Developments in cancer therapy have led to impressive improvements in disease free survival, however, relapse of the underlying disease remains the major cause of treatment failure. A majority of cancer patients respond to high dose chemo and radiation therapy and enter a minimal residual disease (MRD) state, but a significant percentage of these patients will eventually relapse. Understanding why some individuals remain free from relapse and then developing strategies to eradicate minimal disease is a major therapeutic goal, which may significantly enhance the overall results of cancer therapies. Modifications to animal models are necessary to develop and evaluate potential treatment modalities for MRD. Such improvements include a method for detecting small numbers of tumor cells and monitoring their growth in living mammals over time. This contrasts with traditional animal models where detection often requires large numbers of tumor cells and therapeutic endpoints include death, gross tumor growth or tissue analysis following sacrifice of the animal. To enable studies of minimal disease the applicant has developed a sensitive detection system in which as few as 1000 tumor cells can be directly visualized and quantified in living animals, and tumor progression monitored over time. Stable tumor cell lines that express a modified firefly luciferase gene emit sufficient light such that photons transmitted through live mammalian tissue can be detected externally with sensitive photon counting cameras. In this application he will utilize this novel approach with several human and murine tumor cell lines and knockout strains of mice to study immune control of minimal disease and in particular the mechanism of anti-tumor activity for ex vivo expanded T cell populations. Specifically, he will optimize the method of treating MRD with expanded human CD3+CD56+ T cells and evaluate the role of cytokines both in vitro and in vivo which activate this population of T cells. He has expanded an analogous population of murine T cells, which co-express the NK marker NK.1.1. He will study the mechanisms by which these ex vivo activated cells eradicate tumors using normal and various knockout mice as a source of effector cells. Finally he will evaluate the trafficking of the CD3+CD8+NK1.1+ effector T cells by tagging these effector cells and monitoring them over time in vivo. Elucidating the mechanism by which tumor cells are killed by immune cells and maximizing this effect in vivo will greatly enhance our ability to apply these cell therapies to the control of human malignant disease.
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