Local administration of a novel Toll-like receptor 7 agonist in combination with doxorubicin induces durable tumouricidal effects in a murine model of T cell lymphoma

Abstract

BackgroundConventional chemotherapy and radiotherapy for the treatment of lymphoma have notable drawbacks, and passive immunotherapy using a monoclonal antibody is restricted to CD20-positive B cell lymphoma. Therefore, new treatment types are urgently required, especially for T cell lymphoma. One type of new antitumour therapy is the use of active immunotherapeutic agents, such as agonists of the Toll-like receptors (TLRs), which facilitate the induction of prolonged antitumour immune responses.MethodsWe have synthesised a novel TLR7 agonist called SZU-101 and investigated the systemic antitumour effect on a murine model of T cell lymphoma in vivo.ResultsHere, we report that the intratumoural administration of SZU-101 enhanced the effectiveness of a conventionally used chemotherapeutic agent, doxorubicin (DOX). SZU-101 administration improved tumour clearance in a murine model of T cell lymphoma. The novel combination of intratumourally administered SZU-101 and DOX generated strong cytokine production and enhanced the cytotoxic T lymphocyte response, leading to the eradication of both local and distant tumours in tumour-bearing mice.ConclusionsThese findings suggested that combined active immunotherapy can be developed as a promising treatment for T cell lymphoma, which may further improve the effectiveness of the current standard cyclophosphamide, DOX, vincristine and prednisone (CHOP) therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0121-9) contains supplementary material, which is available to authorized users.

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

“…Intratumoral administration of SZU-101 increased the efficacy of doxorubicin, and improved tumor clearance in a T-cell lymphoma mouse model. The new combination of SZU-101 and doxorubicin administered intratumorally induced high cytokine production and improved cytotoxic T cell response, leading to the eradication of local and distal tumors in tumorbearing mice[113]. Gao et al demonstrated the enhancing tumor…”

Immunomodulatory and Antitumor Effects of a Novel TLR7 Agonist Combined with Lapatinib

“…Recently, we have reported the synthesis of a novel TLR 7 agonist, SZU-101, and its use in combination with doxorubicin for cancer therapy. This combination induced durable tumoricidal effects in a murine model of T cell lymphoma11. We have also found that conjugating OCT4 protein to this agonist produces a vaccine that effectively and safely prevents tumor growth in mice12.…”

Antitumor activity of a novel small molecule TLR7 agonist via immune response induction and tumor microenvironment modulation

“…In a previous study, our group used SZU-101 to treat tumors in a murine model of T cell lymphoma. SZU-101 could activated TLR7 NF-κB signaling in a TLR7-specific system at a low concentration of 1 µM after 6 h of stimulation in vitro (15). The anticancer therapies given directly into tumors may be more effective than given systemically, because local therapies could overcome natural suppressive factors in the tumor microenvironment, and induce systemic antitumor immunity (39).…”