Tumor lysate and IL-18 loaded dendritic cells elicits Th1 response, tumor-specific CD8+ cytotoxic T cells in patients with malignant glioma

Abstract

In this study, we demonstrate that tumor lysate-loaded dendritic cells can elicit a specific CD8+ cytotoxic T lymphocyte response against autologous tumor cells in patients with malignant glioma. CTL from three of five patients expressed strong cytolytic activity against autologous glioma cells, did not lyse autologous lymphoblasts and were variably cytotoxic against the LAK-sensitive cell line Daudi. Also, DCs pulsed normal brain lysate failed to induce cytolytic activity against autologous glioma cells, suggesting the lack of autoimmune response. Two of five patients CD8+ T cells expressed a modest cytotoxicity against autologous glioma cells. CD8+ T cells isolated during these ineffective primings secreted large amounts of IL-10, less amounts of IFN-gamma as detected by ELISA, Type 2 bias in the CD8+ T cell response accounts for the lack of cytotoxic effector function from these patients. Cytotoxicity against autologous glioma cells could be significantly inhibited by anti-HLA class I antibody. These data demonstrate that tumor lysate-loaded DC can be an effective tool in inducing glioma-specific CD8+ CTL able to kill autologous glioma cells in vitro. However, high levels of tumor specific tolerance in some patients may account for a significant barrier to therapeutic vaccination. Moreover, cytotoxic responses were augmented by transfecting DC with the gene for IL-18. For all five patients, CD8+T cells treated with IL18 transfected DC produced Th1 response. These results may have important implications for the treatment of malignant glioma patients with immunotherapy. DCs loaded with total tumor lysate and IL-18 may represent a method for inducing Th1 immunoresponses against the entire repertoire of glioma antigens.

Clinical Evaluation of Dendritic Cell Vaccination for Patients with Recurrent Glioma: Results of a Clinical Phase I/II Trial

“…Although there is some probability of shared antigens between tumor and normal central nervous system tissues, and possible contamination of normal tissue in the tumor lysate, no autoimmunity was experienced in vivo. Furthermore, in our in vitro study, dendritic cells pulsed with a normal brain lysate failed to induce cytolytic T-cell activity against autologous glioma cells, suggesting the lack of an autoimmune response (28). The source of the dendritic cells in these cases was immature dendritic cells (6,7) and mature dendritic cells (25).…”

Clinical-scale generation of human anti-Aspergillus T cells for adoptive immunotherapy

“…In this respect, antigen lysates have also been used in the adoptive immunotherapy against various tumors. 18,19 Out of a total of 1.1 Â 10 9 WBCs from the leukapheresis product, a median number of 12 Â 10 7 anti-Aspergillus T H 1 cells was generated within 1-13 days (Table 1). In contrast to T H 2 reactivity that is associated with susceptibility to invasive mycoses, T H 1 cells play a crucial role in the control of Aspergillus infection, but the factors that determine the differential activation of T H 1 or T H 2 cells are not fully understood.…”

Pathophysiological mechanisms regulated by cytokines in gliomas

“…It is noticeable that the initial secretion of IL-18 by activated microglia is further enhanced by the presence of extracellular matrix proteins like vitronectin and fibronectin [35]. On the other hand, paradoxically it overpowers the immune response against glioma by stimulating secretion of IFN-c which in turn causes the proliferation of T cells and at the same time the augmented activity of NK and CD8 cells which mediate cytotoxic immunity [36].…”