Poxvirus-Based Strategies for Combined Vaccine and Tumor Microenvironment Manipulation

Although vaccine strategies for the generation of tumor-specific immunity in patients continue to have great promise, to date they have been less than overwhelming in their antitumor efficacy. Studies from our laboratory and other laboratories have examined the lack of apparent immune recognition of tumor and limited effectiveness of tumor antigen-based vaccines. Such studies have resulted in the definition of a series of "immune escape mechanisms" whereby the tumor microenvironment and draining lymph nodes manifest a balance between effector and regulatory pathways resulting in a systemic lack of responsiveness to tumor and, in some cases, vaccine therapy. Our studies, reviewed in this chapter, have focused on the use of recombinant poxviral vectors to infect/transfect tumor and stromal components in the tumor microenvironment aimed at overcoming "immune escape" and resulting in an effective systemic antitumor immunity. Studies outlined here demonstrate that poxviral vectors are effective in infecting/transfecting tumor in vitro and in vivo, leading to the production of immune-active cytokines at the tumor site. In a series of phase I trials in melanoma and bladder cancer patients, we demonstrated that infection/transfection of the tumor using poxvirus encoding the immune active cytokine granulocyte-macrophage colony-stimulating factor is effective in inducing local immune cell infiltration into the tumor microenvironment. Parallel preclinical studies have found that inclusion of genes encoding tumor antigen into the recombinant poxvirus with or without additional pharmacologic agents modulating immune escape mechanisms is effective in inducing systemic antitumor immunity and manifesting positive antitumor effects. Finally, we describe the translation of these latter findings to an ongoing phase I study of antigen-encoding poxvirus given intratumorally in patients with locally advanced pancreatic cancer.