Abstract 5389: 3M-011, a toll-like-receptor-7/8 agonist, as immunological adjuvans in combined therapy of gastrointestinal tumors

Abstract

Abstract Background: Although there are reports about spontaneous regressions in advanced cancer stages, in most cases the immune response to solid tumors is unable to stop the progression. This immune response is mediated mainly by effectors of the cellular immune system, specifically NK cells and monocytes/macrophages, which are activated by the binding of antigens to toll-like-receptors. 3M-011, an agonist to TLR-7/8 of this sub-family of pattern recognition receptors (PRRs) may be able to boost the antitumoral immune response, especially in combination with other immunostimulatory treatments such as monoclonal antibodies or ionizing radiation. Materials/Methods: In vivo experiments comprised hetero- and orthotopic mouse models of colorectal cancer evaluating 3M-011, m225 (mouse IgG to EGFR) and photon irradiation alone or in combination. End-points were tumor growth, metastasis and tumor cell dissemination. Mice with complete regressions were re-challenged with tumor cells to evaluate the immunization effect of the therapeutic combination. The cytotoxic activity of various immune cell populations (NK cells, CD-8+ T-cells, macrophages) against gastrointestinal cancer cell lines was quantified in 51Cr release assays. Interactions between these subpopulations were investigated by co-culture experiments. NfkB-Activation was quantified by luciferase-based NfkB reporter assays. Results: A distinct growth retardation for subcutaneous tumors and reduction in metastastic activity of orthotopic tumors was demonstrated in vivo. The combination of the TLR-7/8 agonist and m225 or photon irradiation was shown to be over-additive. Mice with complete regressions after radio-immuntherapy showed distinct anti-tumor immunity when re-challenged with tumor cells as compared to control animals. In vitro assays revealed NK cells in combination with monocytes/macrophages as main effectors of the TLR-mediated early immune response followed by T-cell mediated adaptive immune response. Both effects are controlled by plasmacytoid dentritic cells. On a cellular level, NfkB was shown to be the pivotal pathway of the TLR-mediated immunostimulatory effects as well as the combined therapy effects. Conclusion: The addition of a TLR-7/8 agonist to radiotherapy and antibody therapy can achieve supra-additive therapeutic effects by boosting the immune response to the tumor. Therefore, the addition of a TLR-7/8 agonist to the treatment of advanced gastrointestinal cancers is a promising approach and merits further evaluation. 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 5389. doi:1538-7445.AM2012-5389