Experimental brain tumors, dendritic cells and immunotherapy

University dissertation from Lund University

Abstract: Malignant astrocytomas are the most common primary tumors of the adult central nervous system. Surgical resection of tumor mass in combination with radiotherapy and chemotherapy is only palliative and there is a clear need for new and more effective therapeutic strategies. The aim of this study was to develop a dendritic cell (DC)-based vaccine for the treatment of experimental brain tumors with the future prospect of translating this treatment into the clinical application. We first demonstrated that the N29 and N32 rat brain tumors closely resemble human glioblastoma multiforme and anaplastic astrocytoma, respectively, and represent relevant models to study the efficacy of new therapeutic modalities. We also found that vaccination with IFN-?-producing tumor cells led to tumor regression in a fraction of animals in both tumor models. The route of vaccine administration significantly influenced the outcome of the therapy. S.c. immunization with IFN-?-producing tumor cells was far more effective compared to i.d. injection. DCs generated from rat bone marrow progenitor cells exhibited the capacity to take up antigens in an immature state and induce T cell proliferation in a mature state, two functional properties central for the induction of anti-tumor immune response. We tested different antigen preparations and maturation factors in order to establish the optimal conditions for DC activation. Synergistic inhibition of intracerebral tumor growth was observed when rats were vaccinated with a combination of ex vivo tumor cell lysate-pulsed and matured DCs and IFN-?-producing tumor cells. However, we did not observe any benefit of using DC-based vaccines alone regardless of antigen loading or maturation methods compared to immunotherapy with IFN-?-producing tumor cells. In conclusion, we have demonstrated that DC-based vaccines fail to provide protection in a weakly immunogenic brain tumor model but do enhance the anti-tumor immune responses elicited by IFN-?-producing tumor cells. These findings could be pertinent to other tumor models and other immunotherapeutic modalities and thus have important implications for the development of anti-cancer vaccines.