Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers.
Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers.
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DOI：
10.1158/1078-0432.ccr-22-1382
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发表时间：
2022-12-15
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使用单纯疱疹病毒-1（HSV）的溶瘤病毒疗法已显示出治疗儿科和成人脑肿瘤的前景;然而，由于脑室内/鞘内毒性问题，已完成和正在进行的临床试验已使用瘤内/瘤周溶瘤HSV（oHSV）接种。瘤内递送需要侵入性神经外科手术，限制重复注射，并排除直接靶向转移性和软脑膜疾病。为了解决这些局限性，我们确定了脑室内oHSV毒性的原因，并建立了减轻毒性的方法来治疗小鼠中的播散性脑肿瘤。HSV敏感性CBA/J小鼠脑室内接受溶媒、灭活的oHSV或处理剂量（1×107空斑形成单位）的oHSV，通过体重减轻和免疫组织化学评估毒性。评价了降低oHSV毒性的保护性策略，包括在oHSV治疗剂量之前脑室内低剂量oHSV或干扰素诱导剂聚肌苷酸-聚胞苷酸（poly I：C），然后用于评估脑室内oHSV治疗多种播散性CNS疾病模型。标准治疗剂量的脑室内oHSV通过病毒复制和诱导CD 8 + T细胞来损伤室管膜细胞，而溶剂或灭活病毒则没有毒性。随后剂量的脑室内oHSV引起的额外毒性很小。通过低剂量oHSV或poly I：C脑室内预处理，干扰素诱导真核起始因子-2 α（eIF 2 α）磷酸化可减轻室管膜毒性。这种方法能够安全递送临床相关的oHSV G207的多个治疗剂量，并延长播散性脑肿瘤模型中的存活期。可以减轻来自脑室内oHSV的毒性，从而产生治疗益处。这些数据支持脑室内G207的临床翻译。
Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and immunohistochemistry. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. Toxicity from intraventricular oHSV can be mitigated resulting in therapeutic benefit. These data support clinical translation of intraventricular G207.