Nicholas Sanderson, PhD is a postdoctoral researcher at the Board of Governors Gene Therapeutics Research Institute at Cedars-Sinai Medical Center. He is currently working on interactions between cells of the immune system and host cells infected with virus. Results from this work are expected to help in the process of designing therapeutic viral vectors that will target cancer cells.
The BOG-Gene Therapeutics Research Institute has developed adenoviral vectors to treat glioblastoma (GBM), encoding conditional cytotoxic transgenes or targeted toxins used in combination with genes which stimulate anti-cancer immune responses. These approaches significantly improve survival in rodent GBM models. However, a challenge in implementing gene therapeutic approaches in clinical trials is the interaction between vector-infected cells and the host immune response against the vectors, since the majority of humans have some immunity to the adenovirus.
To overcome this inhibition of therapeutic transgene expression, we have developed novel, gutless high capacity adenovirus vectors which are devoid of all viral coding regions in their genomes and are therefore invisible to immune attack once they have infected the target cells. In the course of characterizing the interaction between immune cells and virally infected target cells, we have demonstrated that in animals immunized against adenovirus, CD8+ cytotoxic lymphocytes (CTLs) are instrumental in eliminating the majority of viral vector mediated transgene expression in the brain.
CTLs establish contacts with infected cells at which various membrane proteins are organized into supramolecular activation clusters consisting of an inner region, rich in T cell receptors, and an outer region rich in cell adhesion molecules. Whether this structure, known as an immunological synapse, is essential for CTL-mediated cell killing, and if so, what its functional significance might be, remain open questions.
To answer these questions, we have established a co-culture system in which normal brain cells, or brain glioma derived cell lines, interact with anti-antigen specific CTLs. Using this system, we hope to discover what features of the infected target cell induce formation of the synapse with the CTL, and what the consequences for both the target cell and the immune cell might be. Dr Sanderson received his PhD at the Institute for Neuroscience of the University of Texas at Austin.
