IN VIVO GENERATED DENDRITIC CELL BASED IMMUNOTHERAPY

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DESCRIPTION (provided by applicant): Financial support and protected time is requested for a program of mentored clinical research and formal course work leading to a Master's in Clinical Research. This protected and mentored time is highly goal-oriented towards academic independence and a tenured faculty position. The proposed research project serves as a tool from which to gain mentored experience. Three collaborating mentors will critically evaluate both the clinical and in vitro components of the projects. The unifying objectives of the proposed research projects are to develop DC-based immunotherapy. The strengths of these projects are the two novel Phase I trials from which they arise. The first demonstrating the ability to safely generate DC in vivo by the administration of granulocyte macrophage-colony stimulating factor (GM-CSF) plus interleukin 4 (IL-4) in subjects with advanced cancer. This approach supersedes the large blood draws and processing involved in the ex vivo generation of DC. Evidence of clinical benefit was noted in subjects with CaP. The second trial demonstrated safety and induction of immunity to a genetically engineered vaccine - Vaccinia Virus (VV)-MUC-1-IL-2 in men with CaP and a rising prostate-specific antigen (PSA). The investigators hypothesized that GM-CSF plus IL-4 could be used as an adjuvant to enhance response to the VV-MUC-1-IL-2 vaccine. The generation of DC in vivo prior to vaccination will serve as a source of potent antigen presenting cells capable of displaying MUC-1 to the immune system. Two aims will be explored using the resources of the UCLA-General Clinical Research Center (GCRC): 1) a Phase II trial to characterize the efficacy of parenteral GM-CSF plus IL-4 in subjects with hormone refractory CaP; and 2) a Phase I trial to determine the safety and immunologic effects of expanding DC in vivo with GM-CSF and IL-4, prior to vaccination with VV-MUC-1-IL-2 in patients with CaP and a rising PSA. Outcomes from these studies should provide the basis for applying in vivo generated DC and tumor antigen-based treatment to a variety of cancers. Ultimately, this proposal is a platform from which the candidate seeks training to further cancer research at the clinical and translational interface of oncologic care. Given the support necessary to sustain this period of training, the combination of personal drive, experienced mentors and institutional resources will assure success.