Immunological Strategies to Fight Skin Cancer

B. Berman, MD, PhD; O. A. Perez, MD; D. Zell, MD

Disclosures

Skin Therapy Letter. 2006;11(5):1-7. 

In This Article

Imiquimod

As an immune response modifier, imiquimod induces IFN-α, tumor necrosis factor (TNF)-α, IL-1, IL-6, IL-8, and IL-12 production by monocytes, macrophages and toll-like receptor (TLR)-7-bearing plasmacytoid dendritic cells. TLR-7 is an essential receptor for imiquimod-induced immune responses.[14] Imiquimod also generates production of IFN-α after CD4 cells are stimulated by IL-12. IFN-α stimulates cytotoxic T lymphocytes responsible for killing virus-infected and tumor cells.

Topical imiquimod 5% cream has been found to be effective in the treatment of lentigo maligna (LM, in situ melanoma). In a pilot, open-label, nonrandomized study evaluating the effectiveness of imiquimod 5% cream once daily for a maximum of 13 weeks on five patients with LM, a 100% response rate was observed without reoccurrence during a 3–18 month follow-up interval.[15] Case reports describing multiple metastatic melanoma skin lesions clearing after topical imiquimod 5% cream application have also been published. The two patients studied applied imiquimod 5% cream three times/week to the metastatic skin lesions with a 1cm surrounding margin.[16]

Imiquimod 5% cream has been shown to induce the expression of FasR on BCC cells, and FasR mediated apoptosis may contribute to the effectiveness of imiquimod in BCC treatment.[17] An initial 16-week, dose-ranging, vehicle-controlled trial examining the effect of 5% imiquimod cream on nBCC and sBCC found an overall histological response rate of 83% (20/24) in the 5% imiquimod cream treatment group vs. 9% (1/11) in the vehicle treatment group.[18] Subsequent sBCC randomized, multicenter studies have reported 100% efficacy with twice daily application vs. 73–88% efficacy with once daily application of 5% imiquimod cream.[19–21]

Imiquimod studies in SCC patients are restricted to AK and in situ SCC clinical presentations. A 16-week, twice weekly, imiquimod 5% cream treatment regimen has been approved by the FDA for patients with AK lesions on the face or scalp. This treatment regimen has achieved a 45.1% (97/215) complete clearance and a 59.1% (127/215) partial clearance rate. These clearance rates are significantly higher than the complete and partial clearance rates found in the vehicle group (p < 0.001).[22]

Current therapies for Bowen's disease, or intraepidermal SCC, include 5-Fluorouracil, surgical excision, curettage, electrocautery, cryo-, laser-, photo-, and radiotherapy.[23] In a Phase II open-label study, 16 biopsy-proven plaques of Bowen's disease, with diameters ranging between 1–5.4 cm, were treated once daily for 16 weeks with imiquimod 5% cream. Of the 16 lesions treated, 15 were on the lower extremities and 1 was on the shoulder. Fourteen of 15 patients (93%) had no residual tumor present in the 6-week post-treatment follow-up biopsy. Thirteen patients were followed to 6 months without disease recurrence.[24]

Extramammary Paget's disease (EMPD) is an infrequent epidermal malignancy most commonly occurring in the anogenital and vulvar regions. Therapeutic modalities include wide local excision and Mohs micrographic surgery. A case report of two patients with primary limited cutaneous perineal and genital EMPD describes successful treatment of EMPD with imiquimod 5% cream, with confirmation of cure after 7.5–12 weeks of monotherapy. The treatment-associated morbidity was minimal when compared with other more invasive therapies.[25] Another case study has documented the eradication of EMPD of the scrotum in a 68-year-old male with nightly application of imiquimod 5% cream for 6 weeks, with no signs of reoccurrence at 6 months after discontinuation of therapy.[26]( Table 2 .)

Imiquimod was preconceived as possibly beneficial in the treatment of VIN of human papilloma virus etiology, due to its antiviral and antineoplastic properties; however, the literature shows mixed results. In a prospective, observational study examining the effects of imiquimod 5% cream three times/week for 16 weeks in 15 patients with high-grade VIN, 3 demonstrated local side-effects, including soreness, burning, erythema, ulceration, and blistering. One patient required hospitalization, catheterization, and analgesia. Of the 13 patients who completed the study, four demonstrated clinical improvement. Of these four patients, only one had a negative VIN biopsy. All four patients who responded clinically relapsed 4 months after treatment.[27] However, in a recent study examining the effect of imiquimod 5% cream applied three times/week for a maximum of 16 weeks in eight patients with biopsy-proven bowenoid and basaloid, VIN 2/3 had better results. Total clearance and partial clearance was observed in six patients and two patients, respectively, and the post-treatment biopsy showed an absence of precancerous lesions in seven of eight patients (87.5%).[28]

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