An ideal cancer therapeutic agent would specifically target malignant cells to kill these cells while avoiding normal tissues. Oncolytic viruses are viruses developed to selectively kill tumor cells by infecting, replicating, and ultimately killing these cells. These agents have the appeal of being "self-amplifying" drugs, because each infected tumor cell produces 10,000 more viruses to amplify the number of killed tumor cells. Oncolytic viruses have shown promise in preclinical and clinical trials where they have proved most useful when applied by direct intratumoral injection. While this may be useful for debulking tumors, this approach cannot address distant metastases. Adenoviruses have been engineered to achieve cancer specificity by taking advantage of specific traits of certain cancer cell types or by taking advantage of molecular changes intrinsic to oncogenesis. While these viruses have higher cancer specificity, loss of 90% of the intravenously injected dose to liver reduces the amount of virus available to kill tumor metastases. This loss also produces dose-limiting and sometimes lethal liver damage. In addition to these pharmacologic problems, another significant hurdle to clinical translation is the presence or high levels of neutralizing antibodies against Ad5 in patients. These antibodies deplete most of an injected dose markedly reducing efficacy. Given these problems, this project will apply clinically-relevant interventions to attempt to improve both the pharmacology and immunogenicity of adenoviral oncolytics for systemic cancer therapy. This project will detarget oncolytic viruses from the liver and shield them from the immune system by genetic and chemical engineering. The Molecular Medicine Program at Mayo Clinic has previously translated other oncolytic viruses into the clinic for cancer applications. If this project is successful, it will therefore lay the groundwork for translating these adenovirus oncolytics for the treatment of cancer patients at Mayo Clinic and other sites.
Successful pursuit of this project will enable more specific and less dangerous oncolytic adenoviruses for cancer therapy. This project will work to improve the ability of these cancer killing viruses to be used for systemic therapy to find and kill distant tumor sites in metastatic disease. This work will lay the foundation for future testing in humans.
|Crosby, Catherine M; Barry, Michael A (2014) IIIa deleted adenovirus as a single-cycle genome replicating vector. Virology 462-463:158-65|
|Khare, Reeti; Hillestad, Matthew L; Xu, Zhili et al. (2013) Circulating antibodies and macrophages as modulators of adenovirus pharmacology. J Virol 87:3678-86|
|Khare, Reeti; Reddy, Vijay S; Nemerow, Glen R et al. (2012) Identification of adenovirus serotype 5 hexon regions that interact with scavenger receptors. J Virol 86:2293-301|
|Barry, Michael A; May, Shannon; Weaver, Eric A (2012) Imaging luciferase-expressing viruses. Methods Mol Biol 797:79-87|
|Hofherr, Sean E; Adams, Kristen E; Chen, Christopher Y et al. (2011) Real-time dynamic imaging of virus distribution in vivo. PLoS One 6:e17076|
|Khare, Reeti; May, Shannon M; Vetrini, Francesco et al. (2011) Generation of a Kupffer cell-evading adenovirus for systemic and liver-directed gene transfer. Mol Ther 19:1254-62|
|Weaver, Eric A; Hillestad, Mathew L; Khare, Reeti et al. (2011) Characterization of species C human adenovirus serotype 6 (Ad6). Virology 412:19-27|
|Chen, C Y; Weaver, E A; Khare, R et al. (2011) Mining the adenovirus virome for oncolytics against multiple solid tumor types. Cancer Gene Ther 18:744-50|
|Chen, Christopher Y; Senac, Julien S; Weaver, Eric A et al. (2011) Species D adenoviruses as oncolytics against B-cell cancers. Clin Cancer Res 17:6712-22|