TG6050被设计为改进的溶瘤载体，结合痘苗病毒在肿瘤中选择性复制的内在特性和重组免疫效应子的肿瘤限制性表达来改变肿瘤免疫表型。这些特性可能对“冷”肿瘤特别感兴趣，这些肿瘤要么浸润不良，要么被无能 T 细胞浸润。 TG6050 是一种溶瘤痘苗病毒，编码单链人白细胞介素 12 (hIL-12) 和全长抗细胞毒性 T 淋巴细胞相关抗原 4 (@CTLA-4) 单克隆抗体。 TG6050 的相关特性（复制、细胞病变、转基因表达和功能）在体外得到了广泛的表征。在几种“热”（高度渗透）和“冷”（渗透不良）中研究了病毒载体@CTLA-4和IL-12的生物分布和药代动力学，以及抗肿瘤活性（单独或与免疫检查点抑制剂联合）。 ）同基因小鼠肿瘤模型。通过监测全身和肿瘤内免疫反应以及肿瘤转录组分析，破译了作用机制。在食蟹猴中评估重复静脉注射后 TG6050 的安全性，重点关注循环 IL-12 的水平。 TG6050 在体外和体内肿瘤细胞中的增殖和增殖与功能性 IL-12 和 IL-12 的局部表达相关。 @CTLA-4。这种双重机制在“冷”和“热”肿瘤模型（分别为 B16F10、LLC1 或 EMT6、CT26）中转化为强大的抗肿瘤活性，当与抗程序性细胞死亡蛋白-1 结合时，这种活性进一步增强。对 TG6050 治疗后肿瘤微环境 (TME) 变化的分析显示，干扰素-γ、CD8 T 细胞和 M1/M2 巨噬细胞比率增加，而调节性 T 细胞急剧减少。观察到这些局部修饰同时增强了系统性和特异性抗肿瘤适应性免疫反应。在毒理学研究中，TG6050在食蟹猴中没有表现出任何可观察到的不良反应。TG6050有效地将功能性IL-12和@CTLA-4递送到肿瘤中，从而产生强大的抗肿瘤活性。向发炎 TME 的转变与全身抗肿瘤 T 细胞的增加相关。可靠的临床前数据和有利的获益/风险比为 TG6050 在转移性非小细胞肺癌中的临床评估铺平了道路（NCT05788926 试验正在进行中）。© 作者（或其雇主）2024。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。

TG6050 was designed as an improved oncolytic vector, combining the intrinsic properties of vaccinia virus to selectively replicate in tumors with the tumor-restricted expression of recombinant immune effectors to modify the tumor immune phenotype. These properties might be of particular interest for "cold" tumors, either poorly infiltrated or infiltrated with anergic T cells. TG6050, an oncolytic vaccinia virus encodes single-chain human interleukin-12 (hIL-12) and full-length anti-cytotoxic T-lymphocyte-associated antigen-4 (@CTLA-4) monoclonal antibody. The relevant properties of TG6050 (replication, cytopathy, transgenes expression and functionality) were extensively characterized in vitro. The biodistribution and pharmacokinetics of the viral vector, @CTLA-4 and IL-12, as well as antitumoral activities (alone or combined with immune checkpoint inhibitors) were investigated in several "hot" (highly infiltrated) and "cold" (poorly infiltrated) syngeneic murine tumor models. The mechanism of action was deciphered by monitoring both systemic and intratumoral immune responses, and by tumor transcriptome analysis. The safety of TG6050 after repeated intravenous administrations was evaluated in cynomolgus monkeys, with a focus on the level of circulating IL-12.Multiplication and propagation of TG6050 in tumor cells in vitro and in vivo were associated with local expression of functional IL-12 and @CTLA-4. This dual mechanism translated into a strong antitumoral activity in both "cold" and "hot" tumor models (B16F10, LLC1 or EMT6, CT26, respectively) that was further amplified when combined with anti-programmed cell death protein-1. Analysis of changes in the tumor microenvironment (TME) after treatment with TG6050 showed increases in interferon-gamma, of CD8+T cells, and of M1/M2 macrophages ratio, as well as a drastic decrease of regulatory T cells. These local modifications were observed alongside bolstering a systemic and specific antitumor adaptive immune response. In toxicology studies, TG6050 did not display any observable adverse effects in cynomolgus monkeys.TG6050 effectively delivers functional IL-12 and @CTLA-4 into the tumor, resulting in strong antitumor activity. The shift towards an inflamed TME correlated with a boost in systemic antitumor T cells. The solid preclinical data and favorable benefit/risk ratio paved the way for the clinical evaluation of TG6050 in metastatic non-small cell lung cancer (NCT05788926 trial in progress).© 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.