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， 来测试治疗实验性癌症的新策略。 我们 这种方法是基于观察到爱泼斯坦-巴尔病毒永生化 B细胞仅在裸鼠皮下组织中短暂生长 老鼠. 与此相反，伯基特淋巴瘤和其他肿瘤细胞生长 在同一个地方逐渐地杀死动物。 我们研究 注射EBV感染的B细胞是否可用于诱导小鼠 对伯基特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， 在同一部位注射EBV感染的细胞和恶性肿瘤细胞 或在不同的部位导致肿瘤消退。 此外，我们还展示了 瘤内注射EB病毒永生化细胞会导致消退 的肿瘤。 CXC趋化因子IP-10和Mig，以前被鉴定为 血管生成的有效抑制剂，被发现在 肿瘤消退 与此相反，p53基因突变被发现， 测定裸鼠体内Burkitt瘤的摄取量。 这些研究旨在了解 临床前模型，用于测试旨在产生 通过直接递送细胞因子或诱导抗肿瘤应答， 宿主中的细胞因子应答。 如果能够依靠 临床前模型，以加快产品开发，特别是在致命的 疾病，如癌症。 然而，许多临床前模型具有 证明了有限的效用，部分原因是它们是关键的 与他们试图模仿的人类情况不同。 我们的研究 探索裸鼠模型的有用性，以评估 免疫缺陷患者细胞治疗的安全性和有效性 受惠人士 它们特别适用于评估体细胞 严重T细胞免疫缺陷背景下的细胞和基因疗法， 例如发生在艾滋病和实体器官或骨髓中 移植接受者

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.