UC San Diego

With the advent of targeted immunotherapies, survival rates of some cancers have improved tremendously over the years; however, cancer continues to be the second leading cause of death overall in the United States. Most cancer-related deaths can be attributed to the onset of metastatic disease, defined by the spread of disseminated cancer cells from the primary tumor into distal organs following trafficking into the lymphatic and circulatory systems. Once metastasis has occurred, survival rates drop precipitously as metastatic cancers exhibit therapeutic resistance and plasticity. Therefore, it is imperative that newer technologies that can not only treat metastatic cancers, but also prevent them are continuously developed. In this dissertation, I detail many of these efforts in fighting against metastatic cancer using a repurposed plant virus called the cowpea mosaic virus (CPMV). Past studies have demonstrated the potent immunotherapeutic ability of CPMV as a direct in situ vaccine with efficacy established in murine models of colon, ovarian, glioma, breast cancer, and melanoma as well as in canine patients with melanoma and inflammatory mammary cancer. However, metastatic cancers are uninjectable, which required engineering of the CPMV nanoparticles for the treatment and prophylaxis of metastatic cancers. Specifically, I conjugated peptides termed H6 and G3 that target a protein called S100A9, which becomes overexpressed in a myriad of cancer types and is indicated in lung metastasis. Targeting S100A9 led to intrapulmonary accumulation of CPMV in mice allowing for both prophylaxis and treatment of metastatic breast cancer and melanoma to the lungs. The same nanoparticles were also used to target intraperitoneal metastases from colon cancer leading to improved tumor rejection and survival. While efficacious, CPMV-H6/G3 treatment can be limited to S100A9-expressing cancers. I then broadened the applicability of native CPMV by utilizing it as an adjuvant therapy for the prevention of a wide range of cancers demonstrating its efficacy in four different metastatic cancer models in two species of mice. My data highlight that the antitumor efficacy of CPMV is species, tissue, and tumor-type agnostic.The adjuvanticity of CPMV was also repurposed for vaccine applications – concomitant injection of CPMV with antigens causes potent titer production. Given the role of S100A9 in lung metastasis, I created a vaccine utilizing CPMV and another viral adjuvant Q and chemically conjugated a S100A9 epitope to the viral carriers to induce the production of -S100A9 antibodies leading to reduced metastasis within the lungs. I then further developed the CPMV and Q adjuvant and carrier systems by developing a histidine-tag nickel binding chemistry that allows for the rapid production of plug-and-play vaccine candidates. This allows for the generation of vaccine candidates that co-deliver antigen and adjuvant while still demonstrating plug-and-play capabilities – results with ovalbumin showed that titers against ovalbumin were improved compared to bolus injections leading to improved antitumor responses against specialized ovalbumin-expressing cell lines. Overall, my thesis showcases the potent ability of CPMV to both prevent and treat metastatic cancers in prophylactic, therapeutic, and vaccine formats and highlights the development of CPMV and Q in plug-and-play vaccine applications.