PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models.
PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models.
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DOI：
10.18632/oncotarget.26785
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发表时间：
2019-03-19
期刊：
影响因子：
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通讯作者：
Lin, Amy H
中科院分区：
文献类型：
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作者：
Mitchell, Leah A;Yagiz, Kader;Lin, Amy H
免疫检查点抑制剂（CPI）与许多免疫相关的不良事件和低应答率相关。我们提供了使用对癌细胞具有选择性的逆转录病毒复制载体（RRV）来递送CPI药剂的临床前证据，所述CPI药剂可以规避这些问题并提高功效。编码靶向PD-L1的分泌型单链可变片段的RRV，RRV-scFv-PDL 1，可以有效地与PD-1竞争PD-L1占用。细胞结合测定显示，当感染限于5% RRV-scFv-PDL 1感染的肿瘤细胞时，对培养物中100%的细胞具有反式结合活性。此外，scFv PD-L1拯救PD-1/PD-L1介导的免疫抑制的能力在由人源性免疫细胞组成的共培养系统中得到证实，并在包括颅内肿瘤模型在内的几种同基因小鼠模型中得到进一步证实。这些肿瘤模型显示，用RRV-scFv-PD-L1感染的肿瘤赋予与全身施用的抗PD-1或抗PD-L1单克隆抗体相当或上级的稳健且持久的免疫介导的抗肿瘤活性。重要的是，在血清中检测到的scFv-PD-L1的标称水平比针对靶向免疫检查点的全身施用的治疗性抗体所报道的低50-150倍。这些结果支持以下概念：与目前批准的治疗的全身性单克隆抗体相比，RRV-scFv-PDL 1 CPI策略可提供改善的安全性和有效性特征。
Immune checkpoint inhibitors (CPIs) are associated with a number of immune-related adverse events and low response rates. We provide preclinical evidence for use of a retroviral replicating vector (RRV) selective to cancer cells, to deliver CPI agents that may circumvent such issues and increase efficacy. An RRV, RRV-scFv-PDL1, encoding a secreted single chain variable fragment targeting PD-L1 can effectively compete with PD-1 for PD-L1 occupancy. Cell binding assays showed trans-binding activity on 100% of cells in culture when infection was limited to 5% RRV-scFv-PDL1 infected tumor cells. Further, the ability of scFv PD-L1 to rescue PD-1/PD-L1 mediated immune suppression was demonstrated in a co-culture system consisting of human-derived immune cells and further demonstrated in several syngeneic mouse models including an intracranial tumor model. These tumor models showed that tumors infected with RRV-scFv-PD-L1 conferred robust and durable immune-mediated anti-tumor activity comparable or superior to systemically administered anti-PD-1 or anti PD-L1 monoclonal antibodies. Importantly, the nominal level of scFv-PD-L1 detected in serum is 50-150 fold less than reported for systemically administered therapeutic antibodies targeting immune checkpoints. These results support the concept that RRV-scFv-PDL1 CPI strategy may provide an improved safety and efficacy profile compared to systemic monoclonal antibodies of currently approved therapies.