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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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).
摘要：
背景：TG6050被设计为一种改进的溶瘤载体，结合痘苗病毒在肿瘤中选择性复制的固有特性与肿瘤限制性表达的重组免疫效应因子来修饰肿瘤免疫表型。这些特性可能对“冷”肿瘤特别感兴趣，浸润不良或浸润无能T细胞。
方法：溶瘤痘苗病毒TG6050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的相关属性(复制，细胞病,转基因的表达和功能）在体外进行了广泛的表征。病毒载体的生物分布和药代动力学，@CTLA-4和IL-12，以及抗肿瘤活性（单独或与免疫检查点抑制剂组合）在几个“热”（高浸润）和“冷”（低浸润）同系小鼠肿瘤模型中进行了研究。通过监测全身和肿瘤内免疫反应来破译作用机制，和肿瘤转录组分析。在食蟹猴中评估了TG6050反复静脉给药后的安全性，重点关注循环IL-12的水平。
结果：TG6050在肿瘤细胞体内和体外增殖与功能性IL-12和@CTLA-4的局部表达相关。这种双重机制在“冷”和“热”肿瘤模型（分别为B16F10，LLC1或EMT6，CT26）中都转化为强大的抗肿瘤活性，当与抗程序性细胞死亡蛋白1结合使用时，该活性被进一步放大。对TG6050治疗后肿瘤微环境（TME）变化的分析显示干扰素-γ增加，CD8+T细胞，和M1/M2巨噬细胞比率，以及调节性T细胞的急剧减少。观察到这些局部修饰同时支持系统性和特异性抗肿瘤适应性免疫应答。在毒理学研究中，TG6050在食蟹猴中没有显示任何可观察到的不良反应。
结论：TG6050有效地将功能性IL-12和@CTLA-4传递到肿瘤中，导致强烈的抗肿瘤活性。向发炎的TME的转变与全身性抗肿瘤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)。
方法：溶瘤痘苗病毒TG6050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的相关属性(复制，细胞病,转基因的表达和功能）在体外进行了广泛的表征。病毒载体的生物分布和药代动力学，@CTLA-4和IL-12，以及抗肿瘤活性（单独或与免疫检查点抑制剂组合）在几个“热”（高浸润）和“冷”（低浸润）同系小鼠肿瘤模型中进行了研究。通过监测全身和肿瘤内免疫反应来破译作用机制，和肿瘤转录组分析。在食蟹猴中评估了TG6050反复静脉给药后的安全性，重点关注循环IL-12的水平。
结果：TG6050在肿瘤细胞体内和体外增殖与功能性IL-12和@CTLA-4的局部表达相关。这种双重机制在“冷”和“热”肿瘤模型（分别为B16F10，LLC1或EMT6，CT26）中都转化为强大的抗肿瘤活性，当与抗程序性细胞死亡蛋白1结合使用时，该活性被进一步放大。对TG6050治疗后肿瘤微环境（TME）变化的分析显示干扰素-γ增加，CD8+T细胞，和M1/M2巨噬细胞比率，以及调节性T细胞的急剧减少。观察到这些局部修饰同时支持系统性和特异性抗肿瘤适应性免疫应答。在毒理学研究中，TG6050在食蟹猴中没有显示任何可观察到的不良反应。
结论：TG6050有效地将功能性IL-12和@CTLA-4传递到肿瘤中，导致强烈的抗肿瘤活性。向发炎的TME的转变与全身性抗肿瘤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)。
