Gene therapy of malignant gliomas : A pilot study of vaccination with irradiated autologous glioma and dendritic cells admixed with IL-4 transduced fibroblasts to elicit an immune response

The goal of this study is to evaluate the safety, feasibility and efficacy of vaccine consisting of DCs co-cultured with irradiated tumor cells and local interleukin-4 (IL-4) delivery by co-administration of IL-4 expressing fibroblasts at the vaccine site. The notion is that not only would additional inflammatory cells be recruited to the local vaccine microenvironment, because of endothelial activation, but that the DCs, which engulfed apoptotic tumor cells, will also be able to migrate to regional nodes and enhance the development of an immune response. Reversion to a macrophage phenotype is also less likely because of co-localized DC and IL-4. Endogenous immature DCs such as skin Langerhans cells may be recruited and uptake tumor antigens with the assistance of local IL-4 production. DCs express high levels of the important costimulatory molecules CD80 and CD86 which are promoted by IL-4 and other DC maturational signals. Expression of co-stimulatory molecules on DCs mediate important signals which activate T cells expressing the corresponding T cell receptor for the antigen presented on antigen presenting cells (APC). Lack of the co-stimulatory molecules leads to T cell anergy. In addition, co-transduction of CD80 in cytokine-tumor cell enhances the induction of antitumor immune responses. Expression of co-stimulatory molecules in vaccine cells in vivo will be examined in the context of our phase I trial of IL-4+HSV-TK glioma vaccine (PCI95-033), however, it is anticipated to be very low. In contrast, DC based vaccines are expected to serve as an effective mediator of T cell activation signals. We have the following specific objectives: 1. To assess the local and systemic toxicity associated with this form of vaccine. 2. To evaluate the local immune response engendered by this form of vaccine. 3. To evaluate the ability of these vaccines to induce cytotoxic T-lymphocytes capable of lysing autologous glioma cells in vitro. 4. To evaluate the ability of these vaccines to induce humoral immune response to glioma specific antigens. 5. To evaluate preliminary clinical activity of these vaccines.