How TLR7 Agonists Improve Cancer Radiotherapy

In the treatment of around 50% of cancer patients the radiation therapy is used.  It is remains the most important nonsurgical treatment in the management of solid malignancies. Treatment with ionizing radiation (IR) can render the tumor cells immunogenic and potentially generate antitumor immune responses.

However, several preclinical studies have demonstrated the generation of systemic immune responses following combination therapy with IR and immuno-modulators such as small molecule agonists of the Toll-like receptor (TLR) family members TLR7 and TLR9.

Synthetic small molecule agonists of TLR7 have been developed for the treatment of genital warts and superficial basal cell carcinoma. However, delivery of topical TLR7 agonists to non-cutaneous tumors was challenging and had required image-guided delivery such as ultrasound or computerized tomography.

Scientists from the University of Manchester had demonstrated that systemic delivery of a TLR7-selective small molecule agonist (852A; Pfizer) leads to the priming of systemic immune responses capable of reducing both primary and metastatic tumor burden.

In collaboration with AstraZeneca and Dainippon Sumitomo Pharma, the Manchester group led by Professor Ian Stratford, from Manchester Pharmacy School and Professor Tim Illidge, had looked at another molecule that activates TLR7, known as DSR-6434, which has a higher water solubility and a 300-fold greater potency for human TLR7 than 852A.

The results demonstrate that combination of DSR-6434 with local IR of the primary tumor significantly reduced metastatic burden in the lung, primes an antitumor CD8+ T-cell response leading to improved survival in syngeneic models of colorectal carcinoma and fibrosarcoma and efficacy extends to sites outside of the field of irradiation, reducing metastatic load.