Thus, treatment with TriMix-DC further expanded the pre-existing MAGE-C2 response and additionally induced de novo responses restricted to other MAA that are included in the DC therapy. documented a partial tumor response according to RECIST criteria with a marked reduction in18F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient. Keywords:Dendritic cell, TriMix, Immunotherapy, Melanoma, Administration route == Introduction == Melanoma is the most aggressive Lysyl-tryptophyl-alpha-lysine form of skin cancer, and its incidence is increasing worldwide [1]. Early stages of melanoma can be cured by surgery, but the prognosis for patients with metastatic melanoma is usually grim, with an expected 2-year survival rate of 1020% [2]. Melanoma is known to be an immunogenic cancer, and different melanoma-associated antigens (MAAs) have been described [3]. Recently, ipilimumab, an antibody against cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and the combination of gp100 peptide vaccine with interleukin (IL)-2 showed an improved overall survival in three randomized phase III trials, underlining Lysyl-tryptophyl-alpha-lysine the potential of immunotherapy in metastatic melanoma patients [46]. Dendritic cells (DCs) are known for their unique capacity to induce the activation of nave tumor-specific T lymphocytes [7]. For this reason, a growing number of clinical trials are being performed using tumor antigenloaded DCs as cellular immunotherapy in cancer patients [8,9]. DC-based immunotherapy has shown to induce antitumor immune responses, but so far with limited clinical efficacy. Both the maturation of DC and the route of administration might play a role in determining the quantity and quality of the immune response [1015]. We previously described a single-step approach for effective antigen loading and maturation of DCs by mRNA electroporation offering multiple advantages [16]. First, electroporation with full-length MAA-encoding mRNA facilitates cellular processing and presentation of the full range of antigenic peptides. Consequently, a broader MAA-specific T-cell response can be induced, irrespective of the patients HLA type. Furthermore, enhanced MAA presentation in both HLA class I and II can be achieved by fusion of the MAA-encoding sequence with an HLA class II-targeting signal [17]. Also, the T-cell stimulatory capacity of DCs can be greatly enhanced by co-electroporation with CD40L, CD70 and a constitutively active toll-like receptor 4 (caTLR4)-encoding mRNA (TriMix-DC) [18]. The combination of CD40L and caTLR4 electroporation mimics CD40 ligation and TLR4 signaling of Lysyl-tryptophyl-alpha-lysine the DCs and generates phenotypically mature, cytokine-secreting DCs. Additionally, CD70 electroporation provides a costimulatory signal to CD27+nave T cells by inhibiting activated T-cell apoptosis and by supporting T-cell proliferation [18]. A phase I pilot clinical trial exhibited that intradermal administration of autologous TriMix-DC is usually Lysyl-tryptophyl-alpha-lysine feasible, Rabbit polyclonal to PFKFB3 is usually safe and effectively stimulates CD8+T-cell responses [19]. New insights into the organ-specific trafficking of vaccine-induced T-cell populations indicated that combination of different routes of administration may be beneficial to target different tumor locations [20]. Accumulating evidence from immunization studies in animals has shown that vaccination route impacts around the migratory capacity of the induced effector T cells [14,21,22]. In a mouse melanoma model, the intravenous injection of DCs was shown to be essential for responses against visceral metastases, whereas subcutaneous vaccination resulted in a response against non-visceral metastases [12]. Following intravenous injection, the DCs were only found in the spleen, whereas subcutaneously injected DCs were mainly found in the skin-draining lymph node and to a minor extent in the spleen [12,23]. The same compartmentalization was found for the stimulated CD8+T cells (both primed and memory T cells), and consequently intravenous DC administration was more protective for lung metastasis, whereas subcutaneous injection was protective for subcutaneous tumors [12]. Similarly, injection routedependent distribution of the DCs has been found in human subjects, with intradermal DCs migrating to the skin-draining lymph nodes and intravenously injected DCs migrating to the lungs, with subsequent redistribution to the liver, spleen and bone marrow [24]. Moreover, compartmentalization of the immune response has also been described in melanoma patients: intralymphatic DC injection led mainly to skin-homing CD8+T cells [25]. Therefore, the administration route might play a role in the outcome of DC therapy. To further optimize the immunogenicity and clinical efficacy of autologous TriMix-DC in melanoma patients, we are conducting a prospective phase I clinical trial on combined intravenous and intradermal administration. We.
Thus, treatment with TriMix-DC further expanded the pre-existing MAGE-C2 response and additionally induced de novo responses restricted to other MAA that are included in the DC therapy
