Local gene delivery of tumor necrosis factor alpha can impact primary tumor growth and metastases through a host-mediated response
Local gene delivery of tumor necrosis factor alpha can impact primary tumor growth and metastases through a host-mediated response
复制标题
DOI：
10.1007/s10585-007-9089-3
复制
发表时间：
2007-11-01
影响因子：
4
通讯作者：
King, C. Richter
中科院分区：
文献类型：
--
作者：
MacGill, Randall S.;Davis, Thomas A.;King, C. Richter
TNFerade（TM）是设计用于在Egr-1放射和化学疗法增强启动子的控制下表达人TNF α的复制缺陷型腺载体，并且目前处于II/III期临床试验中。TNFerade在有限的黑色素瘤患者中的I期临床试验数据表明，肿瘤内注射TNFerade后可能影响远端转移。这些临床观察结果和TNFerade的多种潜在机制使我们假设TNFerade +放疗局部治疗可能影响转移性疾病。我们在临床前模型中使用自发转移的同基因B16 F10小鼠黑色素瘤模型探索了这一假设。建立的皮下B16 F10肿瘤用肿瘤内注射TNFerade和局部2戈伊分割放射疗法治疗，模拟临床治疗方案。治疗10-14天后，评价小鼠髂和腋窝淋巴结中的转移发展。转移负荷与对照组的比较表明TNFerade +/-辐射抑制淋巴结中转移的形成。在TNF受体敲除小鼠中进行的其他实验表明，TNFerade的局部和远端活性严重依赖于宿主介导的反应，其中唯一可能的作用是对含有TNF α受体的肿瘤细胞。这些数据提供了直接的临床前证据，用TNFerade局部治疗实体瘤除了对治疗的病变有影响外，还可以减少转移性疾病。此外，我们发现TNFerade在治疗的肿瘤和淋巴结转移中的宿主依赖性反应表明其具有广泛的活性，与肿瘤组织学无关。
TNFerade (TM) is a replication incompetent adenovector designed to express human TNF alpha under control of the Egr-1 radiation and chemotherapy enhanced promoter, and is currently in Phase II/III clinical testing. Data from Phase I clinical testing of TNFerade in a limited set of melanoma patients suggested the potential to impact distal metastases following intratumoral injections of TNFerade. These clinical observations and the multiple potential mechanisms of TNFerade led us to hypothesize local treatment with TNFerade + radiation may impact metastatic disease. We explored this hypothesis in preclinical models using the spontaneously metastatic, syngeneic B16F10 murine melanoma model. Established subcutaneous B16F10 tumors were treated with intratumoral injections of TNFerade and localized 2 Gy fractionated radiation therapy, modeling the clinical treatment regimen. Following 10-14 days of treatment, mice were evaluated for metastases development in the iliac and axillary lymph nodes. Comparisons of metastatic burden to control groups indicated TNFerade +/- radiation suppressed the formation of metastases in the lymph nodes. Additional experiments in TNF receptor knockout mice, where the only possible effects are on tumor cells containing the TNF alpha receptor, indicate TNFerade's local and distal activities are critically dependent on a host-mediated response. These data provide direct preclinical evidence local therapy of a solid tumor with TNFerade can also reduce metastatic disease, in addition to effects on the treated lesion. Furthermore, our finding of a host dependant response(s) for TNFerade at both the treated tumor and on lymph node metastases suggest the potential for broad activity independent of tumor histology.