Characterisation of the inflammatory response triggered by topical ingenol mebutate 0.05% gel in basal cell carcinoma

Abstract

Background/Objective: Ingenol mebutate gel is approved for actinic keratosis field therapy, but little has been published as a treatment of basal cell carcinoma (BCC). Our objective is to characterise the histopathological changes and the infiltrating cell populations to better understand its mechanism of action.Methods: Sixteen patients with various BCC subtypes were prospectively evaluated and treated once daily for two consecutive days with ingenol mebutate gel 0.05% under occlusion. Patients were randomised to two arms: the first arm was biopsied between the third and the tenth day after treatment initiation ('early immune response'), and the second arm was biopsied at day 30 after treatment initiation ('late immune response'). The immunopathology was evaluated by immunohistochemistry: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD56, anti-CD68, anti-Bcl-2, anti-CASP3, anti-FoxP3, anti-GrzB and anti-TIA-1.Results: Ten BCCs were in complete remission after 2 years of follow-up. The early immune response was characterised by a quick recruitment of T lymphocytes, macrophages and natural killer cells. At later time-points, T-regulatory cells and some pro-apoptotic markers were detected. Treatment-related adverse events were described.Conclusion: Ingenol mebutate gel produces a transient immuno-inflammatory response and an important necrosis reaction in BCCs. Larger studies will be required to determine the maximum effective tolerated dose of ingenol mebutate gel for BCC.

Natural Killer Cell Recognition and Control of Epithelial Cancers

“… 65 A similar phase I trial combined the anti-GD2 antibody 3F8 with haploidentical NK cells administered after lymphodepleting chemotherapy in 35 patients. 6 Improved event-free survival was seen in patients receiving more than 10 7 NK cells. 29 These suggest that NK cells can be safely combined with anti-GD2 antibodies with preliminary evidence of antineuroblastoma effects, especially at higher NK cell doses.…”

“…The overall response rate was 61.5% (4 complete responses, 1 very good partial response, and 3 partial responses), and 5 had a stable disease, with 77% overall survival at 1 year 65 . A similar phase I trial combined the anti-GD2 antibody 3F8 with haploidentical NK cells administered after lymphodepleting chemotherapy in 35 patients 6 . Improved event-free survival was seen in patients receiving more than 10 7 NK cells 29 .…”

“… 4 Although isolated NK cell–based therapies have not yet been studied in the treatment of BCC, innate NK cells have been implicated in the local immune response that drives the effectiveness of the topical immunotherapy agents ingenol mebutate and imiquimod. 6 , 7 …”

“…4 Although isolated NK cell-based therapies have not yet been studied in the treatment of BCC, innate NK cells have been implicated in the local immune response that drives the effectiveness of the topical immunotherapy agents ingenol mebutate and imiquimod. 6,7 The incidence of CSCC is also rising. 8 Although most CSCCs are curable by surgical intervention alone, a subset of tumors harbors high-risk features and is at an increased risk of adverse outcomes including local recurrence, regional and distant metastasis, and disease-specific death.…”

“…Furthermore, p53 is necessary for NK ligand upregulation, and p53 mutations have been associated with this activating KIR haplotype, as well as BCC pathogenesis 4 . Although isolated NK cell–based therapies have not yet been studied in the treatment of BCC, innate NK cells have been implicated in the local immune response that drives the effectiveness of the topical immunotherapy agents ingenol mebutate and imiquimod 6,7 …”