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Immune Checkpoint Inhibitors in Melanoma Treatment: Advances and Obstacles

https://doi.org/10.24060/2076-3093-2025-15-1-57-65

Abstract

This paper presents a review of the state-of-the-art in skin melanoma treatment with a particular focus on immunotherapy and checkpoint inhibitors. Melanoma as a malignant neoplasm presents a serious threat given its high mortality rate, which emphasizes the need for further research and development of effective treatment strategies. Immune checkpoint inhibitors have shown a significant increase in the survival rate for skin melanoma patients. Nevertheless, the problem of drug resistance remains unresolved as a reaction to treatment differs from one patient to another even with high mutational burden. Obviously, immunotherapy may be accompanied by complications, which also emphasizes the need for an individualized approach to therapy. In order to predict treatment efficacy and understand possible resistance, mutation burden, T-cell receptor diversity, and specific antigens should be taken into account. All the above confirms the importance of a systematic approach to melanoma treatment including the use of modern drugs as well as a deep understanding of the patient’s immune status. Thus, this paper outlines the need for further research in the mechanisms of action of immunotherapeutic drugs as well as for the identification of biomarkers that may serve as predictors of response to therapy. This may lead to the development of more effective treatment strategies given the available advances in molecular biology and genetics. Addressing issues related to individualization of therapy based on immune status should become an important part of clinical practice.

About the Author

A. V. Sultanbaev
Republican Clinical Oncology Dispensary; Bashkir State Medical University; Republican Medical Genetic Centre
Russian Federation

Alexander V. Sultanbaev — Cand. Sci. (Med.), Assoc. Prof., Antiсancer Drug Therapy Unit, Department of Pedagogy and Psychology

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References

1. Lopes J., Rodrigues C.M.P., Gaspar M.M., Reis C.P. Melanoma management: from epidemiology to treatment and latest advances. Cancers (Basel). 2022;14(19):4652. DOI: 10.3390/cancers14194652

2. Ralli M., Botticelli A., Visconti I.C., Angeletti D., Fiore M., Marchetti P., et al. Immunotherapy in the treatment of metastatic melanoma: current knowledge and future directions. J Immunol Res. 2020;2020:9235638. DOI: 10.1155/2020/9235638

3. Okobi O.E., Abreo E., Sams N.P., Chukwuebuni O.H., Tweneboa Amoako L.A., Wiredu B., et al. Trends in melanoma incidence, prevalence, stage at diagnosis, and survival: an analysis of the United States Cancer Statistics (USCS) Database. Cureus. 2024;16(10):e70697. DOI: 10.7759/cureus.70697

4. Shalata W., Attal Z.G., Solomon A., Shalata S., Abu Saleh O., Tourkey L., et al. Melanoma management: exploring staging, prognosis, and treatment innovations. Int J Mol Sci. 2024;25(11):5794. DOI: 10.3390/ijms25115794

5. Shah V., Panchal V., Shah A., Vyas B., Agrawal S., Bharadwaj S. Immune checkpoint inhibitors in metastatic melanoma therapy (Review). Med Int (Lond). 2024;4(2):13. DOI: 10.3892/mi.2024.137

6. Santos-Briz A., Cañueto J., Carmen S.D., Barrios B., Yuste M., Bellido L., et al. Value of PD-L1, PD-1, and CTLA-4 expression in the clinical practice as predictors of response to nivolumab and ipilimumab in monotherapy in patients with advanced stage melanoma. Am J Dermatopathol. 2021;43(6):423–8. DOI: 10.1097/DAD.0000000000001856

7. Gupta M., Stukalin I., Meyers D., Goutam S., Heng D.Y.C., Cheng T., et al. Treatment-free survival after nivolumab vs pembrolizumab vs nivolumab-ipilimumab for advanced melanoma. JAMA Netw Open. 2023;6(6):e2319607. DOI: 10.1001/jamanetworkopen.2023.19607

8. Bagchi S., Yuan R., Engleman E.G. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49. DOI: 10.1146/annurev-pathol-042020-042741

9. Robert C., Lebbé C., Lesimple T., Lundström E., Nicolas V., Gavillet B., et al. Phase I study of androgen deprivation therapy in combination with anti-PD-1 in melanoma patients pretreated with anti-PD-1. Clin Cancer Res. 2023;29(5):858–65. DOI: 10.1158/1078-0432.CCR-22-2812

10. Ribas A., Wolchok J.D. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350–5. DOI: 10.1126/science.aar4060

11. Birnboim-Perach R., Benhar I. Using combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment. Int J Biol Sci. 2024;20(10):3911–22. DOI: 10.7150/ijbs.93697

12. Sultanbaev A.V., Tuzankina I.A., Musin Sh.I., Kolyadina I.V., Menshikov K.V., Sultanbaev M.V., et al. Specific antitumour immunity and mechanisms of tumour escape from immunological surveillance. P.A. Herzen Journal of Oncology. 2024;13(6):70–7 (In Russ.). DOI: 10.17116/onkolog20241306170

13. Grote C., Bohne A.S., Blome C., Kähler K.C. Quality of life under treatment with the immune checkpoint inhibitors ipilimumab and nivolumab in melanoma patients. Real-world data from a prospective observational study at the Skin Cancer Center Kiel. J Cancer Res Clin Oncol. 2024;150(10):454. DOI: 10.1007/s00432-024-05981-2

14. Alrabadi N.N., Abushukair H.M., Ababneh O.E., Syaj S.S., Al-Horani S.S., Qarqash A.A., et al. Systematic review and meta-analysis efficacy and safety of immune checkpoint inhibitors in advanced melanoma patients with anti-PD-1 progression: a systematic review and meta-analysis. Clin Transl Oncol. 2021;23(9):1885–904. DOI: 10.1007/s12094-021-02598-6

15. Sultanbaev A.V., Tuzankina I.A., Nasretdinov A.F., Sultanbaeva N.I., Musin Sh.I., Menshikov K.V., et al. Mechanisms of formation of specific antitumor im-munity and resistance to immune checkpoint inhibitors. Problems in Oncology. 2024;70(3):433–9 (In Russ). DOI: 10.37469/0507-3758-2024-70-3-433-439

16. Pabst L., Lopes S., Bertrand B., Creusot Q., Kotovskaya M., Pencreach E., et al. Prognostic and predictive biomarkers in the era of immunotherapy for lung cancer. Int J Mol Sci. 2023;24(8):7577. DOI: 10.3390/ijms24087577

17. Jia D.D., Niu Y., Zhu H., Wang S., Ma T., Li T. Prior therapy with pegylated-interferon alfa-2b improves the efficacy of adjuvant pembrolizumab in resectable advanced melanoma. Front Oncol. 2021;11:675873. DOI: 10.3389/fonc.2021.675873

18. Alspach E., Lussier D.M., Schreiber R.D. Interferon γ and Its important roles in promoting and inhibiting spontaneous and therapeutic cancer immunity. Cold Spring Harb Perspect Biol. 2019;11(3):a028480. DOI: 10.1101/cshperspect.a028480

19. Dummer R., Long G.V., Robert C., Tawbi H.A., Flaherty K.T., Ascierto P.A., et al. Randomized phase III trial evaluating spartalizumab plus dabrafenib and trametinib for BRAF V600-mutant unresectable or metastatic melanoma. J Clin Oncol. 2022;40(13):1428–38. DOI: 10.1200/JCO.21.01601

20. Tran K.B., Buchanan C.M., Shepherd P.R. Evolution of molecular targets in melanoma treatment. Curr Pharm Des. 2020;26(4):396–414. DOI: 10.2174/1381612826666200130091318

21. Addeo A., Friedlaender A., Banna G.L., Weiss G.J. TMB or not TMB as a biomarker: That is the question. Crit Rev Oncol Hematol. 2021;163:103374. DOI: 10.1016/j.critrevonc.2021.103374

22. Tímár J., Ladányi A. Molecular pathology of skin melanoma: epidemiology, differential diagnostics, prognosis and therapy prediction. Int J Mol Sci. 2022;23(10):5384. DOI: 10.3390/ijms23105384

23. Trocchia M., Ventrici A., Modestino L., Cristinziano L., Ferrara A.L., Palestra F., et al. Innate immune cells in melanoma: implications for immunotherapy. Int J Mol Sci. 2024;25(15):8523. DOI: 10.3390/ijms25158523

24. Willsmore Z.N., Coumbe B.G.T., Crescioli S., Reci S., Gupta A., Harris R.J., et al. Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action. Eur J Immunol. 2021;51(3):544–56. DOI: 10.1002/eji.202048747

25. Tjulandin S., Demidov L., Moiseyenko V., Protsenko S., Semiglazova T., Odintsova S., et al. Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice. Eur J Cancer. 2021;149:222–32. DOI: 10.1016/j.ejca.2021.02.030

26. Zhang A., Fan T., Liu Y., Yu G., Li C., Jiang Z. Regulatory T cells in immune checkpoint blockade antitumor therapy. Mol Cancer. 2024;23(1):251. DOI: 10.1186/s12943-024-02156-y

27. Ren Z., Yang K., Zhu L., Yin D., Zhou Y. Regulatory T cells as crucial trigger and potential target for hyperprogressive disease subsequent to PD-1/PD-L1 blockade for cancer treatment. Int Immunopharmacol. 2024;132:111934. DOI: 10.1016/j.intimp.2024.111934

28. Cheng W., Kang K., Zhao A., Wu Y. Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. J Hematol Oncol. 2024;17(1):54. DOI: 10.1186/s13045-024-01581-2

29. Hakim M.S., Jariah R.O.A., Spaan M., Boonstra A. Interleukin 15 upregulates the expression of PD-1 and TIM-3 on CD4+ and CD8+ T cells. Am J Clin Exp Immunol. 2020;9(3):10–21. PMID: 32704430

30. Yang J., Riella L.V., Chock S., Liu T., Zhao X., Yuan X., et al. The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol. 2011;187(3):1113–9. DOI: 10.4049/jimmunol.1100056

31. Wang D., Wang T., Liu J., Yu H., Jiao S., Feng B., et al. Acid-activatable versatile micelleplexes for PD-L1 blockade-enhanced cancer photodynamic immunotherapy. Nano Lett. 2016;16(9):5503–13. DOI: 10.1021/acs.nanolett.6b01994

32. Yi M., Zheng X., Niu M., Zhu S., Ge H., Wu K. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022;21(1):28. DOI: 10.1186/s12943-021-01489-2

33. Demidov L., Kharkevich G., Petenko N., Moiseenko V., Protsenko S., Semiglazova T., et al. A phase III study to access the safety and efficacy of prolgolimab 250 mg fixed dose administered every 3 weeks versus prolgolimab 1 mg/kg every 2 weeks in patients with metastatic melanoma (FLAT). Front Oncol. 2024;14:1385685. DOI: 10.3389/fonc.2024.1385685

34. Tjulandin S.A., Fedyanin M., Demidov L.V., Moiseyenko V., Protsenko S., Odintsova S., et al. Final results of phase II trial (MIRACULUM) of the novel PD-1 inhibitor prolgolimab in patients with advanced melanoma. Ann Oncol. 2019;(30):xi44. DOI: 10.1093/annonc/mdz451.027

35. Tran K.B., Kolekar S., Jabed A., Jaynes P., Shih J.H., Wang Q., et al. Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK. BMC Cancer. 2021;21(1):136. DOI: 10.1186/s12885-021-07826-4

36. Bahreyni A., Mohamud Y., Luo H. Recent advancements in immunotherapy of melanoma using nanotechnology-based strategies. Biomed Pharmacother. 2023;159:114243. DOI: 10.1016/j.biopha.2023.114243

37. Xie R., Wang N., Peng C., Zhang S., Zhong A., Chen J. Current application of immunotherapy in melanoma. Chin Med J (Engl). 2023;136(10):1174–6. DOI: 10.1097/CM9.0000000000002660

38. Liu D., Schilling B., Liu D., Sucker A., Livingstone E., Jerby-Arnon L., et al. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nat Med. 2019;25(12):1916–27. DOI: 10.1038/s41591-019-0654-5

39. Hu H., Wang K., Jia R., Zeng Z.X., Zhu M., Deng Y.L., et al. Current status in rechallenge of immunotherapy. Int J Biol Sci. 2023;19(8):2428–42. DOI: 10.7150/ijbs.82776

40. Sultanbaev A.V., Musin S., Menshikov K., Sultanbaeva N., Menshikova I., Fatikhova A., et al. 99P quantitative indicators of TREC and KREC excision rings in malignant neoplasms. ESMO Open. 2023;8(1, Suppl 2):100957. DOI: 10.1016/j.esmoop.2023.100957

41. Sultanbaev A.V., Musin Sh.I., Menshikov K.V., Sultanbaev N.I., Tuzankina I.A., Kudlay D.A. Strategy for enhancing specific antitumor immunity in patients with melanoma. Effective pharmacotherapy. 2024;20(5):116–21 (In Russ.). DOI: 10.33978/2307-3586-2024-20-5-116-121

42. Kozyra P., Krasowska D., Pitucha M. New potential agents for malignant melanoma treatment-most recent studies 2020–2022. Int J Mol Sci. 2022;23(11):6084. DOI: 10.3390/ijms23116084

43. Schneider B.J., Naidoo J., Santomasso B.D., Lacchetti C., Adkins S., Anadkat M., et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073–126. DOI: 10.1200/JCO.21.01440

44. Santomasso B.D., Nastoupil L.J., Adkins S., Lacchetti C., Schneider B.J., Anadkat M., et al. Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guideline. J Clin Oncol. 2021;39(35):3978–92. DOI: 10.1200/JCO.21.01992

45. Atkins M.B., Hodi F.S., Thompson J.A., McDermott D.F., Hwu W.J., Lawrence D.P., et al. Pembrolizumab plus pegylated interferon alfa-2b or ipilimumab for advanced melanoma or renal cell carcinoma: dose-finding results from the phase Ib KEYNOTE-029 Study. Clin Cancer Res. 2018;24(8):1805–15. DOI: 10.1158/1078-0432.CCR-17-3436

46. Atkins M.B., Lee S.J., Chmielowski B., Tarhini A.A., Cohen G.I., Truong T.G., et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186–97. DOI: 10.1200/JCO.22.01763

47. Ascierto P.A., Stroyakovskiy D., Gogas H., Robert C., Lewis K., Protsenko S., et al. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study. Lancet Oncol. 2023;24(1):33–44. DOI: 10.1016/S1470-2045(22)00687-8


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Sultanbaev A.V. Immune Checkpoint Inhibitors in Melanoma Treatment: Advances and Obstacles. Creative surgery and oncology. 2025;15(1):57-65. (In Russ.) https://doi.org/10.24060/2076-3093-2025-15-1-57-65

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ISSN 2076-3093 (Print)
ISSN 2307-0501 (Online)