) This proposal is based upon the premise that a clinically effective cell-mediated immune response against human tumors can be elicited by activation of tumor antigen specific cytotoxic T-cells (CTL). To overcome deficiencies in in vivo antigen presentation, we propose an immunotherapy strategy using specialized antigen presenting cells, DCs, generated and loaded ex vivo with a peptide representing a tumor associated antigen, CEA. We are currently conducting a phase I clinical trial of active immunotherapy in patients with CEA overexpressing metastatic cancer who will receive intravenous infusions of an HLA A2 restricted CTL epitope of CEA (CAP-1) peptide pulsed DC. Preliminary results demonstrate the generation of CAP-1 specific T-cells following immunotherapy. It is hypothesized that the generation of CAP-1 specific CTL after CAP-1 peptide pulsed DC infusion will achieve clinically relevant levels in patients with minimal residual disease. Because CEA is overexpressed in 50 percent of breast cancers, one setting in which we can test this hypothesis is in patients with metastatic breast cancer who have achieved a complete clinical response following high dose chemotherapy (HDC) and autologous PBSCT at risk of disease progression or relapse. We propose a phase I clinical trial of active immunotherapy with CAP-1 peptide pulsed DC to be initiated 6 months following PBSCT. As a control, concomitant immunization with a hepatitis B surface antigen (HBsAg) peptide pulsed DC will be performed. This clinical study is designed to determine the feasibility and toxicity of post-transplant active immunotherapy, but in addition, measurements of immune function will be performed to define the time of reconstitution of antigen specific T-cell immunity in the early post-transplant period. We will also determine the magnitude and persistence of a CAP-1 and HBV specific cellular immune response. A second hypothesis, that active immunotherapy will be more efficacious in the early post-transplant period will be tested after we have determined when functional reconstitution of T-cell immunity has occurred. We also propose to perform a pilot study of active immunotherapy two (2) months post-transplant. The overall goal of these two strategies is to determine the feasibility and optimal timing of active immunotherapy post-transplant as a prelude to performing subsequent clinical trials of post-transplantation active immunotherapy.
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