肿瘤选择性溶瘤病毒载体是有前景的抗癌疗法；然而，晚期/转移性癌症的剂量和效力方面的挑战限制了疗效和使用。 NG-350A 是下一代血液稳定的腺病毒载体，经过改造可表达激动剂抗分化簇 (CD)40 抗体，而不影响肿瘤选择性和溶瘤效力。评估了 NG-350A 的静脉内和瘤内 (IT) 给药在转移性/晚期上皮肿瘤患者的 Ia/Ib 期研究中 (NCT03852511)。分别对静脉注射（有四种剂量水平，每种剂量水平在 57 天治疗期的第 1、3 和 5 天进行输注）和 IT（仅在第 1 天单次注射或在第 1、8、15 天和第 1、8、15 天进行注射）分别进行剂量递增。 22）行政管理。主要目标是安全性和耐受性；次要目标包括确定推荐剂量、药代动力学和免疫原性。总共有 25 名经过深度治疗的患者接受了 NG-350A（16 名静脉注射，9 名 IT 给药）。静脉注射和 IT 给药均具有良好的耐受性，没有证据表明转基因相关或脱靶病毒毒性。静脉内和 IT 给药导致全身 NG-350A Cmax 呈剂量依赖性增加。尽管两种给药途径都会诱导抗病毒抗体，但在最后一次给药后长达 7 周内观察到 NG-350A 在血液样本中持续存在，特别是在静脉注射剂量水平较高的情况下。两种给药途径的活检样本都证明了 NG-350A 能够递送至肿瘤；静脉输注观察到剂量依赖性模式，第 57 天时有 4 名患者的活检中载体 DNA 保持阳性。在 5/12 接受静脉治疗的患者和 1/9 接受 IT 治疗的患者中检测到复制 NG-350A 的转基因信使 RNA注射后观察到炎症细胞因子持续增加，特别是静脉注射剂量水平较高时。这项 1a 期研究为 NG-350A 提供了初步的机制证明，并提供了肿瘤递送、病毒复制和转基因表达的有力证据，尤其是静脉给药后。缺乏转基因相关或脱靶病毒毒性与 NG-350A 的高度选择性递送和复制一致，即使是在全身递送后也是如此。现在将评估静脉给药 NG-350A 与派姆单抗 (NCT05165433) 以及放化疗 (NCT06459869) 组合的疗效。NCT05165433、NCT06459869。© 作者（或其雇主）2024 年。 Re - CC BY-NC 允许使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Tumor-selective oncolytic viral vectors are promising anticancer therapeutics; however, challenges with dosing and potency in advanced/metastatic cancers have limited efficacy and usage. NG-350A is a next-generation blood-stable adenoviral vector engineered to express an agonist anti-cluster of differentiation (CD)40 antibody without affecting tumor-selectivity and oncolytic potency.Intravenous and intratumoral (IT) administration of NG-350A was assessed in a phase Ia/Ib study in patients with metastatic/advanced epithelial tumors (NCT03852511). Dose-escalation was performed separately for intravenous (four dose levels available, each with infusions on Days 1, 3 and 5 of a 57-day treatment period) and IT (single injection on D1 only or injections on Days 1, 8, 15 and 22) administration. The primary objective was safety and tolerability; secondary objectives included determining a recommended dose, pharmacokinetics, and immunogenicity.In total, 25 heavily pretreated patients received NG-350A (16 with intravenous and 9 with IT administration). Intravenous and IT dosing were both well tolerated, with no evidence of transgene-related or off-target viral toxicity. Intravenous and IT dosing resulted in dose-dependent increases in systemic NG-350A Cmax. Despite both routes of administration inducing anti-virus antibodies, sustained persistence of NG-350A in blood samples was observed up to 7 weeks after the last dose, particularly with higher intravenous dose levels. Delivery of NG-350A to tumors was demonstrated in biopsy samples following both routes of administration; a dose-dependent pattern was seen with intravenous infusion, with four patients remaining positive for vector DNA in biopsies at Day 57. Transgene messenger RNA from replicating NG-350A was detected in 5/12 patients with intravenous treatment and 1/9 patients with IT injection, and sustained increases in inflammatory cytokines were observed following dosing, particularly with higher intravenous dose levels.This phase 1a study provided initial proof-of-mechanism for NG-350A, with strong evidence of tumor delivery, viral replication and transgene expression-particularly after intravenous dosing. The lack of transgene-related or off-target viral toxicity was consistent with the highly selective delivery and replication of NG-350A, even after systemic delivery. The efficacy of intravenous-dosed NG-350A will now be evaluated in combination with pembrolizumab (NCT05165433), as well as with chemoradiotherapy (NCT06459869).NCT05165433, NCT06459869.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.