腹膜癌病是癌症的晚期阶段，其中疾病已扩散至腹膜腔。为了恢复该位置被肿瘤细胞破坏的抗肿瘤免疫，我们评估了经改造的安卡拉牛痘病毒 (MVA) 的腹腔给药，该病毒经过改造可表达单链白细胞介素 12 (scIL-12)，以增强抗肿瘤免疫反应。MVA 编码 scIL-12 (MVA.scIL-12)根据腹膜内肿瘤细胞植入的腹膜癌病模型进行评估。在静脉内、肿瘤内或腹膜内施用病毒载体后，评估了 CD8 介导的免疫反应、阐明的抗肿瘤功效和安全性。通过 ELISpot（酶联免疫吸附点）、RNA 测序、流式细胞术、活体显微镜检查以及用单克隆抗体去除淋巴细胞亚群来测量免疫反应。通过体重随访和血液检测评估安全性。使用编码荧光素酶的报告 MVA 通过生物发光分析评估静脉内或腹膜内给药的组织向性。腹膜内或局部区域给药（但不是其他给药途径）导致有效的免疫反应，其特征是肿瘤特异性 CD8 T 淋巴细胞水平增加，能够产生干扰素-γ和肿瘤坏死因子-α。抗肿瘤免疫反应不仅可以在腹膜腔中检测到，而且可以在全身检测到。作为腹膜内治疗的结果，编码scIL-12的MVA.scIL-12的单次施用完全根除植入腹膜腔中的MC38肿瘤，并且还保护治愈的小鼠免受随后的皮下再次攻击。使用 MVA 编码荧光素酶的生物发光成像显示，腹膜内给药将转基因靶向大网膜。大网膜被认为是腹膜腔免疫保护的关键组织。腹膜内给药的安全性也优于静脉内给药，因为当载体局部递送至腹膜腔时，未观察到体重减轻或血液学毒性。编码 scIL-12 的 MVA 载体的腹膜内给药靶向大网膜，即大网膜。腹膜癌病通常开始的组织。 MVA.scIL-12 诱导有效的肿瘤特异性免疫反应，通常会导致播散到腹膜腔的实验性肿瘤的根除。© 作者（或其雇主）2023。CC BY 允许重复使用-NC。不得商业再利用。请参阅权利和权限。英国医学杂志出版。

Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by tumor cells in this location, we evaluated intraperitoneal administrations of modified vaccinia virus Ankara (MVA) engineered to express single-chain interleukin 12 (scIL-12) to increase antitumor immune responses.MVA encoding scIL-12 (MVA.scIL-12) was evaluated against peritoneal carcinomatosis models based on intraperitoneal engraftment of tumor cells. CD8-mediated immune responses, elucidated antitumor efficacy, and safety were evaluated following intravenous, intratumoral, or intraperitoneal administration of the viral vector. The immune response was measured by ELISpot (enzyme-linked immunosorbent spot), RNA sequencing, flow cytometry, intravital microscopy, and depletion of lymphocyte subsets with monoclonal antibodies. Safety was assessed by body-weight follow-up and blood testing. Tissue tropism on intravenous or intraperitoneal administration was assessed by bioluminescence analysis using a reporter MVA encoding luciferase.Intraperitoneal or locoregional administration, but not other routes of administration, resulted in a potent immune response characterized by increased levels of tumor-specific CD8+ T lymphocytes with the ability to produce both interferon-γ and tumor necrosis factor-α. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result of intraperitoneal treatment, a single administration of MVA.scIL-12 encoding scIL-12 completely eradicated MC38 tumors implanted in the peritoneal cavity and also protected cured mice from subsequent subcutaneous rechallenges. Bioluminescence imaging using an MVA encoding luciferase revealed that intraperitoneal administration targets transgene to the omentum. The omentum is considered a key tissue in immune protection of the peritoneal cavity. The safety profile of intraperitoneal administration was also better than that following intravenous administration since no weight loss or hematological toxicity was observed when the vector was locally delivered into the peritoneal cavity.Intraperitoneal administration of MVA vectors encoding scIL-12 targets the omentum, which is the tissue where peritoneal carcinomatosis usually begins. MVA.scIL-12 induces a potent tumor-specific immune response that often leads to the eradication of experimental tumors disseminated to the peritoneal cavity.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.