Immune checkpoint proteins like PD-1/PD-L1 and CTLA-4 represent significant scientific discoveries in the immunotherapy of solid tumors. Humanized monoclonal antibodies, known as PD-L1 inhibitors, suppress the binding of PD-L1, a human transmembrane protein referred to as a checkpoint protein. PD-L1 is involved in the signaling of programmed cell death through the receptor PD-1, a cell surface receptor that plays a crucial role in immune system suppression and promotes tolerance to host cells. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the protein "programmed cell death 1" (PD-1). Humanized monoclonal antibodies targeting these immunological checkpoint proteins have shown success in patients with non-small cell lung cancer (NSCLC), renal cell carcinoma, metastatic melanoma, and head and neck carcinoma. The FDA has approved three categories of immune checkpoint inhibitors: PD-1 inhibitors (Pembrolizumab, Nivolumab, and Cemiplimab), PD-L1 inhibitors (Durvalumab, Atezolizumab, and Avelumab), and CTLA-4 inhibitors (Ipilimumab). Not all patients responded positively, which highlights the role of biomarkers such as PDL-1 expression in predicting the response to immunotherapy with checkpoint inhibitors. This literature review aims to present the latest developments in the field of immunotherapy for the treatment of solid tumors.
Smith, S.M.; Wachter, K.; Burris, H.A. et al . Clinical cancer advances 2021: ASCO’s Report on progress against cancer. J. Clin. Oncol. 2021;39,:1165–1184. doi: 10.1200/JCO.20.03420
Barbari, C.; Fontaine, T.; Parajuli, P. et al. Immunotherapies and Combination Strategies for Immuno-Oncology. Int. J. Mol. Sci. 2020;21(14):5009. doi: 10.3390/ijms21145009
Калев, Д. Имунологична панорама на недребноклетъчния белодробен карцином – между „изплъзването” и „прицелването”. Inspiro. 2017;2:40-50.
Gong J.; Chehrazi-Raffle, A.; Reddi, S.; Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J. ImmunoTherapy of cancer. 2018;6(1):8. doi: 10.1186/s40425-018-0316-z.
Brunet, J.-F.; Denizot, F.; Luciani, M.-F. et al. A new member of the immunoglobulin superfamily—CTLA-4. Nature, 1987,328:267–270. doi: 10.1038/328267a0
Rudd, C.E.; Taylor, A.; Schneider, H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol. Rev. 2009;229(1):12-26. doi: 10.1111/j.1600-065X.2009.00770.x
Shiravand, Y.; Khodadadi, F.; Amin Kashani, S.F. et al. Immune Checkpoint Inhibitors in cancer Therapy. Current Oncology, 2022;29(5):3044- 3060. Doi: 10.3390/curroncol29050247
Rizvi, N.A.; Mazières, J.; Planchard, D. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–265. doi: 10.1016/S1470-2045(15)70054-9
Kazandjian, D.; Suzman, D.L.; Blumenthal, G. et al. FDA Approval Sum- mary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy. Oncologist. 2016;21(5):634–642. doi: 10.1634/theoncologist.2015-0507
Postow, M.A.; Chesney, J.; Pavlick, A.C. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17. doi: 10.1056/NEJMoa1414428
Larkin, J.; Chiarion-Sileni, V.;, Gonzalez, R. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34. doi: 10.1056/NEJMoa1504030
De Felice, F.; Giudice, E.; Bolomini, G. et al. Pembrolizumab for advanced cervical cancer: Safety and efficacy. Expert Rev. Anticancer. Ther. 2021, 21, 221–228. doi: 10.1080/14737140.2021.1850279
Le, D.T.; Durham, J.N.; Smith, K.N. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357(6349):409-413. doi: 10.1126/science.aan6733
https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761223Orig1s000ltr.pdf (Accessed on August 19, 2023)
Andre, T.; Berton, D.; Curigliano, G. et al. Safety and efficacy of anti-PD-1 antibody dostarlimab in patients with mismatch repair-deficient (dMMR) solid cancers: results from the Garnet study (abstract). J Clin Oncol 39, 2021 (suppl 3; abstr 9). Abstract available online at https://meetinglibrary.asco.org/record/194077/abstract (Accessed on August 19, 2023)
Fehrenbacher, L.; Spira, A.; Ballinger, M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-46. doi: 10.1016/S0140-6736(16)00587-0
Rittmeyer, A.; Barlesi, F.; Waterkamp, D. et al. Atezolizumab versus docetaxel in patients with previously treated non- small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255-65. doi: 10.1016/S0140-6736(16)32517-X
Schmid, P.; Adams, S.; Rugo, H.S. et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 2018;379:2108-2121. doi: 10.1056/NEJMoa1809615
Hugo, W.; Zaretsky, J.M.; Sun, L. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165(1):35-44. doi: 10.1016/j.cell.2016.02.065
Zaretsky, J.M.; Garcia-Diaz, A.; Shin, D.S. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819-29. doi: 10.1056/NEJMoa1604958
Champiat, S.; Dercle, L.; Ammari, S. et al Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920–8. doi: 10.1158/1078-0432.CCR-16-1741
Collins, J.M.; Gulley, J.L. Product review: Avelumab, an anti-PD-L1 antibody. Hum. Vaccines Immunother. 2019;15(4):891–908. doi: 10.1080/21645515.2018.1551671
Chambers, C.A.; Sullivan, T.J.; Allison, J.P. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 1997;7(6):885-95. doi: 10.1016/s1074-7613(00)80406-9
Tivol, E.A.; Borriello, F.; Schweitzer, A.N. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541-7. doi: 10.1016/1074-7613(95)90125-6.
Walker, L.S.; Sansom, D.M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 2011;11(12):852-63. doi: 10.1038/nri3108
Callahan, M.K.; Wolchok, J.D. At the bedside: CTLA-4-and PD-1-blocking antibodies in cancer immunotherapy. J. Leukoc. Biol. 2013;94(1):41-53. doi: 10.1189/jlb.1212631
Lebbé, C.; Meyer, N.; Mortier, L. et al. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol 2019;37(11):867-875. doi: 10.1200/JCO.18.01998
Lebbé, C.; Meyer, N.; Mortier, L. et al. Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: Three-year results of CheckMate 511. J Clin Oncol 2021; 39;15S
Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R. et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2019;381:1535-46. doi: 10.1056/NEJMoa1910836
Escudier, B.; Motzer, R.J.; Tannir, N.M. et al. Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214. Eur. Urol. 2020;77(4):449-53. doi: 10.1016/j.eururo.2019.10.025
Regan, M.M.; Jegede, O.A.; Mantia, C.M. et al. Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial. Clin. Cancer Res. 2021;27(24):6687-95. doi: 10.1158/1078-0432.CCR-21-2283
Hellmann, M.D.; Paz-Ares, L.; Bernabe Caro, R. et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2019;381(21):2020-31. doi: 10.1056/NEJMoa1910231
Udall, M.; Rizzo, M.; Kenny, J. et al. PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics. Diagn. Pathol. 2018;13(1):12. doi: 10.1186/s13000-018-0689-9
de Ruiter, E.J.; Mulder, F.J.; Koomen, B.M. et al. Comparison of three PD-L1 immunohistochemical assays in head and neck squamous cell carcinoma (HNSCC). Mod Pathol 2021;34(6):1125-32. doi: 10.1038/s41379-020-0644-7
Email this article (Login required) 
