The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma.,A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients.,This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression.,The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples.,Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed.,One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response.,The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively.,Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment.,The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively.,A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage.,The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.
Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies.,Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development.,Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC.,However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair.,Here, we generated Keap1flox/flox SKH-1 hairless mice in which Nrf2 is disrupted (Keap1flox/flox/Nrf2−/−) and subjected them chronically to solar-simulated UV radiation.,We found that the incidence, multiplicity and burden of cSCC that form in Keap1flox/flox/Nrf2−/− mice are much greater than in their Keap1flox/flox/Nrf2+/+ counterparts, establishing Nrf2 activation as the protection mediator.,Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial.