Zaryab Alam

Background: Merkel cell carcinoma (MCC) is a rare and aggressive cancer caused by the Merkel cell polyomavirus (MCPyV) and sun exposure, commonly found on sun-exposed areas.¹ The Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) pathway is used by cancer cells in MCC to evade the immune system.² Treatment for MCC varies depending on the type and stage, with surgery, radiation therapy, and two FDA-approved anti-PD-1/PD-L1 drugs, Avelumab and Pembrolizumab.^1,2,3 Determining the optimal treatment approach for MCC requires evaluating the duration and dose of anti-PD-1/PD-L1 therapy, understanding long-term outcomes and potential toxicities, and identifying the most appropriate patient population for this therapy.²

Objective: To review the therapeutic potential of the anti-PD-1/PD-L1 therapy as a treatment for Merkel Cell Carcinoma and new strategies to enhance anti-checkpoint immunotherapy for cancer.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “Merkel cell carcinoma,” “PD-1,” “PD-L1,” “immunotherapy.”

Results: Avelumab, a PD-L1 inhibitor, has been approved as the first treatment for metastatic MCC, but questions remain regarding its durability and non-responder treatment options.³ Another study found that the phosphorylation of ITSM-Y248 recruits SHP-2 to form a PD-1:PD-1 dimer, resulting in enzymatic activation, which has implications for developing new therapeutic strategies for cancer immunotherapy.⁴ A high-affinity PD-1 variant was also generated to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which has potential as a new class of PD-1 immune-checkpoint blockade therapy.⁵ A study on the recognition mechanism of PD-L1 monoclonal antibodies proposed a potential inhibition mechanism of the nanobody and guided the design and modification of anticancer monoclonal antibodies.⁶ Additionally, a study reported the crystal structure of pembrolizumab Fab in complex with hPD-1 and showed that pembrolizumab blocks the binding of hPD-L1 or hPD-L2 to hPD-1, with implications for the design and improvement of monoclonal antibody drugs that target hPD-1.⁷

Conclusions: Targeting the PD-1/PD-L1 pathway has shown promise in MCC treatment with FDA-approved drugs Avelumab and Pembrolizumab. However, their durability and non-responder treatment options need further investigation. New strategies like the high-affinity PD-1 variant and monoclonal antibody modifications may enhance T cell responses. Further research is necessary to determine optimal treatment approaches, evaluate long-term outcomes and potential toxicities of anti-PD-1/PD-L1 therapy in MCC.

Works Cited:

1. Hanna GJ, Kacew AJ, Tanguturi AR, et al. Association of Programmed Death 1 Protein Ligand (PD-L1) Expression With Prognosis in Merkel Cell Carcinoma.Front Med (Lausanne). 2020;7:198. Published 2020 Jun 5. doi:10.3389/fmed.2020.00198
2. Gaiser MR, Bongiorno M, Brownell I. PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma.Expert Rev Clin Pharmacol. 2018;11(4):345-359. doi:10.1080/17512433.2018.1445966
3. Patrinely JR Jr, Dewan AK, Johnson DB. The Role of Anti-PD-1/PD-L1 in the Treatment of Skin Cancer.BioDrugs. 2020;34(4):495-503. doi:10.1007/s40259-020-00428-9
4. Patsoukis N, Duke-Cohan JS, Chaudhri A, et al. Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation.Commun Biol. 2020;3(1):128. Published 2020 Mar 17. doi:10.1038/s42003-020-0845-0
5. Li Y, Liang Z, Tian Y, et al. High-affinity PD-1 molecules deliver improved interaction with PD-L1 and PD-L2.Cancer Sci. 2018;109(8):2435-2445. doi:10.1111/cas.13666
6. Sun X, Yan X, Zhuo W, et al. PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations.Int J Mol Sci. 2018;19(7):1984. Published 2018 Jul 7. doi:10.3390/ijms19071984
7. Na Z, Yeo SP, Bharath SR, et al. Structural basis for blocking PD-1-mediated immune suppression by therapeutic antibody pembrolizumab.Cell Res. 2017;27(1):147-150. doi:10.1038/cr.2016.77