Mature Dendritic Cells Induce T-Helper Type-1-Dominant Immune Responses in Patients with Metastatic Renal Cell Carcinoma

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Abstract
We performed a pilot study on a dendritic cell (DC)-based vaccine in 4 patients with advanced renal cell carcinoma. The vaccine consisted of cultured blood DCs loaded with autologous tumor cell lysate plus keyhole limpet hemocyanin (KLH) and matured with a combination of tumor necrosis factor α and prostaglandin E2. We describe the immune response against KLH induced by DC-based immunization in a patient undergoing an objective partial response and compare it with the responses observed in patients with either stable or progressive disease. The patient with the clinical response developed strong delayed-type hypersensitivity (DTH) against KLH after a single vaccination with antigen-loaded DCs, whereas the other patients failed to develop DTH reactivity even after repeated vaccinations. Antigenic stimulation of mononuclear cells (MNCs) induced proliferation and IFN-γ but not IL-4 production as well as expression of the chemokine receptor CXCR3 consistent with a T-helper (Th) type-1 bias. Exogenous IL-12 enhanced and exogenous IL-4 diminished IFN-γ production. In the 2 patients with stable disease two or more vaccinations were required to induce maximal MNC responses. In the patient with progressive disease MNC responses were hardly detectable. Anti-KLH antibodies appeared with different kinetics but could be detected in the serum of all patients. Isotype analysis revealed the presence of IgM, IgG1, IgG2 and IgG3 as well as IgA and complete absence of IgE. The patient with progressive disease also developed IgG4 antibodies indicative of a deviation towards Th2. Cultured blood DCs can be a potent vaccine for the antigen-specific immunization of patients with advanced kidney cancer. KLH serves as a tracer molecule which allows determination of the magnitude, kinetics and Th bias of the cellular and humoral immune response induced by DC-based immunization. The data also suggest that Th type-1-dominant immune responses involving DTH reaction are required for the induction of tumor regression.