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Evaluation of modified Interferon alpha mRNA constructs for the treatment of non-melanoma skin cancer.

ABSTRACT: Application of in vitro transcribed (IVT) messenger ribonucleic acid (mRNA) is an increasingly popular strategy to transiently produce proteins as therapeutics in a tissue or organ of choice. Here, we focused on the skin and aimed to test if whole human skin tissue explant technology can be used to evaluate the expression efficacy of different IVT Interferon alpha (IFN-?) mRNA constructs in situ, after biolistic delivery. Skin explants were viable and intact for at least five days based on histologic analysis and TUNEL staining. Using GFP reporter mRNA formulations, we found mostly epidermal expression after biolistic delivery. Two out of five sequence-optimized IFN-? mRNA variants resulted in significantly improved IFN-? protein expression in human skin compared to native IFN-? mRNA transfection. IFN-? secretion analysis of the surrounding culture media confirmed these results. We provide a proof-of-concept that IFN-? mRNA delivery into intact human full thickness skin explants can be utilized to test mRNA sequence modifications ex vivo. This approach could be used to develop novel mRNA-based treatments of common epidermal skin conditions including non-melanoma skin cancer, where IFN-? protein therapy has previously shown a strong therapeutic effect.

SUBMITTER: Hochmann S

PROVIDER: S-EPMC6113332 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Evaluation of modified Interferon alpha mRNA constructs for the treatment of non-melanoma skin cancer.

Hochmann Sarah S Mittermeir Michaela M Santic Radmila R Koszik Frieder F Griessner Lanay L Sonderegger Alina Sarah AS Hoffmann Thomas T Russe Elisabeth E Scheiblhofer Sandra S Weiss Richard R Mandler Markus M Schneeberger Achim A Strunk Dirk D

Scientific reports 20180828 1

Application of in vitro transcribed (IVT) messenger ribonucleic acid (mRNA) is an increasingly popular strategy to transiently produce proteins as therapeutics in a tissue or organ of choice. Here, we focused on the skin and aimed to test if whole human skin tissue explant technology can be used to evaluate the expression efficacy of different IVT Interferon alpha (IFN-α) mRNA constructs in situ, after biolistic delivery. Skin explants were viable and intact for at least five days based on histo ...[more]

PMID: 30154486

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Project description:Advanced melanoma and non-melanoma skin cancers (NMSCs) are burdened with a dismal prognosis. To improve the survival of these patients, studies on immunotherapy and target therapies in melanoma and NMSCs are rapidly increasing. BRAF and MEK inhibitors improve clinical outcomes, and anti-PD1 therapy demonstrates better results than chemotherapy or anti-CTLA4 therapy in terms of the survival of patients with advanced melanoma. In recent years, the combination therapy of nivolumab plus ipilimumab has gained ground in studies for its survival and response rate benefits in patients with advanced melanoma. In addition, neoadjuvant treatment for stages III and IV melanoma, either as monotherapy or combination therapy, has recently been discussed. Another promising strategy evaluated in recent studies is the triple combination of anti-PD-1/PD-L1 immunotherapy and anti-BRAF plus anti-MEK targeted therapy. On the contrary, in advanced and metastatic BCC, successful therapeutic strategies, such as vismodegib and sonidegib, are based on the inhibition of aberrant activation of the Hedgehog signaling pathway. In these patients, anti-PD-1 therapy with cemiplimab should be reserved as the second-line therapy in case of disease progression or poor response. In patients with locally advanced or metastatic SCC, who are not candidates for surgery or radiotherapy, anti-PD1 agents such as cemiplimab, pembrolizumab, and cosibelimab (CK-301) have shown significant results in terms of response rate. PD-1/PD-L1 inhibitors, such as avelumab, have also been used in Merkel carcinoma, achieving responses in half of the patients with advanced disease. The latest prospect emerging for MCC is the locoregional approach involving the injection of drugs that can stimulate the immune system. Two of the most promising molecules used in combination with immunotherapy are cavrotolimod (a Toll-like receptor 9 agonist) and a Toll-like receptor 7/8 agonist. Another area of study is cellular immunotherapy with natural killer cells stimulated with an IL-15 analog or CD4/CD8 cells stimulated with tumor neoantigens. Neoadjuvant treatment with cemiplimab in CSCCs and nivolumab in MCCs has shown promising results. Despite the successes of these new drugs, the new challenges ahead will be to select patients who will benefit from these treatments based on biomarkers and parameters of the tumor microenvironment.

Dataset Information

Evaluation of modified Interferon alpha mRNA constructs for the treatment of non-melanoma skin cancer.

Publications

Evaluation of modified Interferon alpha mRNA constructs for the treatment of non-melanoma skin cancer.

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