PRECLINICAL MODELS FOR TESTING OF BIOLOGICAL CANCER THERAPEUTICS

在这个项目中，我们试图开发新的临床前模型 测试治疗实验性癌症的新策略。我们的 方法是基于对爱泼斯坦-巴尔病毒不朽的观察 B细胞仅在裸体皮下组织中短暂生长 老鼠。相比之下，Burkitt淋巴瘤和其他肿瘤细胞生长 逐渐地在同一地点，并继续杀死动物。我们检查了 注射EB病毒感染的B细胞能否诱导小鼠 对Burkitt淋巴瘤细胞或其他肿瘤细胞的反应导致 他们的毁灭。我们的研究表明，无论是同时 EBV感染细胞和恶性肿瘤细胞在同一部位注射 或位于不同的部位会导致肿瘤消退。此外，我们还展示了 瘤内注射EBV永生化细胞可导致退化 肿瘤的最新进展。CXC趋化因子IP-10和Mig，以前被鉴定为 有效的血管生成抑制剂，被发现在 肿瘤消退。相比之下，p53基因的突变被发现 测定裸鼠对Burkitt肿瘤的摄取率。 这些研究旨在了解以下各项的优点和局限性 临床前模型用于测试旨在产生 通过直接传递细胞因子或诱导 寄主中的细胞因子反应。如果能够依赖于 加快产品开发的临床前模型，特别是在致命的 癌症等疾病。然而，许多临床前模型已经 显示出有限的实用性，部分原因是它们非常关键 与它们试图模仿的人类情况不同。我们的研究 探索裸鼠模型对评价 细胞疗法治疗免疫缺陷的安全性和有效性 收件人。它们与躯体的评估特别相关 在严重T细胞免疫缺陷的情况下的细胞和基因治疗， 例如在艾滋病中和在固体器官或骨髓中发生 移植受者。

In this project, we sought to develop novel preclinical models in which to test new strategies for the treatment of experimental cancer. Our approach is based on the observation that Epstein-Barr virus-immortalized B cells grow only transiently in the subcutaneous tissues of the nude mouse. In contrast, Burkitt's lymphoma and other tumors cells grow progressively in the same site and go on to kill the animal. We examined whether injection of EBV-infected B cells could be used to induce a murine response to the Burkitt's lymphoma cells or other tumor cells leading to their destruction. Our studies have shown that either simultaneous injection of EBV-infected cells and malignant tumor cells in the same site or in separate sites leads to tumor regression. In addition, we showed that intratumor injections of EBV-immortalized cells leads to regression of the tumors. The CXC chemokines IP-10 and Mig, previously identified as potent inhibitors of angiogenesis, were found to play an important role in tumor regression. In contrast, mutations in the p53 gene were found to determine Burkitt tumor take in the nude mouse. These studies aim at understanding advantages and limitations of preclinical models used to test therapies designed to generate an anti-tumor response by either directly delivering cytokines or inducing a cytokine response in the host. It would be useful to be able to rely on preclinical models to expedite product development, particularly in fatal diseases such as cancer. However, many of the preclinical models have demonstrated limited utility, in part because they are critically different from the human situation they attempt to mimic. Our studies explore the usefulness of a nude mouse model to the evaluation of safety and efficacy of cell therapies delivered to immunodeficient recipients. They are particularly relevant to the evaluation of somatic cell and gene therapies in the context of severe T cell immunodeficiency, such as that occurring in AIDS and in solid organ or bone marrow transplant recipients.