Oncolytic virotherapy with intratumoral injection of vaccinia virus TG6002 and 5-fluorocytosine administration in dogs with malignant tumors.

IF 5.3 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy Oncolytics Pub Date : 2023-09-21 DOI:10.1016/j.omto.2023.07.005

Jérémy Béguin, Eve Laloy, Sandrine Cochin, Murielle Gantzer, Isabelle Farine, Christelle Pichon, Baptiste Moreau, Johann Foloppe, Jean-Marc Balloul, Christelle Machon, Jérôme Guitton, Dominique Tierny, Bernard Klonjkowski, Eric Quéméneur, Christelle Maurey, Philippe Erbs

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Abstract

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.

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肿瘤内注射牛痘病毒TG6002及5-氟胞嘧啶对犬恶性肿瘤的溶瘤病毒治疗。

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。该研究的目的是评估自发性恶性肿瘤狗的耐受性、病毒复制、5-氟尿嘧啶合成和肿瘤微环境改变对治疗的影响。13只狗每周接受一至三次肿瘤内注射TG6002和5-氟胞嘧啶。采用qPCR方法在血液和肿瘤活检中评估病毒基因组。用液相色谱法或高分辨率质谱法测定血清和肿瘤活检中5-氟尿嘧啶的浓度。进行组织学和免疫组织化学分析。在血液(7/13)和肿瘤活检(4/11)中检测到病毒基因组。在6/13只狗中怀疑病毒复制。5-氟尿嘧啶的中位瘤内浓度为314 pg/mg。血液中未检出5-氟尿嘧啶。坏死增加(6/9)，瘤内调节性T淋巴细胞下调(6/6)。TG6002剂量越大，观察到的病毒复制、5-氟尿嘧啶合成和肿瘤微环境变化越频繁。本研究证实了TG6002和5-氟胞嘧啶治疗犬自发性恶性肿瘤的复制特性、靶向化疗合成和免疫抑制肿瘤微环境的逆转。

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来源期刊

Molecular Therapy Oncolytics Medicine-Oncology

CiteScore

10.90

自引率

3.50%

发文量

152

审稿时长

6 weeks

期刊介绍： Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.