PRECLINICAL MODELS FOR TESTING OF BIOLOGICAL CANCER THERAPEUTICS

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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.