Béguin Jérémy, Laloy Eve, Cochin Sandrine, Gantzer Murielle, Farine Isabelle, Pichon Christelle, Moreau Baptiste, Foloppe Johann, Balloul Jean-Marc, Machon Christelle, Guitton Jérôme, Tierny Dominique, Klonjkowski Bernard, Quéméneur Eric, Maurey Christelle, Erbs Philippe
Transgene, 67405 Illkirch-Graffenstaden, France.
UMR Virologie, INRAE, École Nationale Vétérinaire d'Alfort, ANSES, Université Paris-Est, 94700 Maisons-Alfort, France.
Mol Ther Oncolytics. 2023 Jul 20;30:103-116. doi: 10.1016/j.omto.2023.07.005. eCollection 2023 Sep 21.
TG6002 is an oncolytic vaccinia virus expressing FCU1 protein, which converts 5-fluorocytosine into 5-fluorouracil. The study objectives were to assess tolerance, viral replication, 5-fluorouracil synthesis, and tumor microenvironment modifications to treatment in dogs with spontaneous malignant tumors. Thirteen dogs received one to three weekly intratumoral injections of TG6002 and 5-fluorocytosine. The viral genome was assessed in blood and tumor biopsies by qPCR. 5-Fluorouracil concentrations were measured in serum and tumor biopsies by liquid chromatography or high-resolution mass spectrometry. Histological and immunohistochemical analyses were performed. The viral genome was detected in blood (7/13) and tumor biopsies (4/11). Viral replication was suspected in 6/13 dogs. The median intratumoral concentration of 5-fluorouracil was 314 pg/mg. 5-Fluorouracil was not detected in the blood. An increase in necrosis (6/9) and a downregulation of intratumoral regulatory T lymphocytes (6/6) were observed. Viral replication, 5-fluorouracil synthesis, and tumor microenvironment changes were more frequently observed with higher TG6002 doses. This study confirmed the replicative properties, targeted chemotherapy synthesis, and reversion of the immunosuppressive tumor microenvironment in dogs with spontaneous malignant tumors treated with TG6002 and 5-fluorocytosine.
TG6002是一种表达FCU1蛋白的溶瘤痘苗病毒，该蛋白可将5-氟胞嘧啶转化为5-氟尿嘧啶。本研究的目的是评估患有自发性恶性肿瘤的犬对治疗的耐受性、病毒复制、5-氟尿嘧啶的合成以及肿瘤微环境的改变。13只犬每周接受1至3次肿瘤内注射TG6002和5-氟胞嘧啶。通过qPCR在血液和肿瘤活检组织中评估病毒基因组。通过液相色谱或高分辨率质谱法测定血清和肿瘤活检组织中的5-氟尿嘧啶浓度。进行了组织学和免疫组织化学分析。在血液（7/13）和肿瘤活检组织（4/11）中检测到病毒基因组。6/13只犬疑似有病毒复制。肿瘤内5-氟尿嘧啶的中位浓度为314 pg/mg。血液中未检测到5-氟尿嘧啶。观察到坏死增加（6/9）和肿瘤内调节性T淋巴细胞下调（6/6）。使用较高剂量的TG6002时，病毒复制、5-氟尿嘧啶合成和肿瘤微环境变化更为常见。本研究证实了用TG6002和5-氟胞嘧啶治疗的患有自发性恶性肿瘤的犬具有复制特性、靶向化疗合成以及免疫抑制性肿瘤微环境的逆转。
