Background: DC vaccines have proved efficacy in the treatment of cancer and combination strategies are expected to increase anti-tumor activity. Our study explores the efficacy of intratumoral Hiltonol, a potent TLR3 agonist in combination with an autologous vaccine of DC loaded with self-tumor lysates that we developed in a previous pilot trial (Alfaro C, J Immunology 2011) in patients with solid tumors. Hiltonol is an stabilized form of polyI:C, a nucleic acid that mimics viral RNA. It induces local release of cytokines that promote inflammation, induce type I interferon and favour traffic of leukocytes to infiltrate the tissue. Preclinical data indicates that intratumoral administration of Hiltonol triggers pro-inflammatory changes that increase the efficacy of DC vaccination. Methods: In this phase II study, 25 patients with advanced solid tumors non-amenable for conventional treatment are being treated with Hiltonol and DC vaccinations. The vaccination protocol includes the following strategies: (1) pretreatment with cyclophosphamide to decrease regulatory T cells; (2) maturation and activation of DC with TNF-alpha, interferon-alpha and poly I:C, a potent inducer of type I interferon; (3) use of autologous tumor as antigenic source to expose DC to antigens that are exclusive of tumor cells; and (4) daily intradermal doses vaccinations during four consecutive days in 2 cycles every 4 weeks. Two intratumoral ultrasound-guided injections of Hiltonol 0.25 mg are administered on alternate days the week following each DC cycle. Sample size has been calculated using a two-stage Simon´s Minimax design, with alpha error α= 0.05 and beta-error=0.10 for P₀=0.05 and P₁=0.25. The main objective is response rate. Secondary objectives include assessment of toxicity, overall survival and immunologic response (in vitro lymphocyte responses against tumor antigens; delayed hypersensitivity reactions; and assessment of DC maturation by expression of pro-inflammatory cytokines). Clinical trial information: NCT01734564.