Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody.
Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody.
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DOI：
10.18632/oncotarget.16137
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发表时间：
2017-03-28
期刊：
影响因子：
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通讯作者：
Greiner JW
中科院分区：
文献类型：
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作者：
Fallon JK;Vandeveer AJ;Schlom J;Greiner JW
设计用于将 IL-12 递送至实体瘤坏死区域的免疫细胞因子与破坏免疫抑制 PD-1/PD-L1 轴的抗 PD-L1 抗体的组合治疗潜力在多种小鼠肿瘤模型中产生了组合益处。鼠类免疫细胞因子 NHS-muIL12 由识别 DNA/DNA-组蛋白复合物的抗体 (NHS76) 组成，并与鼠类 IL-12 (NHS-muIL12) 的两个分子融合。通过识别暴露的 DNA，NHS-muIL12 将 IL-12 靶向肿瘤的坏死部分；与重组鼠IL-12相比，其血浆半衰期更长，对鼠肿瘤的抗肿瘤功效更好。这里显示，NHS-muIL12 以 IFN-γ 依赖性机制上调小鼠肿瘤上的 mPD-L1 表达，这可以解释为免疫抑制作用。然而，NHS-muIL12 和抗 PD-L1 抗体的同时治疗在表达 PD-L1 的皮下移植肿瘤（MC38、MB49）和膀胱内肿瘤模型（MB49）中产生了叠加/协同抗肿瘤作用。抗肿瘤功效与 (a) 肿瘤抗原特异性脾 CD8+ T 细胞出现频率较高以及 (b) 在较宽的 NHS-muIL12 浓度范围内增强的 T 细胞活化相关。这些发现表明，结合 NHS-muIL12 和抗 PD-L1 抗体可增强肿瘤微环境中的 T 细胞活化和 T 细胞效应功能，从而显着改善整体肿瘤消退。这些结果应该为在临床研究中检查这些药物的组合提供依据。
The combined therapeutic potential of an immunocytokine designed to deliver IL-12 to the necrotic regions of solid tumors with an anti-PD-L1 antibody that disrupts the immunosuppressive PD-1/PD-L1 axis yielded a combinatorial benefit in multiple murine tumor models. The murine version of the immunocytokine, NHS-muIL12, consists of an antibody (NHS76) recognizing DNA/DNA-histone complexes, fused with two molecules of murine IL-12 (NHS-muIL12). By its recognition of exposed DNA, NHS-muIL12 targets IL-12 to the necrotic portions of tumors; it has a longer plasma half-life and better antitumor efficacy against murine tumors than recombinant murine IL-12. It is shown here that NHS-muIL12, in an IFN-γ‒dependent mechanism, upregulates mPD-L1 expression on mouse tumors, which could be construed as an immunosuppressive action. Yet concurrent therapy with NHS-muIL12 and an anti-PD-L1 antibody resulted in additive/synergistic antitumor effects in PD-L1‒expressing subcutaneously transplanted tumors (MC38, MB49) and in an intravesical bladder tumor model (MB49). Antitumor efficacy correlated with (a) with a higher frequency of tumor antigen-specific splenic CD8+ T cells and (b) enhanced T cell activation over a wide range of NHS-muIL12 concentrations. These findings suggest that combining NHS-muIL12 and an anti-PD-L1 antibody enhances T cell activation and T cell effector functions within the tumor microenvironment, significantly improving overall tumor regression. These results should provide the rationale to examine the combination of these agents in clinical studies.