Therapeutic effect of Imiquimod enhanced ALA-PDT on cutaneous squamous cell carcinoma

Anil Kumar Bhatta, Peiru Wang, Uma Keyal, Zijun Zhao, Jie Ji, Lude Zhu, Xiuli Wang, Guolong Zhang
Photodiagnosis and Photodynamic Therapy 2018, 23: 273-280

BACKGROUND: Topical photodynamic therapy (PDT) is approved treatment for actinic keratosis, basal cell carcinoma and Bowen's disease. But currently it is not recommended for invasive squamous cell carcinoma (SCC) of the skin because inadequate penetration of topically applied photosensitizers lead to poor treatment response. Imiquimod (IMQ) as an immune response modifier and Toll-like receptor 7 (TLR7) agonist, is known to exhibit antitumor activity. As an adjunct therapy, it is recently seen to enhance the effect of PDT.

METHOD: This is an in vivo experiment performed on 52 SCC implanted mice model. The mice were equally divided into four groups: IMQ group, IMQ + PDT group, PDT group and control group. The mice in IMQ + PDT group were treated with 3 sessions of 5% IMQ cream and ALA-PDT. Mice in IMQ group received only 5% IMQ cream. Similarly, mice in PDT group received only ALA-PDT and control mice received no treatment. The treatment efficacy was compared among these groups via tumor volume and digital photographs. In addition, immunohistochemical (IHC) markers, q PCR and detection of apoptosis were studied on 12 UV induced mice model. After successful result of this animal experiment, we performed human study on two patients with invasive cSCC on lips and foot. The patients were treated with daily application of 5% imiquimod cream and ALA-PDT at 2 weeks interval. Treatment response was assessed via clinical examination, digital photographs and dermoscopy findings.

RESULTS: The study demonstrated that combination approach of IMQ + PDT has better effect than IMQ alone or PDT alone. It also showed increased expression of IL-6, IL-8, IFN-α, CXCL9, CXCL10 and TNF-α in IMQ + PDT group but at different time points following treatment (P < 0.05). IHC staining showed that the number of CD4+ cells was similar in IMQ + PDT and PDT groups but CD8+ cells was almost double in IMQ + PDT group when compared to PDT group. In addition, the number of apoptotic cell was maximum in IMQ + PDT group. Human study also delivered excellent results in both the patients with complete clearance of lesion after 3-6 sessions of treatment.

CONCLUSION: PDT combined with imiquimod may have enhanced effect for the treatment of invasive cSCC. Maximum number of apoptotic cells in IMQ + PDT group can be attributed to increased number of CD8 + T cells in this group. Additional mechanism of enhanced efficacy in IMQ + PDT group may be due to increased expression of markers tested in this study.

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