Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) holds great promise as a treatment option for human basal cell carcinoma (BCC), the most common of all cancers. Recent evidence suggests that PDT is an immune-altering modality. Here we describe a clinical trial (NCT05020912) to examine the effects of ALA-PDT upon the tumor immune landscape within BCC tumors pre- and post-treatment, to better understand the nature of the tumor-infiltrating immune cells, and accompanying changes in systemic anti-tumor immunity. If better understood, such knowledge could be harnessed to improve therapeutic responses to PDT.
Photodynamic therapy with aminolevulinic acid and blue light is used in Europe for basal cell carcinoma (BCC), but not in the United States due to uncertainties about efficacy. To potentially improve treatment outcomes and make PDT a more attractive as therapy for BCC, we conducted a prospective, double-blind, crossover clinical trial to test whether pretreatment with oral Vitamin D may enhance BCC responses to blue light PDT. Three separate PDT sessions were administered, with patients receiving daily doses of Vitamin D (10,000 units) or placebo for a week prior to PDT. We will report here on interim clinical trial outcomes.
Two different treatment modalities for skin cancer, topical 5-fluorouracil (5FU) and photodynamic therapy (PDT), have several non-overlapping mechanisms of action in addition to inducing long-term anti-tumor immunity mediated by cells of innate and adaptive immune systems. The particular type of PDT (painless, or p-PDT) uses aminolevulinic acid (ALA) and exposure to blue light in a non-apoptotic regimen resulting in lesion clearance mainly by immunological cell death. When combined, 5FU and p-PDT augment each other in multiple ways, including augmentation of anti-tumor immune activation, resulting in greater tumor reduction than possible with either modality alone.
Aminolevulinate-based photodynamic therapy (ALA-PDT) is an effective treatment for cutaneous pre-cancers (Actinic Keratoses; AK) and Basal Cell Carcinoma (BCC), the most common skin malignancies. When administered in a conventional regimen with 1-4 h of ALA preincubation prior to light exposure, ALA-PDT elicits stinging pain during illumination that patients find objectionable. To avoid this pain, we have described a new regimen called metronomic PDT (mPDT) which is similar to daylight PDT but uses blue light (Kaw et al, J Am Acad Dermatol 2019). Metronomic PDT is not only painless but also nearly as effective as conventional PDT for AK lesion clearance. In this investigation, murine models of AK induced by repeated UVB exposure were treated with mPDT, followed by time-course analyses of immune responses in the lesions harvested. Our preliminary data showed that relative to conventional PDT, cell death (apoptosis) and generation of Reactive Oxygen Species (ROS) were compromised in mPDT samples. However, relative to untreated controls, enhanced recruitment/infiltration of immune cells that mediate innate immunity [neutrophils (Ly6G+) and macrophages (F4/80+)] was observed at early times after mPDT. Just as importantly, enhanced presence of cells regulating adaptive immune responses [T cells (CD3+, CD8+ and Foxp3+)] was observed at later times post mPDT. Activation of calreticulin and HMGB1 (markers of Damage Associated Molecular Patterns, DAMPs) were also observed in mPDT treated lesions. Our results suggest that mPDT can be just as effective as conventional PDT for treatment of skin cancer and pre-cancer, and that the therapeutic mechanisms may involve immune cell responses triggered by metronomic PDT.
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