The objective of this proposed study group for clinical trials of cancer therapy with biologic response modifiers (CATBRM Study Group) is to coordinate a highly focused effort in biologic therapies within an established multidisciplinary cancer therapeutics program at Duke University Medical Center (DUMC), the Molecular Therapeutics Program. The Molecular Therapeutics Program has an established track record of translating basic science observations into clinical trials, with a specific goal of testing the hypothesis that the presence of sufficient tumor antigen specific T cells in patients with cancer will lead to a reduction in tumor progression. We propose a CATBRM Study Group to explore the use of specialized antigen presenting cells to initiate cellular immune responses in patients with cancer, specifically focusing on the use of dendritic cells (DC) which are recognized to play a pivotal role in initiating all T-cell responses in vivo. We have focused not only on exploring the use of DCs as antigen presenting cells, but have pioneered the use of cells that are modified to present high levels of antigen and serve as potent inducers of antigen specific T cells in vitro and in in vivo models. In order to remain focused on methods to optimize antigen specific T cell activation, we will initially utilize a single model tumor antigen, carcinoembryonic antigen (CEA). Although a number of tumor antigens have been identified, CEA was chosen as the initial tumor antigen for these studies because it is widely expressed on many common solid tumors (gastrointestinal as well as lung and breast cancers). Furthermore, phase I clinical trials of CEA vaccines have demonstrated its safety and the limited induction of T cell responses against CEA expressing tumor cells and a HLA A2 restricted 9 amino acid peptide epitope, CAP-I from the peripheral blood of patients following vaccination. The use of the CAP-I peptide will allow us to use a highly defined epitope as a stimulator and target for the proposed clinical trial. The three interactive programs proposed for this CATBRM are: Laboratory Program 1. Generation of potent autologous DCs for the in vivo generation of CEA specific T cells. Clinical Program 2. A phase I clinical trial of active immunotherapy with autologous DCs pulsed with a CEA peptide, CAP-I. Laboratory Program 3. Laboratory analysis to monitor the presence, persistence and function of CAP-I specific T cells in the treated patients.
