UC San Diego

Oncolytic viruses are viruses that conditionally replicate in tumor cells (1, 2). One viral family utilized to this end is Adenoviridea, specifically, type C human adenoviruses (hAdV-C), often, hAdV-C5 (Ad5). An unmet need in the area of adenovirus oncolytics is the need for immunocompetent mouse models. Adenoviruses evolve to infect different species, which they then preferentially infect; as such, each adenovirus either does not, or poorly infects species to which they are not selective for (3–5). An example of this phenomenon, human adenoviruses are not able to undergo a productive lytic replication in mouse cells (3). This presents a challenge for pre-clinical development of adenovirus oncolytics in the standard mouse model. hAdV-Cs replicate in neither transformed nor non-transformed murine cells, preventing both selectivity and productivity of the virus, critical aspects of an oncolytic, from being quantitated. To circumvent this and acquire in vivo data assessing the virus' anti-tumor ability, Ad5 derived oncolytics are tested against xenogeneic human tumors implanted into immune-depleted mouse models (4, 5). Since xenograft models are in immune deficient mice, the role of a potentially anti-viral and/or anti-tumor immune response, which is critical to understand for oncolytic therapies, cannot be evaluated (9–12). From a clinical perspective, the lack of an immunocompetent animal model prevents an understanding of how pre-existing or induced immunity influences the therapeutic outcome of oncolytic viral therapies and identification of patients and/or strategies that could improve clinical benefit. The goal of my thesis research was to systematically identify mechanisms underlying the failure of Ad5 to replicate in mouse versus human cells. The ultimate goal is to use this knowledge to enable the rational engineering of an Ad5 that can replicate in both mouse and human cells, which would enable hAdV oncolytic therapies to be potentially tested in immune competent mouse models.