Anti-PD-1 Therapy with Adjuvant Ablative Fractional Laser Improves Anti-Tumor Response in Basal Cell Carcinomas.

Uffe Høgh Olesen,Ditte Elisabeth Jæhger,Martin Wiinberg,Merete Haedersdal,Thomas Lars Andresen,Catharina Margrethe Lerche

doi:10.3390/cancers13246326

Abstract

Simple SummaryIn some mouse models, ablative fractional laser (AFL) enhances the efficacy of anti-programmed cell death1 therapy (aPD-1), which was recently approved for basal cell carcinoma (BCC). In this explorative study, we aimed to assess locally applied AFL as an adjuvant to systemic aPD-1 treatment in a clinically relevant BCC model. BCC-carrying mice received aPD-1 alone, AFL alone, aPD-1+AFL, or no treatment. Both aPD-1 and AFL alone significantly increased survival time relative to the untreated controls, while aPD-1 that had been complemented with AFL further promoted survival and improved tumor clearance and growth rates. The BCCs were poorly immune infiltrated, but aPD-1 with adjuvant AFL and AFL alone induced substantial immune cell infiltration in tumors and increased the levels of relevant immune cell subtypes. Thus, the anti-tumor response that was generated by aPD-1 with adjuvant AFL may potentially be promoted by increased immune activity in tumors. In conclusion, the use of a local AFL adjuvant to systemic aPD-1 therapy could hold substantial promise for BCC treatment.The efficacy of anti-programmedcelldeath1therapy (aPD-1), which was recently approved for basal cell carcinoma (BCC) treatment, can be enhanced by adjuvant ablative fractional laser (AFL) in syngeneic murine tumor models. In this explorative study, we aimed to assess locally applied AFL as an adjuvant to systemic aPD-1 treatment in a clinically relevant autochthonous BCC model. BCC tumors (n = 72) were induced in Ptch1+/−K14-CreER2p53fl/fl-mice (n = 34), and the mice subsequently received aPD-1 alone, AFL alone, aPD-1+AFL, or no treatment. The outcome measures included mouse survival time, tumor clearance, tumor growth rates, and tumor immune infiltration. Both aPD-1 and AFL alone significantly increased survival time relative to untreated controls (31 d and 34.5 d, respectively vs. 14 d, p = 0.0348–0.0392). Complementing aPD-1 with AFL further promoted survival (60 d, p = 0.0198 vs. aPD-1) and improved tumor clearance and growth rates. The BCCs were poorly immune infiltrated, but aPD-1 with adjuvant AFL and AFL alone induced substantial immune cell infiltration in the tumors. Similar to AFL alone, combined aPD-1 and AFL increased neutrophil counts (4-fold, p = 0.0242), the proportion of MHCII-positive neutrophils (p = 0.0121), and concordantly, CD4+ and CD8+ T-cell infiltration (p = 0.0061–0.0242). These descriptive results suggest that the anti-tumor response that is generated by aPD-1 with adjuvant AFL is potentially promoted by increased neutrophil and T-cell engraftment in tumors. In conclusion, local AFL shows substantial promise as an adjuvant to systemic aPD-1 therapy in a clinically relevant preclinical BCC model.

Highlights

Basal cell carcinoma (BCC) is the major subtype of keratinocyte cancer; it is the most prevalent human cancer worldwide, with an estimated 5.4 million cases in the US alone [1]
This study is the first to demonstrate a significant impact of adjuvant ablative fractional laser (AFL) on Anti-programmed cell death-1 immune checkpoint therapy (aPD-1) treatment for BCC tumors in a clinically relevant autochthonous murine model [29] and suggests a role of local AFL exposure to BCC tumors in boosting the tumor response to systemic aPD-1 treatment. While both aPD-1 and AFL increased survival time compared to untreated controls when they were used as monotherapies, complementing aPD-1 treatment with AFL significantly improved survival time and tumor growth rates compared to either treatment alone, and the combination treatment obtained the highest cleared tumor proportion of any of the treatment interventions
Using a similar treatment strategy, the authors showed how a single exposure to AFL substantially increased tumor clearance in response to systemic aPD-1. They reported that AFL leads to a potent CD8+ T-cell and neutrophil anti-tumor immune response and the induction of systemic anti-tumor immunity that likely contributed to tumor clearance in this highly immunogenic model [30]

Summary

Introduction

Basal cell carcinoma (BCC) is the major subtype of keratinocyte cancer; it is the most prevalent human cancer worldwide, with an estimated 5.4 million cases in the US alone [1]. Anti-programmed cell death-1 immune checkpoint therapy (aPD-1) is a cancer immunotherapy that has revolutionized cancer treatment regimens in recent years and is of interest for the treatment of complex keratinocyte carcinoma cases. A high mutation rate increases the likelihood of generating immunogenic neoantigens and concordantly inducing tumor-specific T-cells that can be reinvigorated by aPD-1 therapy [7,8,9]. The aPD-1 drug cemiplimab was FDA approved in 2018 for the treatment of locally advanced and metastatic squamous cell carcinomas, another subtype of keratinocyte cancer [11]. A substantial clinical response to aPD-1 has only been observed in a subset of treated patients; it is important to identify adjuvant treatments that can act synergistically to increase treatment response rates [17]

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