The long term goal of this project is to develop new therapies for the treatment of malignant glioma based on the development of immune effector cells with genetically engineered novel targeting and effector functions. It is hypothesized that T cells and potentially other effector cells can be engineered to directly recognize and kill the both the developing tumor vasculature and tumor cells themselves. This shall be accomplished through the use of gene transfer vectors that encode chimeric T cell receptors (cTCR) directed against specific endothelial cell surface receptors and glioma related tumor neoantigens. Retroviral gene transfer will also be used in an attempt to generate genetically-modified T cells which allow for the expression of additional functions including co-stimulation, tetracycline responsiveness, and release of specific gene products with potent anti-angiogenic activity. The activity of T cells transduced by the different vectors will be characterized in vitro for their target cell specificity and cytolytic function and, subsequently for anti-tumor activity in several different pre-existing tumor models including intracerebral models. In addition to assessing the therapeutic efficacy of the transduced cells, we will characterize the persistence and trafficking characteristics of the transplanted cells. We will also compare the anti-tumor activity achieved by adoptive transfer of genetically modified T cells to that achieved by the engraftment of lethally irradiated recipients by hematopoietic stem cells transduced by the chimeric T cell receptor vectors. This project shall provide the candidate with a research foundation in gene transfer technologies, tumor immunotherapy, and anti-angiogenesis as part of a long-term strategy to develop translational therapies for the treatment of cerebral glioma in man.
