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PhD Defense, Vishnu Raman, “Creation of a tumor specific, Salmonella based, intracellular cancer therapy”

Date/Time: 

Thursday, May 28, 2020 - 12:00pm

Location: 

via Zoom (email wallace at ecs dot umass dot edu)

Details: 

ABSTRACT

Sixty percent of all proteins are located inside cells. Many of these proteins are involved in pathways that regulate a variety of critical cancer cell survival and immunomodulatory processes.  However, conventional macromolecular therapies targeting these intracellular pathways in   cancer face several transport barriers including, tumor selective accumulation, dispersion,  cell internalization and endosomal release. Therefore, an effective delivery vehicle is needed to circumvent the transport limitations associated with macromolecular therapies. 

Salmonella is an ideal intracellular macromolecular delivery vehicle  for cancer therapy/immunotherapy. Non-pathogenic versions of the bacteria colonize and grow in  tumors at ratios greater than ten thousand to one over any other organ. The bacteria are highly motile, disperse and efficiently invade non-phagocytic, epithelial cells. After cell invasion,  Salmonella activate a unique set of genes selectively inside cells to upregulate  type three  secretion system-two activity, which, enables intracellular survival. This combination of  traits is unique to Salmonella, making genetically engineered versions of the bacteria ideal for intracellular therapeutic delivery selectively within tumor cells. 

The purpose of this thesis was to (1) determine the critical driving mechanisms governing intracellular therapeutic delivery in tumor cells and genetically engineer a delivery strain of Salmonella based on this information and (2) demonstrate, for the very first time, that the engineered Salmonella could deliver protein antigen into tumor cells and refocus   preexisting, vaccine induced, immune cells to target cancer. We hypothesized that  controlled expression of the master motility regulator, flhDC, in Salmonella drives tumor  colonization, bacterial dispersion, invasion and protein delivery selectively inside tumor cells.  To test this hypothesis, we employed a range of genetic engineering techniques, cell-based  infection assays, in vitro tumor- on-a-chip and in vivo infection/tumor models to elucidate   the driving delivery mechanisms of engineered Salmonella. Controlled expression of flhDC  enabled high levels of intracellular protein delivery selectively inside tumor cells. 

 
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