接治疗的肿瘤中诱导并维持抗肿瘤CD 8 + T细胞应答，并且证明比使用未修饰的粘液瘤和全身性α PD 1抗体的联合治疗更安全和更有效。局部vPD 1治疗结合全身性消除调节性T细胞对已经在次级实体器官中建立的转移性疾病具有有效的协同作用。这些结果表明，PD 1/PDL 1通路的肿瘤局部抑制可以显著改善溶瘤病毒治疗期间的结果。此外，他们建立了一个可行的路径，将这些发现转化为临床相关疾病。
Oncolytic virotherapy represents an attractive option for the treatment of a variety of aggressive or refractory tumors. While this therapy is effective at rapidly debulking directly injected tumor masses, achieving complete eradication of established disease has proven difficult. One method to overcome this challenge is to use oncolytic viruses to induce secondary anti-tumor immune responses. Unfortunately, while the initial induction of these immune responses is typically robust, their subsequent efficacy is often inhibited through a variety of immunoregulatory mechanisms, including the PD1/PDL1 T-cell checkpoint pathway. To overcome this inhibition, we generated a novel recombinant myxoma virus (vPD1) which inhibits the PD1/PDL1 pathway specifically within the tumor microenvironment by secreting a soluble form of PD1 from infected cells. This virus both induced and maintained anti-tumor CD8+ T-cell responses within directly treated tumors and proved safer and more effective than combination therapy using unmodified myxoma and systemic αPD1 antibodies. Localized vPD1 treatment combined with systemic elimination of regulatory T cells had potent synergistic effects against metastatic disease that was already established in secondary solid organs. These results demonstrate that tumor-localized inhibition of the PD1/PDL1 pathway can significantly improve outcomes during oncolytic virotherapy. Furthermore, they establish a feasible path to translate these findings against clinically relevant disease.