Increased appearance of dendritic cells (DC) within human solid tumor masses in situ has been associated indirectly with better prognosis. Immature DC can efficiently acquire antigen from apoptotic cell bodies and induce MHC class I-restricted, antigen- specific cytotoxic T lymphocytes. This finding adds additional support to the concept that DC may play the predominant role in """"""""cross-priming"""""""" events for the elicitation of an immune response in vivo. Our previous studies demonstrated that DC in early culture are highly active at uptaking high molecular weight dextran particles as well as whole tumor lysates in vitro. Because of these findings, it is conceivable that DC may offer an efficient means for triggering immune responses within tumors, particularly in those masses containing a significant baseline level of apoptotic cell bodies. Indeed, we have found that direct intratumoral (IT) injections of """"""""unpulsed"""""""" (i.e. not tumor antigen-loaded or pulsed) DC can mediate the regression of established breast tumor nodules in mice. This antitumor effect appears to be directly correlated with the level of baseline apoptosis measured within the tumor mass before the local delivery of DC. Of importance, tumor nodules at distant sites from the DC-injected tumor nodule also underwent regression. The immunotherapeutic effect elicited by IT injections of DC in this murine breast tumor model is critically dependent upon activation of a host-derived T cell (CD8+) immune response, both locally and systemically. The hypothesis driving this RO1 application is that approaches that elicit enhanced apoptosis of tumors in vivo will augment both the therapeutic efficacy and immune stimulatory capacity of DC. We propose to develop new experimental and clinical strategies for the treatment of breast cancer that utilize potent antigen presenting DC combined with agents that can selectively elicit tumor apoptosis in vivo. Our rationale is based on experimental data and methodologies that we have developed in both murine and human tumor systems.
The Specific Aims of our proposal are to: 1. Investigate experimentally the direct IT administration of DC alone and combined with tumor cell apoptosis-inducing agents in a relevant murine breast (MT-901) tumor model; 2. Investigate clinically in phase II trials the direct IT administration of DC in patients with advanced breast cancer. The overall goal of our translational research effort will be to develop a new, innovative strategy for the treatment of advanced breast cancer that employs tumor apoptosis-inducing agents combined with DC.
