Electronic Thesis/Dissertation


Development of a Recombinant Attenuated Salmonella Cancer Vaccine Open Access

New treatments for neuroblastoma are desperately needed; high-risk neuroblastoma patients have a less than 50% five-year survival rate despite intensive treatment. The greatest impact on improving survival rates for cancer patients in recent years is the result of a number of immunotherapeutic approaches. A proportion of high-risk neuroblastoma patients undergo spontaneous regression, possibly mediated by the immune system, indicating the potential of immunotherapies targeting neuroblastoma-associated antigens. Recombinant attenuated Salmonella vaccines (RASV) are cost-effective and have shown efficacy against a number of pathogen-associated antigens and are easily adapted for use as cancer immunotherapies. Here we cloned survivin, a neuroblastoma tumor-associated antigen into RASV expression plasmids to develop 24 RASV candidate vaccines with an array of select phenotypes. While conventional recombinant attenuated Salmonella vaccines are permanently attenuated, the RASV used here are engineered with inducible in vivo attenuation and other delayed phenotypes shown to improve immune responses. Survivin expression did not impact the growth or stability of any of the RASV constructs. Six of the constructs were tested in vivo, the RASV survived in the gut lumen, and all RASV-immunized mice produced anti-Salmonella responses. Protein/adjuvant immunized mice produced humoral and cellular survivin specific immune responses; however two independent in vivo experiments showed that no survivin specific immune responses were induced in survivin-expressing RASV immunized mice. Based on the results, a number of improvements to the future development of the vaccine are suggested.

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