ABSTRACT
Antigen-specific T cells encountering and responding to tumor cells are regulated by a variety of mechanisms including inhibitory receptors and regulatory T cells to prevent overexposure immune responses. These regulatory mechanisms, so called ‘‘immune checkpoints’’, suppress T cell response. Thus, it prevents tissue damage and the development of autoimmunity by preventing an excessive immune response. Immune checkpoint inhibitors are increasingly used in clinical practice and have become part of the standard treatment approach for the treatment of various tumor types. These agents are antibody-based treatments targeting cytotoxic T-lymphocyte antigen-4, programmed cell death-1 and programmed cell death ligand-1. They have been used in the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, and some other tumor types. The incidence of toxicities has expanded with increasing clinical use. The side effects resulting from the immunological effects of these treatments are called ‘‘immune-related adverse events’’ and affect many organs in a wide spectrum, unlike conventional chemotherapy side effects. In order to understand the mechanisms of action and side effects of these therapies, which are more frequently encountered in clinical practice, it is necessary to understand immune checkpoints and inhibitors. In this review, receptors that function as immunological checkpoints, as well as the drugs targeting them, are described.
Keywords:
PD-1, PD-L1, CTLA-4, Cancer, Immunotherapy
References
1Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991;3-11.
2Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.
3Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med. 2016;375:1767-1778.
4Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682-687.
5Waterhouse P1, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985-988.
6Lo B, Zhang K, Lu W, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349:436-440.
7Qureshi OS, Zheng Y, Nakamura K, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332:600-603.
8Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271-275.
9Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies. J Exp Med. 2009;206:1717-1725.
10Garris CS, Arlauckas SP, Kohler RH, et al., Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity. 2018;49:1148-1161.e7.
11Patsoukis N, Bardhan K, Chatterjee P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692.
12Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793-800.
13Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-2028.
14Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-319.
15Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376:1015-1026.
16Emens LA, Ascierto PA, Darcy PK, et al. Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017;81:116-129.
17Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39.
18Markham A, Duggan S. Cemiplimab: first global approval. Drugs. 2018;78:1841-1846.
19Cortese I, Muranski P, Enose-Akahata Y, et al. Pembrolizumab Treatment for Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2019;380:1597-1605.
20Walter O, Treiner E, Bonneville F, et al., Treatment of Progressive Multifocal Leukoencephalopathy with Nivolumab. N Engl J Med. 2019;380:1674-1676.
21Touat M, Talmasov D, Ricard D, et al. Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol. 2017;30:659-668.
22Psimaras D, Velasco R, Birzu C, et al. Immune checkpoint inhibitors‐induced neuromuscular toxicity: from pathogenesis to treatment. J Peripher Nerv Syst. 2019.
23Cardiovascular toxicity of immune checkpoint inhibitors in cancer patients: A review when cardiology meets immuno-oncology.J Formos Med Assoc. 2019.
24Cappelli LC, Gutierrez AK, Bingham CO 3rd, et al. Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature. A Arthritis Care Res (Hoboken). 2017;69:1751-1763.
25Ladak K, Bass AR. Checkpoint inhibitor-associated autoimmunity. Best Pract Res Clin Rheumatol. 2018;32:781-802.
26Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158-168.
27Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.
28Salem JE, Allenbach Y, Vozy A, et al. Abatacept for Severe Immune Checkpoint Inhibitor–Associated Myocarditis. N Engl J Med. 2019;380:2377-2379.