The Treatment of Patients With Disseminated Malignant Melanoma by Vaccination With Autologous Cell Hybrids of Tumor Cells and Dendritic Cells

Abstract

Malignant melanoma has been shown to be susceptible to T cell-mediated immunity and, therefore, is a candidate for vaccination approaches. Clinical trials using dendritic cells (DC) loaded with peptides corresponding to tumor antigens are ongoing in several institutions, and some promising results have already been published. However, every single peptide-based vaccine can only be used in a patient with a given single HLA type, and this strategy is not appropriate for patients with rare HLA types or with tumors without defined antigens. A clinical pilot study in patients with disseminated melanoma refractory to standard therapy was initiated using a different approach. The authors generated autologous monocyte-derived DC and fused these DC with gamma-irradiated primary autologous tumor cells by incubation in polyethylene glycol. In previous experiments, the authors had shown that these fused cell products are potent inducers of a T-cell response in a mixed lymphocyte tumor cell culture. Seventeen patients were immunized with the cell product by s.c. injection in monthly intervals without any serious side effects. Of these patients, one had a partial response with decrease in size of all evaluable tumor manifestations. In one patient, some of the metastases were regressing despite an overall progressive disease, and one patient achieved disease stabilization for six months. In the responding patient, in parallel to tumor regression, circumscript hair depigmentation occurred. These data show, that a hybrid vaccine of DC and tumor cells can be safely applied and can induce tumor regressions, however, the clinical efficacy of the approach in its present form is insufficient.

Hybrids of Dendritic Cells and Tumor Cells Generated by Electrofusion Simultaneously Present Immunodominant Epitopes from Multiple Human Tumor-Associated Antigens in the Context of MHC Class I and Class II Molecules

“…In preclinical murine models, DC-TC hybrids have stimulated potent protective and therapeutic immune responses to carcinomas, lymphomas, melanomas, and gliomas (23)(24)(25)(26)(27)(28)(29). However, in two recent human clinical trials, fusions of DCs and autologous tumor cells were primarily ineffective for the treatment of patients with melanoma and glioma (35,36). In both of these protocols, PEG was used as the fusogenic reagent.…”

“…Two human clinical trials have been reported in which patients with melanoma (35) or malignant glioma (36) were vaccinated with autologous DC-TC hybrids made with the fusogenic agent polyethylene glycol (PEG). Although the treatments were safe and well-tolerated, few clinical responses were observed.…”

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

“…This was measured by post-therapy increment in antitumour cytolytic activity, by increased cytokine production of lymphocytes to tumour antigens and by rearranged TCR repertoire, which indicates the expansion of specific clones, in peripheral blood or within the tumour (Soiffer et al, 1998;Krause et al, 2002;Manne et al, 2002). DTH reaction to tumour cells is a useful clinical test that reflects cell-mediated antitumour immunity.…”

Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells

“…Various fusion cells have been constructed by alternating the fusion partners, DC, and/or tumor cells. DC have been fused to autologous tumor cells [2][3][4][5]. In this case, the tumor antigens, known or unidentified, can be fully presented in the context of self HLA class I and class II molecules to autologous T cells.…”