A Non-Invasive Deep Photoablation Technique to Inhibit DCIS Progression and Induce Antitumor Immunity

SIMPLE SUMMARY: Fewer than half of ductal carcinoma in situ (DCIS) cases progress to invasive breast cancer (BC); however, most are treated surgically, which raises a concern of overtreatment. Novel approaches to the management of DCIS that do not rely on surgery are warranted. In this study, we assessed the efficacy of heat shock protein 90 (Hsp90)-targeted photodynamic therapy (HS201-PDT) as a novel alternative treatment to target DCIS and prevent progression to invasive BC. The preventive application of HS201-PDT to the mammary glands of spontaneous murine DCIS models significantly improved disease-free survival. Enhancement of immune response with systemically administered anti-PD-L1 antibodies along with repeated HS201-PDT to mammary glands was effective even in a more aggressive DCIS model. Thus, HS201-PDT monotherapy or the combination with anti-PD-L1 antibodies is a promising strategy that could serve as an alternative treatment of DCIS to prevent progression to invasive BC. ABSTRACT: Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) (p = 0.0328) and tended to improve overall survival compared to the no-treatment control (p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 (p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway.