24,702 people die in the United States each year because of recurrence following surgical resection of early stage colorectal cancer that might be eliminated with new approaches. There is increasing evidence that the immune system plays a role in controlling micrometastic colorectal cancer and in determining survival. The presence of an increased inflammatory infiltrate in primary tumors, including dendritic cells and T-helper-1 lymphocytes has been independently associated with improved survival. In this proposal we will utilize neoadjuvant photodynamic therapy (PDT) to induce the immune response while the tumor is in situ, maximizing the strength and breadth of the anti-tumor immune response. This should have marked advantages over post-surgical vaccine or other immunomodulatory approaches. Photodynamic therapy (PDT) involves the administration of photosensitizer followed by local illumination with a fixed wavelength in the visible spectrum, generating a localized cytotoxic effect and a local inflammatory/immune response. The localized tissue damage and cell death leads to the formation of a depot of tumor-associated antigens in a microenvironment of damage-associated molecular pattern (DAMP) molecules that are known to activate both the innate and adaptive arms of the immune system leading to priming of the immune system for increased anti-tumor immune responses. We will conduct an initial, phase I/II clinical study to address the central hypothesis that it is safe and feasible to administer intraluminal PDT to colon cancers, via colonoscopy, in the neoadjuvant setting to induce localized tumor cell death and an inflammatory/immune response with an increased Th1 component. First, we will demonstrate the feasibility and safety of colonoscopic, neoadjuvant PDT for colon cancer patients. Next, we will characterize the inflammatory and immune response induced by PDT at the tumor site. Finally, we will evaluate the impact of neoadjuvant PDT on the regional and systemic anti-tumor immune response. To our knowledge this study will be the first evaluation of PDT as an immunomodulator in the neoadjuvant setting for colon cancer. If our hypothesis is demonstrated to be correct, this will provide an easily administered therapeutic maneuver that lacks systemic toxicity, with the potential to modulate the natural biology of colorectal cancers, improve control of micrometastatic tumor, decrease relapse rates and improve survival. PUBLIC HEALTH RELEVANCE: New approaches are needed to reduce the incidence of relapse for patients undergoing surgical resection of colon cancer, the third most common cause of cancer death for women and men in the United States. We will test the hypothesis that neoadjuvant photodynamic therapy will induce an inflammatory and immune response directed against tumor antigens within the tumor microenvironment. These studies may provide the basis for the development of new strategies to improve colon cancer survival.