The slow release of IL-12 and GM-CSF from biodegradable microspheres into a single primary tumor nodule promotes the development of potent systemic anti-tumor immunity and the complete eradication of disseminated tumor nodules in a metastatic murine tumor model. The immune mechanisms that mediate the eradication of systemic disease have not yet been defined in this model. Our hypothesis is that the local and sustained release of IL-12 and GM-CSF into the tumor microenvironment promotes the activation of the tumor-associated effector memory T-cells, which then initiate a cascade of local inflammatory events that result in the development of a systemic anti-tumor immunity. To this end, in Aim 1 we will phenotypically and functionally define the T cells that are present in the primary tumor microenvironment and characterize the downstream events that follow their activation. Studies proposed in Aim 2 will address the continuing hypothesis that the induction of inflammatory activity within the primary tumor will prime the development of a long-term systemic anti-tumor T-cell response that effectively infiltrates and suppresses metastatic tumors. ? Preliminary observations suggest that a systemic NKT/NK cell response is also involved in the suppression of metastatic tumors.
In Aim 3 we will test the notion that activation of a systemic but transient NKT/NK response accompanies the early local immune events and that co-induction of innate and adaptive immunity is critical to effective eradication of systemic disease. Finally, in Aim 4 we will test the hypothesis that the intensity of the immediate effector memory T-cell response that is induced within the primary tumor microenvironment determines the efficacy of long-term cure in individual mice. The information derived from these studies is expected to provide valuable insights for the design of an effective, cytokine-based immunotherapeutic strategy for the treatment of cancer patients. ? ?
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