白介素 12 (IL-12) 基因电转移 (GET) 递送对于诱导小鼠和人类黑色素瘤及其他实体瘤的长期、完全消退非常有效。免疫检查点抑制剂增强了治疗效果，IL-12质粒GET（pIL-12 GET）与抗程序性细胞死亡蛋白1（PD-1）单克隆抗体的组合已进入临床试验。在这项研究中，我们设计了编码 pembrolizumab 和 nivolumab 程序性细胞死亡 1 配体 1 (PD-L1) 结合区的小鼠同源物的肽和质粒。我们假设肿瘤内自分泌/旁分泌肽表达会阻断 PD-1/PD-L1 结合，并为癌症患者提供有效且经济高效的治疗替代方案。我们证明了派姆单抗的小鼠同源物可在体外有效阻断 PD-1/PD-L1。肿瘤内质粒递送后，两种肽均与肿瘤细胞上的 PD-L1 结合。我们确定，将质粒 DNA 递送到体内肿瘤或体外肿瘤细胞上调了几种免疫调节剂以及 PD-L1 mRNA 和蛋白质，从而增强了这种疗法。最后，我们测试了 pIL-12 GET 疗法和肽质粒的组合。我们确定，通过与编码 pembrolizumab 小鼠同源物的质粒组合，可以增强 pIL-12 GET 的治疗效果。© 2024 作者。

Interleukin-12 (IL-12) gene electrotransfer (GET) delivery is highly effective in inducing long-term, complete regression in mouse and human melanoma and other solid tumors. Therapeutic efficacy is enhanced by immune checkpoint inhibitors, and the combination of IL-12 plasmid GET (pIL-12 GET) and anti-programmed cell death protein 1 (PD-1) monoclonal antibodies has reached clinical trials. In this study, we designed peptides and plasmids encoding the mouse homologs of the pembrolizumab and nivolumab programmed cell death 1 ligand 1 (PD-L1) binding regions. We hypothesized that intratumor autocrine/paracrine peptide expression would block PD-1/PD-L1 binding and provide cancer patients with an effective and cost-efficient treatment alternative. We demonstrated that the mouse homolog to pembrolizumab was effective at blocking PD-1/PD-L1 in vitro. After intratumor plasmid delivery, both peptides bound PD-L1 on tumor cells. We established that plasmid DNA delivery to tumors in vivo or to tumor cells in vitro upregulated several immune modulators and PD-L1 mRNA and protein, potentiating this therapy. Finally, we tested the combination of pIL-12 GET therapy and peptide plasmids. We determined that pIL-12 GET therapeutic efficacy could be enhanced by combination with the plasmid encoding the pembrolizumab mouse homolog.© 2024 The Author(s).