The majority of ovarian cancer patients have advanced disease at the time of diagnosis, and ovarian cancer has the highest mortality rate among gynecological malignancies. Immunotherapy based on induction of tumor-specific cytotoxic T lymphocyte (CTL) responses may represent a viable treatment for these patients. The prospects for immunological treatment of cancer have risen sharply in recent years, based in part on concerted efforts to identify tumor-specific antigens that may serve as CTL targets, and in part on the application of dendritic cells (DC) as powerful inducers of tumor-specific T cell responses. DCV Technologies will exploit the identification of a series of novel ovarian tumor antigens, in particular stratum corneum chymotryptic enzyme (SCCE), for the development of therapeutic DC vaccines for ovarian cancer. SCCE is highly expressed in ovarian cancer, but not in normal ovaries or other normal adult tissues. DC pulsed with SCCE peptides can stimulate CD4+ helper T cell responses and HLA A2.1-restricted CD8+ CTL that kill A2.1-matched ovarian tumor cells. The 1st Specific Aim will identify further 25-30 residue peptides with the ability to stimulate SCCE-specific CD4+ T cell responses. In the 2nd Specific Aim, we will determine whether DC loaded with extended peptides are also capable of cross-priming SCCE-specific CD8+ CTL responses. The rationale for this strategy is that antigen-specific CD4+ T cells provide essential help for the induction of effective CD8+ T cell responses, both in terms of supporting. DC maturation and also for supporting the persistence of antigen-specific CD8+ T cells in vivo. Peptide-loaded DC immunotherapy that is capable of inducing both CD8+ CTL responses and CD4+ helper T cell responses thus offers greater potential for inducing durable immune responses and clinical benefit than treatment with DC loaded withCD8+ CTL peptide epitopes alone. This project is designed to support the development of clinical trial protocols for therapeutic DC vaccination in patients with ovarian cancer.

R41CA108257

2005-05-01

2007-04-30