Radiation therapy is used in the treatment of around 50% of cancer patients and remains the most important nonsurgical treatment in the management of solid malignancies. Treatment with ionizing radiation (IR) induces lethal DNA damage leading to cellular death through mitotic catastrophe, necrosis and apoptosis. Recent evidence also suggests that treatment with IR can render the tumor cells immunogenic and potentially generate antitumor immune responses.

Exposure of cancer cells to IR leads to cellular stress and the expression of several damage-associated molecular patterns (DAMPs). These include High Mobility Group Box 1 (HMGB1) and the extracellular release of ATP, which can activate professional antigen presenting cells (APCs), such as the dendritic cell (DC), and engender tumor antigen-specific T-cell responses. In addition, the induction of DNA damage subsequent to treatment with IR can lead to the production of novel (and potentially immunogenic) proteins and has been shown to upregulate tumor cell expression of class I MHC. Taken together, these data demonstrate the immunogenic potential of radiation therapy for cancer. Data from preclinical studies, however, demonstrate that established tumors foster immunosuppressive microenvironments that favor angiogenesis and the production of cytokines such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which attenuate TH−1 cytotoxic activity. Consequently, in both preclinical and clinical studies the use of IR alone is rarely capable of generating durable tumor antigen-specific immune responses. However, several preclinical studies have demonstrated the generation of systemic immune responses following combination therapy with IR and immuno-modulators such as monoclonal antibodies to CTLA4 and CD40, and small molecule agonists of the Toll-like receptor (TLR) family members TLR7 and TLR9.

Members of the TLR family are responsible for recognizing a diverse array of evolutionarily conserved pathogen-associated molecular patterns and are constitutively expressed by both professional APCs and effector immune cell populations. Activation of TLR7, which is localized intracellularly in endosomal membranes and recognizes viral guanosine and/or uridine-rich single-stranded RNA, leads to a MyD88-dependent signaling cascade ultimately resulting in interferon regulatory factor-7 (IRF-7), AP-1 or NFκB-mediated transcription of TH1 cytokines, predominantly Type I interferon (IFN).

Synthetic small molecule agonists of TLR7 have been developed such as imiquimod (Aldara 5% cream, 3M), which is FDA-approved for the treatment of genital warts and superficial basal cell carcinoma. However, delivery of topical TLR7 agonists to noncutaneous tumors is challenging and would require image-guided delivery such as ultrasound or computerized tomography. We have previously demonstrated that systemic delivery of a TLR7-selective small molecule agonist leads to the priming of systemic immune responses capable of reducing both primary and metastatic tumor burden. The TLR7 agonist 852A (Pfizer) is currently one of the most extensively studied compounds to be tested systemically in clinical trials. Amy L. Adlard et al. assessed the antitumor efficacy of a newly described systemically administered 8-oxoadenine derivative, DSR-6434, which has a higher water solubility and a 300-fold greater potency for human TLR7 than 852A. Their results demonstrate that systemic administration of DSR-6434 can enhance the effectiveness of radiotherapy in two syngeneic tumor models and that this occurs as a consequence of TLR7 activation and the generation of tumor-specific immune responses.

Reference:

A novel systemically administered toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models. Tumor Immunology . 2014;135:820-829