Combining topical imiquimod with local radiotherapy for treatment of mycosis fungoides

Mycosis fungoides (MF) is the most common subtype of cutaneous T cell lymphoma (MF) and is characterized by cutaneous patches, plaques and tumors. MF patients are generally incurable with standard treatment modalities, with 5-year disease specific survival rates ranging from 70 to 88% for early stage disease to 24% for patients with advanced disease.1 Those with advanced disease are plagued with disfiguring tumors or plaques and frequent infections that cause death in 27 to 60% of patients 2. Radiation therapy (RT) is a frequently pursued management option for CTCL, especially in patients with more advanced skin disease. The neoplastic T-cells of CTCL are highly radiosensitive and dramatic regression of treated lesions can be achieved with single doses as low as 1.0 Gy.3,4 Furthermore, RT is known to occasionally induce a systemic abscopal effect, including rare reports of individuals undergoing RT-treated CTCL.5-8 Despite these advantages, abscopal responses are rare and the magnitude and durability of the RT disease response is low in advanced stage disease (e.g. T4 disease has <10% 5-year RFS rate).9 Thus, there is a need to improve the systemic antitumor effects induced by RT. Besides the advantages provided by its skin presentation, CTCL’s radiosensitivity (and typical palliative doses <8 Gys) makes it an excellent model for studying these effects as doses above 12-18 Gys have been shown to greatly attenuate tumor immunogenicity.10 Imiquimod is a topical TLR7 agonist that is used for treatment of actinic keratoses but is used off-label for CTCL. Imiquimod stimulates a Th1 lymphocyte response with increased IL-2 and IFN- but also induces IFN-α, TNF-α, IL-1α, IL-6, and IL-8, thereby bridging both innate and adaptive immunity. In recent years, imiquimod has been shown to exhibit adjuvant activity when combined with local radiotherapy in a mouse model and one small clinical trial of cutaneous breast carcinoma11,12 and enhanced antitumor immunity induced by therapeutic HPV DNA vaccination in tumor-bearing mice.13 Generally, RT and imiquimod are used separately in the treatment of CTCL; RT is primarily used in MF with thick plaques or tumors and imiquimod in MF with patches or thin plaques, but we hypothesize that its use in combination on the same lesions will enhance antitumor responses from RT and provide longer response durability. The primary aim of this study is to assess the effectiveness of a combination local radiotherapy and topical imiquimod approach to lesions of conventional (CD4+) MF. Translational aims will investigate changes in the tumor-associated (lesional skin) and gut microbiomes before and after RT/imiquimod treatment and tumor-associated and serum immune biomarkers before and after RT/imiquimod treatment. In each of these, we will characterize the differences between systemic responders and non-responders. Just as the gut microbiome has been shown to modulate antitumor responses, accurate characterization can further efforts to maximize the effects of RT in CTCL by altering the microbiome.