Colorectal cancer is a relatively common malignancy with few curative options once metastases develop. Among the new approaches under development for further treatment of colorectal cancer patients are immunotherapy and oncolytic virotherapywhich show promising results in animal models. A newly developed unique dendritic cell (DC) maturation process produces highly activated DC's, coined aDC1. aDC1 vaccination has been particularly effective in animal models and in human clinical trials at producing high levels of circulating Tc1/Th1 anti-tumor effector cells. The next step in successful vaccination is to modify the tumor microenvironment to allow attraction of these circulating effector cells into the tumor. We and others have found that the chemokine milieu in the tumor microenvironment favors the attraction of Tc2/Th2 and Treg cells over Teff (Th1/Tc1) cells. Circulating cytotoxic T cells fail to traffic to the tumor environment and mediate an anti-tumor effect. Over the last 10 years, we have developed tumor-selective replicating recombinant vaccinia viruses (W) that effectively target tumor after systemic delivery, spread through the tumor, and express high levels of transgenes in the tumor environment. In this study, we propose to investigate the effects W has on the chemokine milieu in the tumor microenvironment, and investigate ways to improve the effects via mutation of immune relevant W genes and expression of selective Th1/Tc1-attracting or Treg-attracting chemokines from the tumor- targeted virus. The recombinant vaccinia serves two roles: as an oncolytic virus per se, and as a vector to express the Teff-attracting chemokines in the tumor tissue. Our hypothesis is that the combination of the two approaches would lead to a highly efficacious cancer therapy regimen for colorectal cancer. Specifically, we have three aims.
Aim 1 is to determine the profile of chemokine expression and the composition of the inflammatory infiltrate in the tumor induced by recombinant, tumor-selective W.
Aim 2 is to study the ability of the most promising W from Aim1 to enhance trafficking to the tumor of tumor-specific T cells derived from either adoptive cell transfer or aDC1 cancer vaccine, and to lead to improved anti-tumor response in combination therapy. And finally aim 3 will be performing a phase I clinical trial testing the safety and efficacy of a combination of aDC1 vaccination with systemic W administration in CRCpatients.
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