Abstract P5-01-06: Remodeling the tumor immune microenvironment via intratumoral administration of immunomodulatory agents

Abstract

Abstract Background: Immune dysregulation has been implicated in the poor outcomes associated with high grade and/or triple negative (Tneg) breast cancers. This suggests that a multi-modal approach to stimulating the immune system could be an effective therapeutic strategy for Tneg breast cancer. However, many immunotherapeutic agents demonstrate significant toxicities when administered systemically at high doses. Therefore, we investigated the therapeutic efficacy of local, intratumoral administration of immunomodulators in a mouse model of Tneg breast cancer. Methods: 4T1, an aggressive, Tneg mammary carcinoma, was implanted orthotopically into syngeneic BALB/c mice. Treatment was initiated when tumors were 0.5-1.0 cm in the largest dimension. We examined various combinations of Toll-like receptor agonists (CpG oligonucleotide [TLR9] and imiquimod [TLR7]) with immunomodulatory antibodies (anti-CD40, anti-CTLA-4, anti-OX40). These agents were administered intratumorally (i.t.), either in PBS or formulated in an in situ depot forming drug delivery system. Growth of the injected tumors was monitored over time. In some experiments, tumors and spleens were harvested 3-10 days post therapy and analyzed for the presence of CD4+ T cells, CD8+ T cells, immunoregulatory T cells (Treg), and myeloid derived suppressor cells (MDSC). To test whether local immunotherapy generates a systemic antitumor immune response, 4T1 tumors were implanted at 2 sites on opposite sides of the mice, with one (left) used as the site of in situ immunomodulation (i.t. injections) and the other (right) observed to assess the systemic antitumor immune response. Results: Intratumoral administration of various combinations of immunomodulators resulted in complete regression of the injected tumor. These regressions were associated with a reduction in the number of MDSCs in the tumor as well as activation of both CD4+ and CD8+ T cells. Furthermore, local immunotherapy generated a systemic antitumor immune response that inhibited tumors growing at a distant site. Conclusions: Our findings demonstrate that remodeling the tumor immune microenvironment via intratumoral administration of immunomodulatory agents elicits antitumor immunity that eradicates tumor cells locally as well as systemically at distant sites. The prospect of delivering immunotherapeutics only where it matters most, namely within the tumor microenvironment, is extremely attractive as this would likely be substantially less toxic and more specific than many of the current cancer treatments. Ongoing studies include identifying companion diagnostics that can indicate which patients would benefit most from such an immunotherapeutic approach. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-01-06.