A novel systemically administered toll‐like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models

Abstract

Although topical TLR7 therapies such as imiquimod have proved successful in the treatment of dermatological malignancy, systemic delivery may be required for optimal immunotherapy of nondermatological tumors. We report that intravenous delivery of the novel small molecule TLR7 agonist, DSR-6434, leads to the induction of type 1 interferon and activation of T and B lymphocytes, NK and NKT cells. Our data demonstrate that systemic administration of DSR-6434 enhances the efficacy of ionizing radiation (IR) and leads to improved survival in mice bearing either CT26 or KHT tumors. Of the CT26 tumor-bearing mice that received combined therapy, 55% experienced complete tumor resolution. Our data reveal that these long-term surviving mice have a significantly greater frequency of tumor antigen specific CD8+ T cells when compared to age-matched tumor-naïve cells. To evaluate therapeutic effects on spontaneous metastases, we showed that combination of DSR-6434 with local IR of the primary tumor significantly reduced metastatic burden in the lung, when compared to time-matched cohorts treated with IR alone. The data demonstrate that systemic administration of the novel TLR7 agonist DSR-6434 in combination with IR primes an antitumor CD8+ T-cell response leading to improved survival in syngeneic models of colorectal carcinoma and fibrosarcoma. Importantly, efficacy extends to sites outside of the field of irradiation, reducing metastatic load. Clinical evaluation of systemic TLR7 therapy in combination with IR for the treatment of solid malignancy is warranted.What's new?Recent evidence suggests that damage from ionizing radiation (IR) can render tumor cells immunogenic. Unfortunately, established tumors often suppress this anti-tumor immune response. Combination therapy with IR and immune-modulators such as Toll-like-receptor (TLR) family agonists may overcome this problem. In this proof-of-concept study, the authors examined one such small-molecule drug, called DSR-6434. They found that systemic administration of DSR-6434 can enhance the effectiveness of radiotherapy in mice, and that this occurs via the generation of tumor-specific immune responses. Easily delivered drugs that activate TLR-family molecules may thus offer a promising therapeutic approach.

TLR activation and ionizing radiation induce strong immune responses against multiple tumor entities

“…Our findings were consistent with recently published and independent data from murine models of fibrosarcoma and lymphoma using different TLR 7/8 agonists. 6,7 Taken together, these data support the notion that the combination of local irradiation and a TLR agonist is robustly effective against a wide C T cells or both. As we hypothesized that dendritic cells are the pivotal hub between innate and adaptive immune response and may be the main facilitator of the combined treatment effects, we also selectively eliminated CD11c C dendritic cells in tumor-bearing CD11c-DTR mice.…”

Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas

“…As a TLR7 agonist, IQM stimulates innate immunity, including tumor-associated macrophages (TAMs) (1)(2)(3). In an experimental murine model, the addition of IQM to cryosurgery increased the cellular immune response against tumor antigens, leading to complete rejection of B16OVA melanoma (4).…”

Combination therapy with TLR7 agonist and radiation is effective for the treatment of solid cancer

“…Recently, several other investigators have examined the anti-tumor effect of combination therapy with a TLR7 agonist and local radiation (10,11). In subcutaneous and orthotropic mouse models of colorectal and pancreatic cancer, combined treatment with local irradiation and systemic administration of a TLR7 agonist was highly effective against established tumors.…”

“…Moreover, T cells and NK cells markedly contributed to the enhancement of anti-tumor efficacy of the combination therapy. In a spontaneous lung metastasis model, the combination therapy of primary tumors significantly reduced metastatic burden in the lung and improved survival (10). Lung metastatic lesions were never exposed to radiation directly.…”