Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus
Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus
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DOI：
10.1093/neuonc/not317
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发表时间：
2014-08-01
期刊：
影响因子：
15.9
通讯作者：
Rabkin, Samuel D.
中科院分区：
文献类型：
--
作者：
Antoszczyk, Slawomir;Spyra, Melanie;Rabkin, Samuel D.
恶性周围神经鞘瘤 (MPNST) 是一种侵袭性且通常致命的肉瘤，常发生于 1 型神经纤维瘤病 (NF1) 患者中。我们开发了新的临床前 MPNST 模型，并测试了溶瘤单纯疱疹病毒 (oHSV) 的功效，这是一种有前景的癌症治疗药物，可选择性地在癌细胞中复制并杀死癌细胞。将小鼠 NF1(-) MPNST 细胞系和人 NF1(-) MPNST 干细胞 (MSLC) 分别植入免疫活性小鼠和无胸腺小鼠的坐骨神经中。使用后肢评分系统进行外部测量和坐骨神经缺陷来跟踪肿瘤生长。将溶瘤 HSV G47 Delta 以及表达血小板因子 4 (PF4) 或白细胞介素 (IL)-12 的“武装”G47 Delta 瘤内注射到已建立的坐骨神经肿瘤中。小鼠 MPNST 细胞系形成具有不同生长动力学的肿瘤。在来自无胸腺小鼠的人 S462 MSLC 或免疫活性小鼠的小鼠 M2 (37-3-18-4) 细胞的坐骨神经肿瘤中单次瘤内注射 G47 Delta 可显着抑制肿瘤生长并延长生存期。局部 IL-12 表达显着提高了同基因小鼠中 G47 Delta 的功效，而 PF4 表达则延长了生存期。将 G47 Delta 直接注射到无胸腺小鼠的坐骨神经中仅导致轻微症状，与磷酸盐缓冲盐水对照没有差异。描述了两种新的原位 MPNST 模型，包括在同系小鼠中，扩大了临床前测试的选择。溶瘤 HSV G47 Delta 在免疫缺陷和免疫功能正常的 MPNST 模型中均表现出强大的功效，同时保持安全性。 IL-12 表达提高了疗效。这些研究支持 G47 Delta 对 MPNST 患者的临床转化。
Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive and often lethal sarcoma that frequently develops in patients with neurofibromatosis type 1 (NF1). We developed new preclinical MPNST models and tested the efficacy of oncolytic herpes simplex viruses (oHSVs), a promising cancer therapeutic that selectively replicates in and kills cancer cells.Mouse NF1(-) MPNST cell lines and human NF1(-) MPNST stemlike cells (MSLCs) were implanted into the sciatic nerves of immunocompetent and athymic mice, respectively. Tumor growth was followed by external measurement and sciatic nerve deficit using a hind-limb scoring system. Oncolytic HSV G47 Delta as well as "armed" G47 Delta expressing platelet factor 4 (PF4) or interleukin (IL)-12 were injected intratumorally into established sciatic nerve tumors.Mouse MPNST cell lines formed tumors with varying growth kinetics. A single intratumoral injection of G47 Delta in sciatic nerve tumors derived from human S462 MSLCs in athymic mice or mouse M2 (37-3-18-4) cells in immunocompetent mice significantly inhibited tumor growth and prolonged survival. Local IL-12 expression significantly improved the efficacy of G47 Delta in syngeneic mice, while PF4 expression prolonged survival. Injection of G47 Delta directly into the sciatic nerve of athymic mice resulted in only mild symptoms that did not differ from phosphate buffered saline control.Two new orthotopic MPNST models are described, including in syngeneic mice, expanding the options for preclinical testing. Oncolytic HSV G47 Delta exhibited robust efficacy in both immunodeficient and immunocompetent MPNST models while maintaining safety. Interleukin-12 expression improved efficacy. These studies support the clinical translation of G47 Delta for patients with MPNST.