Intratracheal and oral administration of SM-276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer

摘要

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. What's new? Toll-like receptors (TLRs) are expressed on several types of immune cells. They serve to alert the immune system to infection, and stimulate a number of acute immune responses. TLRs are also being investigated for anti-tumour properties. The authors report that a compound called SM-276001 activates the immune system specifically via a TLR called TLR7, and is able to reduce carcinomas in mice. In addition, they found that either oral or tracheal administration of SM-276001 could reduce the frequency of metastasis in a mouse model of ovarian cancer. Thus, this type of compound might provide a valuable adjunct to surgery.