Abstract 5243: Reductions in hypoxia in the tumor microenvironment after Listeria monocytogenes-LLO based immunotherapy

Abstract

Abstract As a consequence of increasing growth and outpacing blood supply, tumors become hypoxic as they get larger, with the interior of the tumor becoming extremely hypoxic. This makes therapeutic immune responses difficult, as lymphocytes do not typically infiltrate the interior regions of large tumors due to the hypoxic nature of these tumors. Initial observations in preclinical studies after Listeria monocytogenes (Lm)-LLO based immunotherapy specifically targeted to the hypoxia marker CA9 show the hypoxic nature of the interior of the tumor microenvironment is altered. Initially the tumors are extremely hypoxic (as evidenced by HIF-1α and HIF-2α staining) however, after Lm-LLO-CA9 vaccination they show reduced expression of these hypoxic markers. This change in hypoxia is seen with irrelevant Lm vaccines that overexpress listeriolysin O (LLO) and also with Lm vaccines targeting CA9 fused to LLO: however the change is much more dramatic and complete in the case of the Lm-LLO-CA9 immunotherapy. The irrelevant Lm-LLO effect may be seen due to the fact that the irrelevant vaccine is actually specific for a tumor associated antigen being expressed by the tumor. This does limit the growth of the tumor and may not allow it to reach the same level of hypoxia as an untreated tumor. In current studies, an additional truly irrelevant Lm-LLO vaccine is being added to see if there is a truly Listeria-driven component to the hypoxic changes being observed. As compared to the naïve untreated tumors or an irrelevant Lm-LLO control, tumors treated with the CA9 Lm-LLO immunotherapy show an increase in lymphocyte infiltration into the interior areas of the tumor. Studies are underway to determine if this increase in infiltration has an impact on the regression of these tumors by combining the Lm-LLO-CA9 vaccine with a vaccine that is specific for a tumor associated antigen. In addition, the function of these infiltrating lymphocytes are being studied under normoxic and hypoxic conditions, to determine if the infiltrating cells are functional CTLs after the tumor's hypoxic levels change. Finally, studies are being conducted to determine the exact signaling mechanism involved in the hypoxic changes of the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5243. doi:1538-7445.AM2012-5243