Project 2: Multiple Antigen-Engineered DC Immunization and IFNa Boost for Metastatic MelanomaThis application will build on progress made in our previous tumor antigen targeting trials to test a newgenetically engineered dendritic cell-based vaccine regimen designed to more potently activate CDS andCD4 T cells specific to multiple melanoma antigens. We will couple this vaccine trial with thoroughimmunological monitoring to study T cell responses to the vaccine and the importance of determinantspreading for clinical response. We hypothesize that vaccination with multiple full length tumor antigens willactivate a broad range of CD4 and CDS T cells, and that in the subset of patients who further activate anddiversify their T cell response to include other antigens expressed by their tumor (or undergo 'determinantspreading'), objective clinical response will be observed. We also hypothesize that systemic IFNa deliveredafter the vaccine will boost the vaccine-specific T cell responses.A.
Specific Aims :A.1. Conduct an Antigen-Engineered DC Trial with an IFNa Boost. We will treat 30 subjects with antigenengineered DC and randomize half to receive an IFNa boost.A.2.Assess the Biology of the CDS and CD4 Immune Responses to Immunizing Antigens MART-1,Tyrosinase and MAGE-A6. We will follow CDS and CD4 T cell responses to the three immunizing antigens,as well as the adenovirus vector. We will also investigate TIL responses to the immunizing antigens andtumor antigen expression in accessible tumor deposits.A.3. Assess Determinant Spreading. We will also follow the CDS and CD4 T cell responses to definedmelanoma-associated antigens not included in the vaccine but commonly expressed by tumors (includinggplOO) and uncharacterized antigens expressed by autologous tumor to determine the importance ofdeterminant spreading to objective clinical response.
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