Review Article

Revolutionizing Skin Cancer Treatment: The Rise of PD-1/PDL-1 and CTLA-4 as Key Therapeutic Targets

Author(s): Neha Sharma*, Rupa Mazumder and Pallavi Rai

Volume 25, Issue 15, 2024

Published on: 10 September, 2024

Page: [1012 - 1026] Pages: 15

DOI: 10.2174/0113894501320281240822052657

Price: $65

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Abstract

Skin cancer is a significant health concern, affecting millions of individuals globally on an annual basis. According to data from the World Health Organization, it stands as the most prevalent form of cancer within the white population. Current treatments for skin cancer typically involve a combination of chemotherapy, radiation therapy, and surgery. However, these methods often come with drawbacks, such as side effects and potential scarring. Therefore, there is a growing need for alternative treatments that can offer effective results with fewer adverse effects, driving ongoing research in skin cancer therapy. The advancement of immune checkpoint inhibitors has been facilitated by a more profound comprehension of the interplay between tumors and the immune system, along with the regulatory mechanisms governing T-cells. As cancer treatment continues to evolve, immunotherapy is emerging as a powerful strategy, leading to a growing interest in the role of immunological checkpoints in skin cancer. Various types of immune checkpoints and their expression, including PD-1, PDL-1, CTLA-4, lymphocyte activation gene 3, and B7-H3, along with their blockers and monoclonal antibodies, have been established for various cancers. PD-1, PDL-1, and CTLA-4 are crucial immune system regulators, acting as brakes to prevent T-- cell overactivation and potential autoimmunity. However, tumors can exploit these checkpoints to evade immune detection. Inhibiting these immune checkpoints can enhance the body's ability to recognize and attack cancer cells. This review focuses on the characteristics of PD-1, PDL-1, and CTLA-4 immune checkpoints, their mechanism of action, and their role in skin cancer. Additionally, it summarizes the ongoing clinical trials sponsored or conducted by various pharmaceutical companies and provides insights into the latest patent data.

Keywords: Skin cancer, immunotherapy, clinical trials, immune-checkpoints blockers, PD-1/PDL-1, CTLA-4.

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[1]
Chen JT, Kempton SJ, Rao VK. The economics of skin cancer: An analysis of Medicare payment data. Plast Reconstr Surg Glob Open 2016; 4(9): e868.
[http://dx.doi.org/10.1097/GOX.0000000000000826] [PMID: 27757333]
[2]
Bennardo L, Bennardo F, Giudice A, et al. Local chemotherapy as an adjuvant treatment in unresectable squamous cell carcinoma: What do we know so far? Curr Oncol 2021; 28(4): 2317-25.
[http://dx.doi.org/10.3390/curroncol28040213] [PMID: 34201867]
[3]
Lansbury L, Bath-Hextall F, Perkins W, Stanton W, Leonardi-Bee J. Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies. BMJ 2013; 347(nov04 1): f6153.
[http://dx.doi.org/10.1136/bmj.f6153] [PMID: 24191270]
[4]
Rare cancers of childhood treatment (PDQ®): Patient version. PDQ Cancer Information Summaries . Bethesda (MD): National Cancer Institute (US) 2002.
[5]
Anthony ML. Surgical treatment of nonmelanoma skin cancer. AORN J 2000; 71(3): 550-64.
[http://dx.doi.org/10.1016/S0001-2092(06)61577-9]
[6]
National Comprehensive Cancer Network. Squamous Cell Skin Cancer (Version 5.2022). 2022. Available from: https://www.nccn. org/professionals/physician_gls/pdf/squamous.pdf
[7]
Badash I, Shauly O, Lui CG, Gould DJ, Patel KM. Nonmelanoma facial skin cancer: A review of diagnostic strategies, surgical treatment, and reconstructive techniques. Clin Med Insights Ear Nose Throat 2019; 12
[http://dx.doi.org/10.1177/1179550619865278] [PMID: 31384136]
[8]
Zeng L, Gowda BHJ, Ahmed MG, et al. Advancements in nanoparticle-based treatment approaches for skin cancer therapy. Mol Cancer 2023; 22(1): 10.
[http://dx.doi.org/10.1186/s12943-022-01708-4] [PMID: 36635761]
[9]
Muto P, Pastore F. Radiotherapy in the adjuvant and advanced setting of CSCC. Dermatol Pract Concept 2021; 11(Suppl 2)
[http://dx.doi.org/10.5826/dpc.11S2a168S]
[10]
Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carcinoma. J Clin Aesthet Dermatol 2010; 3(4): 39-48.
[PMID: 20725546]
[11]
Calzavara-Pinton PG, Venturini M, Sala R, et al. Methylaminolaevulinate-based photodynamic therapy of Bowen’s disease and squamous cell carcinoma. Br J Dermatol 2008; 159(1): 137-44.
[http://dx.doi.org/10.1111/j.1365-2133.2008.08593.x] [PMID: 18489606]
[12]
Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic therapy for the treatment of nonmelanoma skin cancer. Dermatol Surg 2004; 30(2 Pt 2): 264-71.
[PMID: 14871220]
[13]
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36(17): 1714-68.
[http://dx.doi.org/10.1200/JCO.2017.77.6385] [PMID: 29442540]
[14]
Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016; 374(26): 2542-52.
[http://dx.doi.org/10.1056/NEJMoa1603702] [PMID: 27093365]
[15]
Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous cell carcinoma. N Engl J Med 2018; 379(4): 341-51.
[http://dx.doi.org/10.1056/NEJMoa1805131] [PMID: 29863979]
[16]
Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499(7457): 214-8.
[http://dx.doi.org/10.1038/nature12213] [PMID: 23770567]
[17]
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations. Front Oncol 2018; 8: 86.
[http://dx.doi.org/10.3389/fonc.2018.00086] [PMID: 29644214]
[18]
Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM. T cell responses: Naïve to memory and everything in between. Adv Physiol Educ 2013; 37(4): 273-83.
[http://dx.doi.org/10.1152/advan.00066.2013] [PMID: 24292902]
[19]
Teng MWL, Galon J, Fridman WH, Smyth MJ. From mice to humans: Developments in cancer immunoediting. J Clin Invest 2015; 125(9): 3338-46.
[http://dx.doi.org/10.1172/JCI80004] [PMID: 26241053]
[20]
Otsuka A, Dreier J, Cheng PF, et al. Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma. Clin Cancer Res 2015; 21(6): 1289-97.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2110] [PMID: 25593302]
[21]
Otsuka A, Levesque MP, Dummer R, Kabashima K. Hedgehog signaling in basal cell carcinoma. J Dermatol Sci 2015; 78(2): 95-100.
[http://dx.doi.org/10.1016/j.jdermsci.2015.02.007] [PMID: 25766766]
[22]
Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016; 375(9): 819-29.
[http://dx.doi.org/10.1056/NEJMoa1604958] [PMID: 27433843]
[23]
Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015; 35(Suppl): S185-98.
[24]
Sarvaria A, Madrigal JA, Saudemont A. B cell regulation in cancer and anti-tumor immunity. Cell Mol Immunol 2017; 14(8): 662-74.
[http://dx.doi.org/10.1038/cmi.2017.35] [PMID: 28626234]
[25]
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11(11): 3887-95.
[http://dx.doi.org/10.1002/j.1460-2075.1992.tb05481.x] [PMID: 1396582]
[26]
Sharma N, Mazumder R, Rai P, Debnath A. Role of PD-1 in skin cancer: Molecular mechanism, clinical applications, and resistance. Chem Biol Drug Des 2024; 104(3): e14613.
[27]
Shindo Y, Yoshimura K, Kuramasu A, et al. Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. Anticancer Res 2015; 35(1): 129-36.
[PMID: 25550543]
[28]
Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol 2015; 51(3): 221-8.
[http://dx.doi.org/10.1016/j.oraloncology.2014.11.014] [PMID: 25500094]
[29]
Sun JY, Zhang D, Wu S, et al. Resistance to PD-1/PD-L1 blockade cancer immunotherapy: Mechanisms, predictive factors, and future perspectives. Biomark Res 2020; 8(1): 35.
[http://dx.doi.org/10.1186/s40364-020-00212-5] [PMID: 32864132]
[30]
Chen L, Han X. Anti–PD-1/PD-L1 therapy of human cancer: Past, present, and future. J Clin Invest 2015; 125(9): 3384-91.
[http://dx.doi.org/10.1172/JCI80011] [PMID: 26325035]
[31]
Perkins D, Wang Z, Donovan C, et al. Regulation of CTLA-4 expression during T cell activation. J Immunol 1996; 156(11): 4154-9.
[32]
Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol 2015; 6: 418.
[http://dx.doi.org/10.3389/fimmu.2015.00418] [PMID: 26347741]
[33]
Koury J, Lucero M, Cato C, et al. Immunotherapies: Exploiting the immune system for cancer treatment. J Immunol Res 2018; 2018
[http://dx.doi.org/10.1155/2018/9585614]
[34]
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-23.
[http://dx.doi.org/10.1056/NEJMoa1003466] [PMID: 20525992]
[35]
O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Cancer 2007; 110(12): 2614-27.
[http://dx.doi.org/10.1002/cncr.23086] [PMID: 18000991]
[36]
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224(1): 166-82.
[http://dx.doi.org/10.1111/j.1600-065X.2008.00662.x] [PMID: 18759926]
[37]
Stamper CC, Zhang Y, Tobin JF, et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 2001; 410(6828): 608-11.
[http://dx.doi.org/10.1038/35069118] [PMID: 11279502]
[38]
Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008; 322(5899): 271-5.
[http://dx.doi.org/10.1126/science.1160062] [PMID: 18845758]
[39]
Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: A phase I/II study. Ann Surg Oncol 2005; 12(12): 1005-16.
[http://dx.doi.org/10.1245/ASO.2005.03.536] [PMID: 16283570]
[40]
Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018; 378(2): 158-68.
[http://dx.doi.org/10.1056/NEJMra1703481] [PMID: 29320654]
[41]
Yi M, Yu S, Qin S, et al. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J Hematol Oncol 2018; 11(1): 47.
[http://dx.doi.org/10.1186/s13045-018-0592-6] [PMID: 29580257]
[42]
Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother 2016; 12(11): 2777-89.
[43]
Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 2014; 384(9948): 1109-17.
[http://dx.doi.org/10.1016/S0140-6736(14)60958-2] [PMID: 25034862]
[44]
Oro-Ayude M, Suh-Oh HJ, Sacristán-Santos V, Vázquez-Bartolomé P, Flórez Á. Nivolumab for metastatic cutaneous squamous cell carcinoma. Case Rep Dermatol 2020; 12(1): 37-41.
[http://dx.doi.org/10.1159/000505478] [PMID: 32595466]
[45]
Zambrano-Román M, Padilla-Gutiérrez JR, Valle Y, Muñoz-Valle JF, Valdés-Alvarado E. Non-melanoma skin cancer: A genetic update and future perspectives. Cancers 2022; 14(10): 2371.
[http://dx.doi.org/10.3390/cancers14102371] [PMID: 35625975]
[46]
Chang J, Zhu GA, Cheung C, Li S, Kim J, Chang ALS. Association between programmed death ligand 1 expression in patients with basal cell carcinomas and the number of treatment modalities. JAMA Dermatol 2017; 153(4): 285-90.
[http://dx.doi.org/10.1001/jamadermatol.2016.5062] [PMID: 28259105]
[47]
Ikeda S, Goodman AM, Cohen PR, et al. Metastatic basal cell carcinoma with amplification of PD-L1: Exceptional response to anti-PD1 therapy. NPJ Genom Med 2016; 1(1): 16037.
[http://dx.doi.org/10.1038/npjgenmed.2016.37] [PMID: 27942391]
[48]
Mohan SV, Kuo KY, Chang ALS. Incidental regression of an advanced basal cell carcinoma after ipilimumab exposure for metastatic melanoma. JAAD Case Rep 2016; 2(1): 13-5.
[http://dx.doi.org/10.1016/j.jdcr.2015.11.007] [PMID: 27051815]
[49]
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.
[http://dx.doi.org/10.1007/s40259-020-00428-9] [PMID: 32447657]
[50]
Chuk MK, Chang JT, Theoret MR, et al. FDA approval summary: Accelerated approval of pembrolizumab for second-line treatment of metastatic melanoma. Clin Cancer Res 2017; 23(19): 5666-70.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0663] [PMID: 28235882]
[51]
Ahmed SR, Petersen E, Patel R, Migden MR. Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma. Expert Rev Clin Pharmacol 2019; 12(10): 947-51.
[http://dx.doi.org/10.1080/17512433.2019.1665026] [PMID: 31524530]
[52]
Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 2018; 379(8): 722-30.
[http://dx.doi.org/10.1056/NEJMoa1805453] [PMID: 30134131]
[53]
Ramagopal UA, Liu W, Garrett-Thomson SC, et al. Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. Proc Natl Acad Sci USA 2017; 114(21): E4223-32.
[http://dx.doi.org/10.1073/pnas.1617941114] [PMID: 28484017]
[54]
Jazirehi AR, Lim A, Dinh T. PD-1 inhibition and treatment of advanced melanoma-role of pembrolizumab. Am J Cancer Res 2016; 6(10): 2117-28.
[PMID: 27822406]
[55]
Choi J, Lee SY. Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors. Immune Netw 2020; 20(1): e9.
[http://dx.doi.org/10.4110/in.2020.20.e9] [PMID: 32158597]
[56]
Nasser H, John MS. Immunotherapeutic approaches to head and neck cancer. Crit Rev Oncog 2018; 23(3-4)
[http://dx.doi.org/10.1615/CritRevOncog.2018027641]
[57]
Bansal P, Osman D, Gan GN, Simon GR, Boumber Y. Recent advances in immunotherapy in metastatic NSCLC. Front Oncol 2016; 6: 239.
[http://dx.doi.org/10.3389/fonc.2016.00239] [PMID: 27896216]
[58]
Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers 2020; 12(3): 738.
[http://dx.doi.org/10.3390/cancers12030738] [PMID: 32245016]
[59]
Zhang Q, Huo G, Zhang H, Song Y. Efficacy of pembrolizumab for advanced/metastatic melanoma: A meta-analysis. Open Med 2020; 15(1): 447-56.
[http://dx.doi.org/10.1515/med-2020-0110] [PMID: 33313405]
[60]
Jackson-Spence F, Szabados B, Toms C, Yang YH, Sng C, Powles T. Avelumab in locally advanced or metastatic urothelial carcinoma. Expert Rev Anticancer Ther 2022; 22(2): 135-40.
[http://dx.doi.org/10.1080/14737140.2022.2028621] [PMID: 35015593]
[61]
Tsang J, Wong JSL, Kwok GGW, et al. Nivolumab + Ipilimumab for patients with hepatocellular carcinoma previously treated with Sorafenib. Expert Rev Gastroenterol Hepatol 2021; 15(6): 589-98.
[http://dx.doi.org/10.1080/17474124.2021.1899808] [PMID: 33666530]
[62]
Gao J, Zhang C, Wei Z, Ye X. Immunotherapy for early-stage non-small cell lung cancer: A system review. J Cancer Res Ther 2023; 19(4): 849-65.
[http://dx.doi.org/10.4103/jcrt.jcrt_723_23] [PMID: 37675709]
[63]
Lamba N, Ott PA, Iorgulescu JB. Use of first-line immune checkpoint inhibitors and association with overall survival among patients with metastatic melanoma in the anti–PD-1 era. JAMA Netw Open 2022; 5(8): e2225459.
[http://dx.doi.org/10.1001/jamanetworkopen.2022.25459] [PMID: 36006646]
[64]
Kang C. Retifanlimab: First approval. Drugs 2023; 83(8): 731-7.
[http://dx.doi.org/10.1007/s40265-023-01884-7] [PMID: 37184754]
[65]
Neo-adjuvant nivolumab or nivolumab with ipilimumab in advanced cutaneous squamous cell carcinoma prior to surgery (MATISSE). Patent NCT04620200, 2020.
[66]
Study of cemiplimab in patients with type of skin cancer stage II to IV cutaneous squamous cell carcinoma. Patent NCT04154943, 2020.
[67]
Neoadjuvant atezolizumab in surgically resectable advanced cutaneous squamous cell carcinoma. Patent NCT04710498, 2020.
[68]
Intralesional cemiplimab for adult patients with cutaneous squamous cell carcinoma or basal cell carcinoma. Patent NCT03889912, 2020.
[69]
Study of adjuvant cemiplimab versus placebo after surgery and radiation therapy in patients with high-risk cutaneous squamous cell carcinoma. Patent NCT03969004, 2020.
[70]
Nivolumab in patients with advanced cutaneous squamous cell carcinoma (CA209-9JC). Patent NCT03834233, 2020.
[71]
Neoadjuvant pembrolizumab in cutaneous squamous cell carcinoma (DESQUAMATE). Patent NCT05025813, 2020.
[72]
Study of REGN2810 in patients with advanced cutaneous squamous cell carcinoma. Patent NCT02760498, 2020.
[73]
Cemiplimab-rwlc for unresectable locally recurrent and/or metastatic CSCC. Patent NCT04242173, 2020.
[74]
Radiotherapy in combination with atezolizumab in locally advanced borderline resectable or unresectable cutaneous SCC. Patent NCT05085496, 2020.
[75]
Cemiplimab in AlloSCT/SOT recipients with CSCC (CONTRAC). Patent NCT04339062, 2020.
[76]
Study evaluating cemiplimab alone and combined with rp1 in treating advanced squamous skin cancer (CERPASS). Patent NCT04050436, 2020.
[77]
Neoadjuvant plus adjuvant treatment with cemiplimab in cutaneaous squamous cell carcinoma. Patent NCT04632433, 2020.
[78]
Atezolizumab before surgery for the treatment of regionally metastatic head and neck squamous cell cancer with an unknown or historic primary site. Patent NCT05110781, 2020.
[79]
Before C, Surgery A. Cemiplimab before and after surgery for the treatment of high-risk cutaneous squamous cell cancer. Patent NCT04428671, 2020.
[80]
Nivolumab for treatment of squamous cell carcinoma of the skin. Patent NCT04204837, 2020.
[81]
Neoadjuvant study of PD-1 inhibitor pembrolizumab in PD-1 naive cutaneous squamous cell carcinoma (cSCC). Patent NCT04808999, 2020.
[82]
Avelumab with or without cetuximab in treating patients with advanced skin squamous cell cancer. Patent NCT03944941, 2020.
[83]
Study of Pembrolizumab (MK-3475) in Adults with Recurrent/Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) or Locally Advanced Unresectable cSCC (MK-3475-629/KEYNOTE-629). Patent NCT03284424, 2020.
[84]
Study of Pembrolizumab (MK-3475) in Adults with Recurrent/Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) or Locally Advanced Unresectable cSCC (MK-3475-629/KEYNOTE-629). Patent NCT03737721, 2020.
[85]
Pembrolizumab (MK-3475) versus Placebo Following Surgery and Radiation in Participants with Locally Advanced Cutaneous Squamous Cell Carcinoma (MK-3475-630/KEYNOTE-630) Patent NCT03833167, 2020.
[86]
Post-operative radiation with cetuximab for locally advanced cutaneous squamous cell carcinoma of the head and neck. Patent NCT01979211, 2020.
[87]
Talimogene laherparepvec and panitumumab for the treatment of locally advanced or metastatic squamous cell carcinoma of the skin. Patent NCT04163952, 2020.
[88]
Pembrolizumab in patients with locally advanced or metastatic skin cancer. Patent NCT02964559, 2020.
[89]
CemiplimAb Survivorship Epidemiology (CASE). Patent NCT03836105, 2020.
[90]
Cetuximab before surgery in treating patients with aggressive locally advanced skin cancer. Patent NCT02324608, 2020.
[91]
Talimogene laherparepvec and nivolumab in treating patients with refractory lymphomas or advanced or refractory non-melanoma skin cancers. Patent NCT02978625, 2020.
[92]
High-risk skin cancers with atezolizumab plus NT-I7. Patent NCT03901573, 2020.
[93]
An open-label study using ASP-1929 photoimmunotherapy in combination with anti-PD1 therapy in EGFR expressing advanced solid tumors. Patent NCT04305795, 2020.
[94]
A study of SAR444245 combined with cemiplimab for the treatment of participants with various advanced skin cancers (Pegathor Skin 201). Patent NCT04913220, 2020.
[95]
Quad shot radiotherapy in combination with immune checkpoint inhibition. Patent NCT04454489, 2020.
[96]
Pembrolizumab Combined with Cetuximab for Treatment of Recurrent/Metastatic Head & Neck Squamous Cell Carcinoma. Patent NCT03082534, 2020.
[97]
Abexinostat in combination with pembrolizumab in patients with advanced solid tumor malignancies. Patent NCT03590054, 2020.
[98]
Cobimetinib and atezolizumab in treating participants with advanced or refractory rare tumors. Patent NCT03108131, 2020.
[99]
Phase 1 study of CK-301 (Cosibelimab) as a single agent in subjects with advanced cancers. Patent NCT03212404, 2020.
[100]
Sonidegib and pembrolizumab in treating patients with advanced solid tumors. Patent NCT04007744, 2020.
[101]
Pembrolizumab in Treating Patients with Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic. Patent NCT02721732, 2020.
[102]
Study of SO-C101 and SO-C101 in Combination with Pembro in Adult Patients with Advanced/Metastatic Solid Tumors Patent NCT02721732, 2020.
[103]
Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients with Selected Unresectable or Metastatic Cancers. Patent NCT03816332, 2020.
[104]
Administration of PD-1 inhibitors for treating skin cancer. Patent EP3930848, 2022.
[105]
Intralesional administration of pd-1 inhibitors for treating skin cancer. Patent EP3880186, 2021.
[106]
A method of determining risk for skin cancer development and skin cancer therapeutic prevention by measuring pd-1/pd-l1 signaling pathway members. Patent WO2020118208, 2020.
[107]
Fury Matthew G. Methods of treating cancer by administering a pd-1 inhibitor. Patent EP4204592, 2023.
[108]
Harrath BM, Hong G, Kumar PB. Combination therapy with notch and PD-1 Or PD-L1 inhibitors. Patent EP3458091, 2019.
[109]
Ilona G. Combination of an ahr-inhibitor and a pd-1inhibitor antibody and its use in the treatment of cancer. Patent EP4076462, 2022.
[110]
Desai J, Seluzhytsky MG, Alexandermehta NP. Methods of treating cancer in immunosuppressed or immunocompromised patients by administering a pd-1 inhibitor. Patent CA3170902, 2022.
[111]
Sheng J, Zhou G, Hao H, et al. PD-1/PD-L1 polypeptide inhibitor and medical application thereof. Patent CN111909240, 2020.
[112]
Chen M, Xing S, Cheng L, Zhang L, Yang C. Application of combination of anti-pd-1 antibody and il-15 protein compound in preparation of medicines for tumor treatment. Patent CN110448691, 2019.
[113]
Sheng B, Yang R. IgY and micromolecular Fab antibody capable of blocking PD-1/PD-L1 pathway and preparation and applications thereof. Patent CN109694412, 2019.
[114]
Gabriel M. PD-1 peptide inhibitors. Patent JP2022190026, 2022.
[115]
Gutierrez Gabriel M. PD-1 and CTLA-4 dual inhibitor peptides. Patent Ep3630807, 2020.
[116]
Dzhon Sung. Combined therapy with tetracyclic quinolone analogues for cancer treatment. Patent RU0002752506, 2019.
[117]
Wang Y, Lijunhuang SW. Use of bacteroides fragilis combined with immune checkpoint inhibitor in treatment of skin tumors. Patent WO2023134195, 2023.
[118]
Kumar M, Thangavel C, Becker RC, Sadayappan S. Monoclonal antibody-based immunotherapy and its role in the development of cardiac toxicity. Cancers 2020; 13(1): 86.
[http://dx.doi.org/10.3390/cancers13010086] [PMID: 33396766]
[119]
Bondhopadhyay B, Sisodiya S, Chikara A, et al. Cancer immunotherapy: A promising dawn in cancer research. Am J Blood Res 2020; 10(6): 375-85.
[PMID: 33489447]
[120]
Lee J, Han Y, Wang W, et al. Phytochemicals in cancer immune checkpoint inhibitor therapy. Biomolecules 2021; 11(8): 1107.
[http://dx.doi.org/10.3390/biom11081107] [PMID: 34439774]
[121]
Messeha SS, Zarmouh NO, Soliman KFA. Polyphenols modulating effects of PD-L1/PD-1 checkpoint and EMT-mediated PD-L1 overexpression in breast cancer. Nutrients 2021; 13(5): 1718.
[http://dx.doi.org/10.3390/nu13051718] [PMID: 34069461]
[122]
Liu K, Sun Q, Liu Q, Li H, Zhang W, Sun C. Focus on immune checkpoint PD-1/PD-L1 pathway: New advances of polyphenol phytochemicals in tumor immunotherapy. Biomed Pharmacother 2022; 154: 113618.
[http://dx.doi.org/10.1016/j.biopha.2022.113618] [PMID: 36055113]
[123]
Pouliquen DL, Trošelj KG, Anto RJ. Curcuminoids as anticancer drugs: Pleiotropic effects, potential for metabolic reprogramming and prospects for the future. Pharmaceutics 2023; 15(6): 1612.
[http://dx.doi.org/10.3390/pharmaceutics15061612] [PMID: 37376060]
[124]
Dong M, Meng Z, Kuerban K, et al. Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota. Cell Death Dis 2018; 9(10): 1039.
[http://dx.doi.org/10.1038/s41419-018-1099-3] [PMID: 30305604]
[125]
Yanaki M, Kobayashi M, Aruga A, Nomura M, Ozaki M. in vivo antitumor effects of MK615 led by PD-L1 downregulation. Integr Cancer Ther 2018; 17(3): 646-53.
[http://dx.doi.org/10.1177/1534735418766403] [PMID: 29665734]
[126]
Peng M, Fan S, Li J, et al. Programmed death-ligand 1 signaling and expression are reversible by lycopene via PI3K/AKT and Raf/MEK/ERK pathways in tongue squamous cell carcinoma. Genes Nutr 2022; 17(1): 3.
[http://dx.doi.org/10.1186/s12263-022-00705-y] [PMID: 35164673]
[127]
Li L, Zhang M, Liu T, et al. Quercetin-ferrum nanoparticles enhance photothermal therapy by modulating the tumor immunosuppressive microenvironment. Acta Biomater 2023; 154: 454-66.
[http://dx.doi.org/10.1016/j.actbio.2022.10.008]
[128]
Ravindran Menon D, Li Y, Yamauchi T, et al. EGCG inhibits tumor growth in melanoma by targeting JAK-STAT signaling and its downstream PD-L1/PD-L2-PD1 axis in tumors and enhancing cytotoxic T-cell responses. Pharmaceuticals 2021; 14(11): 1081.
[http://dx.doi.org/10.3390/ph14111081] [PMID: 34832863]
[129]
Hao H, Zhang Q, Zhu H, et al. Icaritin promotes tumor T-cell infiltration and induces antitumor immunity in mice. Eur J Immunol 2019; 49(12): 2235-44.
[http://dx.doi.org/10.1002/eji.201948225] [PMID: 31465113]

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