ABSTRACT
Topical TLR7 agonists such as imiquimod are highly effective for the treatment of dermatological malignancies; however, their efficacy in the treatment of nondermatological tumors has been less successful. We report that oral administration of the novel TLR7-selective small molecule agonist; SM-276001, leads to the induction of an inflammatory cytokine and chemokine milieu and to the activation of a diverse population of immune effector cells including T and B lymphocytes, NK and NKT cells. Oral administration of SM-276001 leads to the induction of IFNα, TNFα and IL-12p40 and a reduction in tumor burden in the Balb/c syngeneic Renca and CT26 models. Using the OV2944-HM-1 model of ovarian cancer which spontaneously metastasizes to the lungs following subcutaneous implantation, we evaluated the efficacy of intratracheal and oral administration of SM-276001 in an adjuvant setting following surgical resection of the primary tumor. We show that both oral and intratracheal TLR7 therapy can reduce the frequency of pulmonary metastasis, and metastasis to the axillary lymph nodes. These results demonstrate that SM-276001 is a potent selective TLR7 agonist that can induce antitumor immune responses when dosed either intratracheally or orally.
Subject(s)
Antineoplastic Agents/administration & dosage , Lymphocyte Activation/drug effects , Membrane Glycoproteins/agonists , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/immunology , Toll-Like Receptor 7/agonists , Administration, Oral , Animals , Antigens, CD/biosynthesis , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Antineoplastic Agents/therapeutic use , B-Lymphocytes/drug effects , Cell Line, Tumor , Chemokines/biosynthesis , Cytokines/biosynthesis , Drug Evaluation, Preclinical , Female , Interferon-alpha/biosynthesis , Interleukin-12 Subunit p40/biosynthesis , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lectins, C-Type/biosynthesis , Lung Neoplasms/secondary , Lymphatic Metastasis/prevention & control , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Natural Killer T-Cells/drug effects , Natural Killer T-Cells/immunology , T-Lymphocytes/drug effects , Toll-Like Receptor 7/metabolism , Trachea , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
PURPOSE: The multikinase and tyrosine kinase inhibitor sorafenib has antitumor activity in patients with advanced renal cell carcinoma. Recent reports show the ability of sorafenib to synergize with interferon-α, leading to greater antitumor activity. We examined the underlying mechanism of sorafenib and interferon-α synergism for renal cell carcinoma treatment in vitro and in tumor bearing murine models. MATERIALS AND METHODS: We used murine and human renal cell carcinoma cell lines for in vitro cell proliferation assay. ACHN (ATCC®) and RENCA tumors were subcutaneously transplanted into NCr-nu/nu and syngeneic BALB/c mice (Charles River Laboratories, Yokohama, Japan), respectively. Mice were treated with sorafenib and/or interferon-α, and tumor growth was monitored. Immunological assays were done in the RENCA model. RESULTS: In the ACHN and RENCA cell lines combination index analysis clearly revealed the synergistic antiproliferative effects of interferon-α and sorafenib in vitro. In the ACHN NCr-nu/nu model we clearly noted the synergistic antitumor effects of interferon-α and sorafenib, indicating the synergistic direct effects of each drug on tumor growth. In the RENCA BALB/c model flow cytometry showed no change in the proportion of lymphocytes. However, while sorafenib alone did not induce natural killer or cytotoxic T-lymphocyte activity against RENCA in that model, interferon-α alone or combined with sorafenib induced natural killer and cytotoxic T-lymphocyte activity. CONCLUSIONS: Our results show the synergistic activity of interferon-α and sorafenib. These findings provided the rationale for combination therapy with interferon-α and sorafenib in patients with advanced renal cell carcinoma.
