Immune checkpoint proteins: Introduction

Immune checkpoint blockade in oncology:
Many types of cancer cells evolve mechanisms to evade control and elimination by the immune system. Such mechanisms can include inhibition of so-called 'immune checkpoints', which would normally be involved in the maintenance of immune homeostasis. An increasingly important area of clinical oncology research is the development of new agents which impede these evasion techniques, thereby switching immune vigilance back on, and effecting immune destruction of cancer cells. Checkpoint proteins include co-inhibitory and co-stimulatory receptors on immune effectors cells. Three co-inhibitory checkpoint receptors which are being extensively pursued are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Using antibody-based therapies targeting these pathways, clinical responses have been reported in various tumour types, including melanoma, renal cell carcinoma [8] and non-small cell lung cancer [5,7].

Despite the clinical success of checkpoint inhibitors, only a small number of cancer patients exhibit durable responses. Understanding the resistance mechanisms at play will inform future developments, by identifying new strategies, such as combination therapies, that may improve clinical outcomes for increased numbers of patients [6].

Pembrolizumab was the first-in-class, anti-PD-1 antibody to be approved by the US FDA, followed in quick succession by nivolumab. Although immune checkpoint pathway inhibitors have revolutionized cancer treatment for some patients, the majority of patients show incomplete responses and/or develop resistance, and managing adverse events can be challenging. To combat such shortcomings other approaches are being investigated. One example is the development of synthetic small-molecule PD-1 inhibitors [4] such as Curis' CA-170, an orally active PD-1/VISTA antagonist that is in Phase 1 clinical trial (NCT02812875) in patients with advanced solid tumours and lymphomas. Another approach is identifying and targeting additional immunomodulatory mechanisms that activate anti-tumour immune responses [2], including targeting co-stimulatory receptors such as GITR, ICOS and OX40 [3]. Additionally, combining inhibitors of different checkpoints, or combining checkpoint inhibitors with other anti-cancer therapeutics such as kinase inhibitors, so targeting multiple disease relevant pathways simultaneously is proving efficacious. Indeed there are hundreds of clinical trials in progress that are evaluating the efficacy of such combination drug regimens. Combining these new immunotherapeutics provides potential approaches for the provision of precision medicine that could transform cancer treatment [10].

Immune checkpoint blockade in Alzheimer's disease (AD): In mouse models of AD anti-PD-1 antibody treatment was used to induce immune checkpoint blockade. The biological response included an interferon (IFN)-γ-dependent systemic immune response and recruitment of monocyte-derived macrophages to the brain, which was associated with amyloid β plaque clearance and improved cognitive function. These results point to immune checkpoints as valid targets for therapeutic intervention in AD [1].

Other clinical settings amenable to immune checkpoint blockade: Checkpoint blockade also represents a viable mechanism for the development of novel treatments for immune disease (e.g asthma and autoimmune conditions, and transplantation) prevention and control, and for infectious diseases [9,11].


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3. Cabo M, Offringa R, Zitvogel L, Kroemer G, Muntasell A, Galluzzi L. (2017) Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications. Oncoimmunology, 6 (12): e1371896. [PMID:29209572]

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5. Johnson DB, Rioth MJ, Horn L. (2014) Immune checkpoint inhibitors in NSCLC. Curr Treat Options Oncol, 15 (4): 658-69. [PMID:25096781]

6. Li X, Shao C, Shi Y, Han W. (2018) Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. J Hematol Oncol, 11 (1): 31. [PMID:29482595]

7. Malas S, Harrasser M, Lacy KE, Karagiannis SN. (2014) Antibody therapies for melanoma: New and emerging opportunities to activate immunity (Review). Oncol Rep, 32 (3): 875-86. [PMID:24969320]

8. Pal SK, Hu A, Chang M, Figlin RA. (2014) Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions. Clin Adv Hematol Oncol, 12 (2): 90-9. [PMID:24892254]

9. Roussey JA, Viglianti SP, Teitz-Tennenbaum S, Olszewski MA, Osterholzer JJ. (2017) Anti-PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice. J Immunol, 199 (10): 3535-3546. [PMID:29038249]

10. Wilson RAM, Evans TRJ, Fraser AR, Nibbs RJB. (2018) Immune checkpoint inhibitors: new strategies to checkmate cancer. Clin Exp Immunol, 191 (2): 133-148. [PMID:29139554]

11. Wykes MN, Lewin SR. (2018) Immune checkpoint blockade in infectious diseases. Nat Rev Immunol, 18 (2): 91-104. [PMID:28990586]

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Immune checkpoint proteins, introduction. Last modified on 07/03/2018. Accessed on 14/06/2024. IUPHAR/BPS Guide to PHARMACOLOGY,