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Examining CIK cell trafficking to breast tumor tissue in vivo
Background: A promising new direction in cancer therapy is the use of cytokine-induced killer (CIK) cells as broadly active tumoricidal agents. CIK cells derive from blood samples stimulated ex vivo, and these activated immune cells are capable of recognizing and destroying a plethora of tumor targets in vivo. In fact, CIK cells have demonstrated efficacy in clinical trials to treat patients with hepatoma, renal cell cancer, and hematological malignancies, and pre-clinical studies suggest they will also be efficacious in treating breast cancer. Despite the remarkable clinical promise of this therapy, little is known about the mechanisms that govern CIK cell migration from the bloodstream to tumor tissue in vivo. Understanding the trafficking patterns of these potent immune cells is of critical importance to advancing their use in humans Objective/Hypothesis: This proposal seeks to investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue. Specific Aims: 1. Screen ex vivo expanded CIK cells for markers of vascular adhesion; 2. Profile tumor-infiltrating CIK cells for novel markers of tumor recognition; 3. Visualize CIK trafficking to breast tumors using bioluminescence imaging (BLI) Study design: A variety of experimental approaches will be employed to investigate CIK cell trafficking from the bloodstream to tumor targets. First, CIK cells and breast tumor endothelia will be screened for the presence of proteins and glycans known to mediate leukocyte-blood vessel adhesion during the inflammatory response. Second, global profiling experiments will be performed on CIK cells to identify potentially novel CIK cell markers involved in the migration process. Last, the effects of the putative tumor-targeting molecules on CIK cell migration will be examined in murine tumor models using bioluminescence imaging (BLI). Potential Outcomes and Benefits: Collectively, these experiments will define the repertoire of molecules employed in CIK cell recognition of the breast tumor vasculature. Such information will guide the development of improved CIK cell-mediated cancer therapies, along with new mechanisms for targeted delivery of anticancer agents to tumor tissue. While we will focus our efforts on models of breast cancer, the potential exists to apply our findings to multiple types of malignancy and minimal residual disease.
Background: One of the most promising directions in breast cancer therapy involves stimulating the immune system to seek out and destroy tumors. Tumor cells possess several abnormal traits that, in theory, should render them "foreign" to the immune system. However, cancer cells are often able to escape targeted destruction by the body's defenses. Immunotherapies aim to provide an extra "boost" to the body?s immune cells to promote tumor cell killing. Once stimulated, the immune cells are better equipped to attack and reject tumor tissue. Cytokine-induced killer (CIK) cells are among the most potent of these activated immune cells. They derive from patient blood samples that are treated with an assortment of stimulants ex vivo, and then introduced back into the host. CIK cells have demonstrated remarkable tumor-killing properties in both mouse models of cancer and human patients. Despite the remarkable clinical promise of CIK cell therapy, little is known about the mechanisms that govern CIK cell migration to tumor tissue in vivo. Understanding the trafficking patterns of these potent agents is of critical importance to advancing their use in a clinical setting. Objective/Aims/Study Design: This proposal seeks to investigate CIK cell trafficking from the bloodstream to breast tumor targets, and a variety of experimental approaches will be employed toward this end. First, CIK cells and breast tumor samples will be screened for the presence of markers known to regulate interactions between normal immune cells and blood vessel walls. Second, global profiling experiments will be performed on CIK cells to identify potentially novel molecules involved in the migration process. Last, the effects of these molecules on CIK cell migration will be examined in living animals using noninvasive imaging technologies. Potential Outcomes and Benefits: Collectively, these experiments will define the repertoire of molecules employed in CIK cell migration to breast tumor tissue and guide the development of improved CIK cell therapies for clinical use. Additionally, such information could be used to engineer novel homing mechanisms into other cell types for tumor-specific delivery of therapeutic agents.