TNFerade, an adenovector carrying the transgene for human tumor necrosis factor α, for patients with advanced solid tumors:: Surgical experience and long-term follow-up
TNFerade, an adenovector carrying the transgene for human tumor necrosis factor α, for patients with advanced solid tumors:: Surgical experience and long-term follow-up
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DOI：
10.1245/aso.2005.03.023
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发表时间：
2005-10-01
影响因子：
3.7
通讯作者：
Kuhn, JA
中科院分区：
文献类型：
--
作者：
McLoughlin, JM;McCarty, TM;Kuhn, JA
背景：在过去的几年中，人们尝试利用肿瘤坏死因子（TNF）-α的杀肿瘤作用来治疗癌症。其中许多研究证明高浓度 TNF-α 会产生剂量限制性全身副作用。最近的重点是开发 TNF-α 的局部递送系统，以尽量减少全身反应。 方法：本研究是使用 TNFerade 的 I 期开放标签多机构试验的一部分。我们专注于贝勒大学医学中心治疗的患者，并提供术后和长期随访。 TNFerade 使用第二代非复制腺病毒作为传递人类转基因 TNF-α 的载体。早期生长反应 I 启动子置于 TNF-α 基因的上游。该启动子由电离辐射激活，从而可以在时间和空间上控制 TNF-α 的释放。肿瘤注射时间超过 5 周，注射后 3 天进行电离辐射，持续 6 周。通过计算机断层扫描和体检来测量肿瘤反应。结果：正如我们最初的经验所述，每次注射剂量达 4 x 10(11) 颗粒时，没有患者出现剂量限制性毒性。注射的肿瘤表现出独立于组织学的反应。四名患者注射的肿瘤完全消退。三名完全消退的患者自治疗起存活≥2年。结论：观察到TNFerade的短期和长期安全性。这些数据表明需要进行 II 期试验。
Background: Over the last several years, attempts have been made to use the tumoricidal effects of tumor necrosis factor (TNF)-alpha to treat cancer. Many of these studies demonstrated dose-limiting systemic side effects from high concentrations of TNF-alpha. The recent focus has been on developing a local delivery system for TNF-alpha to minimize the systemic response.Methods: This study was part of a phase I open-label multi-institutional trial using TNFerade. We focus on the patients treated at Baylor University Medical Center and provide postoperative and long-term follow-up. TNFerade uses a second-generation nonreplicating adenovirus as the vector for delivery of the human transgene TNF-alpha. An early growth response I promoter was placed upstream from the TNF-alpha gene. This promoter is activated by ionizing radiation, thus allowing for temporal and spatial control of TNF-alpha release. Tumors were injected over 5 weeks with ionizing radiation given 3 days after injections for 6 weeks. Tumor response was measured by computed tomographic imaging and physical examination.Results: As described in our original experience, no patients experienced dose-limiting toxicities up to doses of 4 x 10(11) particles per injection. Tumors injected demonstrated a response independently of histology. Four patients had complete regression of the tumor injected. Three patients with complete regression have survived >= 2 years from the time of treatment.Conclusions: Both short-term and long-term safety are observed with TNFerade. These data demonstrate the need for phase II trials.