Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mol Ther. 2021 Feb 3;29(2):658-670. doi: 10.1016/j.ymthe.2020.11.001. Epub 2020 Nov 5.
Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen-presenting cell activation, and T cell stimulation. This phase I dose-escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A single intra-tumoral AdV-tk injection in three dose cohorts (maximum 10 viral particles) was performed during diagnostic staging, followed by a 14-day course of the prodrug valacyclovir, and subsequent surgery 1 week later. Twelve patients participated after appropriate informed consent. Vector-related adverse events were minimal. Immune biomarkers were evaluated in tumor and blood before and after GMCI. Significantly increased infiltration of CD8 T cells was found in resected tumors. Expression of activation, inhibitory, and proliferation markers, such as human leukocyte antigen (HLA)-DR, CD38, Ki67, PD-1, CD39, and CTLA-4, were significantly increased in both the tumor and peripheral CD8 T cells. Thus, intratumoral AdV-tk injection into non-small-cell lung cancer (NSCLC) proved safe and feasible, and it effectively induced CD8 T cell activation. These data provide a foundation for additional clinical trials of GMCI for lung cancer patients with potential benefit if combined with other immune therapies.
基因介导的细胞毒性免疫疗法（GMCI）是一种肿瘤免疫治疗方法，涉及局部递送表达单纯疱疹胸苷激酶（AdV-tk）的复制缺陷型腺病毒，然后进行抗疱疹前药激活，促进免疫原性肿瘤细胞死亡、抗原呈递细胞激活和 T 细胞刺激。这项 I 期剂量递增试验评估了怀疑患有肺癌且适合手术的患者支气管内递送 AdV-tk。在诊断分期期间，在三个剂量组（最多 10 个病毒颗粒）中进行单次肿瘤内 AdV-tk 注射，然后使用前药伐昔洛韦 14 天，并在 1 周后进行手术。在适当的知情同意后，有 12 名患者参与了试验。载体相关不良事件较少。在 GMCI 前后评估了肿瘤和血液中的免疫生物标志物。在切除的肿瘤中发现 CD8 T 细胞浸润显著增加。在肿瘤和外周血 CD8 T 细胞中，激活、抑制和增殖标志物（如人类白细胞抗原（HLA）-DR、CD38、Ki67、PD-1、CD39 和 CTLA-4）的表达均显著增加。因此，非小细胞肺癌（NSCLC）肿瘤内注射 AdV-tk 安全可行，并能有效诱导 CD8 T 细胞激活。这些数据为 GMCI 联合其他免疫疗法治疗肺癌患者的进一步临床试验提供了基础，如果联合其他免疫疗法，可能会带来潜在益处。
