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.