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Review
. 2020 Jan 29;21(3):879.
doi: 10.3390/ijms21030879.

The Role of Immune Checkpoint Blockade in Uveal Melanoma

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Free PMC article
Review

The Role of Immune Checkpoint Blockade in Uveal Melanoma

Anja Wessely et al. Int J Mol Sci. .
Free PMC article

Abstract

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.

Keywords: CTLA-4; PD-1; cytotoxic T lymphocyte-associated antigen; immune checkpoint blockade; ipilimumab; nivolumab; ocular melanoma; pembrolizumab; programmed death 1; uveal melanoma.

Conflict of interest statement

L.H. has received fees as consultant/member of advisory boards by Amgen, MSD, BMS, Roche, Curevac, Pierre-Fabre, Novartis, and Sanofi-Aventis and research grants to institution from Novartis. M.S. received honoraria for lectures from MSD, BMS, Roche, and Pierre-Fabre and served on advisory boards for Novartis, Roche, MSD, and Pierre-Fabre. C.B. has received speaker´s honoraria or fees as member of advisory boards by Amgen, BMS, Immunocore, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi-Aventis. C.B. has been investigator of clinical trials sponsored by Amgen, Array Pharma, AstraZeneca, BMS, MSD, Novartis, Regeneron, and Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; nor in the decision to publish the results. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular mechanism of immune checkpoints. (a) CTLA-4 is a critical negative regulator of the T cell response in the early activation phase of the adaptive immune response. It binds to the costimulatory ligands CD80 and CD86 on antigen-presenting cells with a higher affinity than CD28 and thereby prevents their interaction with CD28 and subsequent T cell activation. Anti-CTLA-4 antibodies block the interaction of CTLA-4 and CD80/86 and boost T cell activation and the anti-tumor response. (b) The PD-1–PD-L1 axis is an important mechanism to avoid tissue damage from autoreactive T cells and maintains the peripheral tolerance. Binding of PD-L1 to its receptor PD-1 blocks T cell receptor (TCR) signaling, resulting in limited T cell function. Antibodies targeting PD-1 or its ligand PD-L1 are able to inhibit their interaction and prevent the inactivation of tumor-reactive immune cells.
Figure 2
Figure 2
Promising future immunotherapy options for UM patients. (A) Dendritic cell vaccination: Monocytes or other hematopoietic progenitors are isolated from the tumor patient via leukapheresis and develop in vitro in the presence of stimulatory cytokines to mature DCs. These are then loaded with tumor-specific peptides (i.e., gp100, tyrosinase) or mRNA encoding these antigens and retransferred into the patient in order to boost the anti-tumor response. (B) Adoptive T cell transfer: TILs are isolated from hepatic metastases and expanded in vitro. After a lymphodepleting chemotherapy, the patient receives the expanded TILs followed by IL-2 administration. (C) Bispecific proteins, i.e., IMCgp100 (tebentafusp): The bispecific protein IMCgp100 combines a TCR against gp100 and CD3 scFv. The engineered TCR of the molecule binds to gp100 on UM cells presented by the MHC class I protein HLA-A*02:01, and the anti-CD3 antibody fragment binds to and activates CD3+ T cells. DC = dendritic cell, TILs: tumor-infiltrating lymphocytes, CD3 scFv = anti-CD3 single-chain antibody fragment, MHC I = major histocompatibility complex I, TCR = T cell receptor, IL-2 = interleukin-2.

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