Heller Loree C, Shi Guilan, Sales Conniff Amanda, Singh Julie, Mannarino Samantha, Synowiec Jody, Heller Richard
Department of Medical Engineering, University of South Florida, Morsani College of Medicine and College of Engineering, 12901 Bruce B. Downs Blvd., MDC111, Tampa, FL 33612, USA.
Mol Ther Nucleic Acids. 2024 Jul 16;35(3):102267. doi: 10.1016/j.omtn.2024.102267. eCollection 2024 Sep 10.
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 . After intratumor plasmid delivery, both peptides bound PD-L1 on tumor cells. We established that plasmid DNA delivery to tumors or to tumor cells 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.
白细胞介素-12（IL-12）基因电穿孔递送（GET）在诱导小鼠和人类黑色素瘤及其他实体瘤的长期完全消退方面非常有效。免疫检查点抑制剂可增强治疗效果，IL-12质粒GET（pIL-12 GET）与抗程序性细胞死亡蛋白1（PD-1）单克隆抗体的联合应用已进入临床试验阶段。在本研究中，我们设计了编码帕博利珠单抗和纳武利尤单抗程序性细胞死亡1配体1（PD-L1）结合区域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，并为癌症患者提供一种有效且经济高效的治疗选择。我们证明帕博利珠单抗的小鼠同源物在阻断PD-1/PD-L1方面是有效的。在肿瘤内递送质粒后，两种肽均能与肿瘤细胞上的PD-L1结合。我们证实，将质粒DNA递送至肿瘤或肿瘤细胞会上调多种免疫调节因子以及PD-L1的mRNA和蛋白水平，从而增强这种治疗效果。最后，我们测试了pIL-12 GET疗法与肽质粒的联合应用。我们确定，与编码帕博利珠单抗小鼠同源物的质粒联合使用可增强pIL-12 GET的治疗效果。
