Ramlah Khan

Introduction. Melanoma is a cancer of melanocytes and is the cause of the most skin cancer related deaths per year with incidence rates increasing by 1.5% per year.^1,2  Current treatments for melanoma include surgical resection, chemotherapy, targeted therapy, and immunotherapy, but some patients don’t respond to these therapies, develop resistance, or experience severe side-effects.³ Researchers have been studying a new form of therapy that is centered around gene delivery to dendritic cells, but there have been many challenges in efficiently and effectively delivering tumor associated antigens to dendritic cells in in lymphoid organs.⁴ Methods. Multiple nanoparticles containing liposomal RNA (RNA-LPX) vaccine were developed with varying compositions, charge ratios, and ionic conditions and then their particle size, colloid stability, and RNA stability was analyzed.⁴ The different RNA-LPX vaccines were then intravenously injected into mice to assess biodistribution of the molecules. An RNA-LPX formulation that was stable and effectively targeted the RNA to the spleen was selected and used for in further experiments to the determine the mechanism by which an immune response was brought about.⁴ Results. RNA-LPX formulations with a high negative charge were found to selectively targeted the spleen.⁴ The RNA-LPX bind to the TLR7 receptor, one of the receptors used by viruses to induce immune response, on CD11c+ cells, which are mostly human dendritic cells.⁴ The RNA-LPX results in release of IFN-α, a type I interferon, from dendritic cells, which is a similar immune response activated in response to viruses. Type I interferons are essential for effective antigen specific CD8+ T cells.⁴ Secretion of molecules like granzyme B and TNF- α in the studies led the researchers to believe that effective antigen specific T-cells were produced by the immune response.⁴ In a phase I clinical trial using RNA-LPX with one of four common melanoma associated antigens encoded, a strong IFN- α and antigen specific CD8+ T cells response was recorded in patients.⁵ Conclusions. RNA-LPX with a negative charge can systemically target dendritic cells in the spleen to induce a strong type I IFN driven immune response in mouse models and clinical trials.^4,5 Type I IFN are vital for fully effective antigen specific T cells.⁴ Any tumor associated antigen can be encoded as and RNA-LPX and this provides a new immunotherapy treatment that can be used for many different cancers.⁴

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2. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Updated based on November 2019 SEER data submission. https://seer.cancer.gov/csr/1975_2017/
3. Chang C-Y, Park H, Malone DC, et al. Immune Checkpoint Inhibitors and Immune-Related Adverse Events in Patients with Advanced Melanoma. JAMA Network Open; 2020.
4. Kranz LM, Diken M, Haas H, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. Jun 16 2016;534(7607):396-401. doi:10.1038/nature18300
5. Sahin U, Oehm P, Derhovanessian E, et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature. 2020;585(7823):107-112. doi:10.1038/s41586-020-2537-9