Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy

Abstract

Strategies to augment anti-cancer immune responses have recently demonstrated therapeutic utility. To date clinical success has been achieved through targeting co-inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1. However, approaches that target co-activatory pathways are also being actively being developed. Here we report that the novel TLR7-selective agonist DSR-29133 is well tolerated in mice and leads to acute immune activation. Administration of DSR-29133 leads to the induction of IFNα/γ, IP-10, TNFα, IL-1Ra and IL-12p70, and to a reduction in tumor burden in syngeneic models of renal cancer (Renca), metastatic osteosarcoma (LM8) and colorectal cancer (CT26). Moreover, we show that the efficacy of DSR-29133 was significantly improved when administered in combination with low-dose fractionated radiotherapy (RT). Effective combination therapy required weekly administration of DSR-29133 commencing on day 1 of a fractionated RT treatment cycle, whereas no enhancement of radiation response was observed when DSR-29133 was administered at the end of the fractionated RT cycle. Combined therapy resulted in curative responses in a high proportion of mice bearing established CT26 tumors which was dependent on the activity of CD8+ T-cells but independent of CD4+ T-cells and NK/NKT cells. Moreover, long-term surviving mice originally treated with DSR-29133 and RT were protected by a tumor-specific memory immune response which could prevent tumor growth upon rechallenge. These results demonstrate that DSR-29133 is a potent selective TLR7 agonist that when administered intravenously can induce anti-tumor immune responses that can be further enhanced through combination with low-dose fractionated RT.

The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer

“…However, with further optimization, it is possible that immune-based therapies could provide effective tumor responses without the same degree of systemic toxicity as cytotoxic chemotherapy. Several recent studies highlight the dual potential for benefit and harm of TLR7 agonists, which hold substantial promise as anti-tumor agents but cause acute toxicities [34][35][36] . Indeed, we observed that treatment induction was associated with acute hypophagia, weight loss, and decreased locomotor activity.…”

Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies

“…In addition, combinations of MEDI9197 with standard of care treatments for cancer, such as chemotherapy and radiotherapy, that drive release of tumor antigens are attractive given the observed vaccine adjuvant activity of MEDI9197 [22, 41–43]. Indeed, TLR7 agonists have previously been reported to enhance efficacy in combination with radiotherapy and chemotherapy in syngeneic mouse tumor models [44, 45].…”

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

“…Moreover, the efficacy of DSR-29133 was significantly improved when administered in combination with low-dose fractionated radiotherapy. Long-term surviving mice originally treated with DSR-29133 and radiotherapy were protected by a tumor-specific memory immune response which could prevent tumor growth [120]. [121].…”