Human glioma immunology and immunogene therapy.

摘要

Gliomas are the most common primary central nervous system tumors in humans. Despite intensive efforts to improve standard therapy, the prognosis for most glioma patients remains grim. This has led to a search for novel therapeutic strategies reflecting a concomitant explosion in molecular biologic knowledge. In particular, interest in glioma immunotherapy has been rejuvenated by increased insight into molecular immunology. This thesis represents a series of experiments that capitalize on these new data by examining novel aspects of human glioma immunobiology and describing a new method for stimulating anti-glioma immune responses (immunogene therapy).; All experiments were performed with human gliomas (as opposed to animal glioma models) in hopes of increasing our data's clinical relevance. This was facilitated by initial studies in which human glioma cell culture methods were improved. Using cultured human glioma cells, expression of several key immunologic factors was examined. Finally, efforts were made to genetically alter glioma cells' immunogenicity in order to stimulate anti-glioma immunity (immunogene therapy).; Using a simple modification to standard techniques, success rates for establishing human glioma cultures were nearly doubled. Immunobiologic studies with these cultured cells indicated that, while human gliomas are potentially sensitive to anti-tumor immunity, they secrete factors that inhibit immune response activation. Utilizing genetically engineered retroviruses, pro-inflammatory genes could be efficiently transferred to human glioma cells in vitro . Vaccination with these immunogenetically altered glioma cells markedly inhibited growth of pre-established wild type tumors in a novel human lymphocyte/severe combined immunodeficient mouse model.; Based on these studies, it can be concluded that stimulating effective immune responses against human gliomas should be possible. Vaccination with human glioma cells genetically altered to increase their immunogenicity (immunogene therapy) may be one way to accomplish this. The studies in this thesis suggest that human glioma immunogene therapy is both feasible and promising. This has set the stage for pilot glioma immunogene therapy clinical trials. In addition, this work has suggested several other avenues of human glioma immunology investigation that may lead to novel glioma immunotherapy methods.