Immunotherapy of Uveal Melanoma: Vaccination Against Cancer

Abstract

Uveal melanoma is the most frequently occurring primary intraocular tumor in adults, with an incidence of about 5 out of 100,000 per year, the incidence rising with increasing age (Lipski, Klin Monbl Augenheilkd 230:1005-1019, 2013; Metz et al., Klin Monbl Augenheilkd 230:686-691, 2013; Singh and Topham, Ophthalmology 110:956-961, 2003). Often diagnosed late due to a lack of early symptoms, this kind of melanoma is associated with a poor prognosis. Approximately 50 % of the patients develop distant metastases (Lipski, Klin Monbl Augenheilkd 230:1005-1019, 2013; Metz et al., Klin Monbl Augenheilkd 230:686-691, 2013; Singh and Topham, Ophthalmology 110:956-961, 2003). In sharp contrast to cutaneous melanoma, uveal melanoma shows a strong liver tropism and spreads exclusively via the hematogenous route (except for tumors with extraocular expansion) (Heindl et al., Arch Ophthalmol 128:1001-1008, 2010). The most likely reason for this observation is the lack of lymphatic vessels in the choroid and alymphatic barrier of the sclera (Schlereth et al., Exp Eye Res 125:203-209, 2014; Schroedl et al., Invest Ophthalmol Vis Sci 49:5222-5229, 2008). Due to its location in the immune-privileged eye, the uveal melanoma is widely protected from the immune system. Therefore, the goal of the approach presented here, of a "personalized vaccination therapy" is to help the immune system recognize and fight the tumor.

The prognostic values of m6A RNA methylation regulators in uveal melanoma

“…GSEA analysis showed that positive regulation of T cell mediated pathways and malignant hallmarks such as mTORC1 signaling, oxidative phosphorylation, interferon-a response and apoptosis signaling positively activate in C1 subgroup. In fact, T cells like active CD 4 + and CD 8 + cells have antitumor immunity and therapy functions [17]. As to C1 molecular subtype, lots of malignant hallmark of pathways were enriched.…”

Characterization of CD4+ T cells primed and boosted by MHCII primary uveal melanoma cell-based vaccines

“…Patients with high metastatic risk can be identified using validated prognostic tests such as chromosome 3 status [42], gene testing for class 1 (low metastatic risk) and class 2 (high metastatic risk) [43] or molecular stratification according to somatic copy number alterations and DNA methylation profiles [44]. There are innovative clinical trials in which high risk, monosomy 3, HLA-A2+ uveal melanoma patients are vaccinated with either melanoma antigen-derived peptides or melanoma antigen-encoding mRNA transfected-DC in the prophylactic setting [45–48]. These immunotherapy trials are unique in that patients are vaccinated at early time points when there is no clinical evidence of metastatic disease.…”

Uveal melanoma: physiopathology and new in situ-specific therapies

“…The eye is considered an immune-privileged organ which influences the immune response against uveal melanoma cells and provides escape mechanisms for uveal melanoma [95]. The following factors play an important role in the immune privilege of the eye: aqueous humor is rich in immunosuppressive proteins, such as transforming growth factor β (TGF-β), vasoactive intestinal peptide (VIP), α-melanocyte-stimulating hormone (α-MSH), and complement regulatory proteins (CRPs); the blood-eye barrier restricts inflammatory cell access to the eye; eye cells reduce major histocompatibility complex (MHC) class Ia expression to escape cytotoxic-mediated lyses; and ocular cells express programmed death ligand-1(PD-L1) which inhibits T-cell response.…”

“…To date, there are no treatments that target NK cells or macrophages. Regarding adaptive immune response, the mechanisms that interfere with immunity are the production of indoleamine 2,3-dioxygenase (IDO), overexpression of PD-L1, alteration of FasL expression, and resistance to perforin [16,95].…”