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The growing incidence of melanoma is an increasing threat, and effective treatment options for advanced forms of melanoma are scarce. Although recently approved targeted- and immunotherapies have shown objective beneficial effects in metastatic melanoma, in most cases the disease still relapses. In this project we are interested to understand the differences of immune responses against on one side vaccine vector intrinsic epitopes compared to tumor associated antigens consisting of classical melanoma antigens (melanA, gp100, trp2) and also recently characterized neoepitopes (emerged through de novo mutations in rapidly evolving tumor cells) - all provided by the same vaccine. These antigens will be presented in the context of the non-propagating recombinant lymphocytic choriomeningitis or adenovirus based vaccine vectors. For both of them we have well described Db restricted epitopes: FQPQNGQFI (NP396), FALSNAEDL (dbp43) respectively. In order to further increase the potency of the T cell immune response we will combine these with prime-boost immunizations using DNA plasmid, vaccinia virus, listeria vaccine vectors against the same antigens. Specifically we will pursue the following goals:
1) To understand the topographic distribution and quality of simultaneously vaccine-induced T cells against auto-, neo- and foreign antigens in different immune compartments (skin, lymph nodes, blood, and spleen) in relation to the route of immunization over time.
2) To characterize the behavior of anti-tumor and anti-virus T cells after tumor respectively virus challenge not only in the immune compartments but also in the tumor and its microenvironment using classical immunological assays and single cell real-time PCR.
3) To unravel the effect of currently used immune activators (CTLA-4 and PD-1 blocking antibodies) on tumor and virus (EBV, CMV, Influenza) specific T cells in patients.
A completion of these experiments may stimulate a discussion on thinking of a paradigm change in terms of prophylactic melanoma vaccination in high-risk individuals (Breslow >2mm and positive sentinel lymph node) instead of therapeutic immunotherapy in end stage melanoma.