Checkpoint blockade therapy using programmed death-1 (PD-1) with its ligands (PD-L1/2)

Harnessing the immune system to fight cancer is an exciting advancement in lung cancer therapy

• antitumour immunity can be augmented by checkpoint blockade therapy, which removes the inhibition/brakes imposed on the immune system by the tumour
  • checkpoint blockade therapy with anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death ligand 1 (anti-PDL-1) antibodies causes tumour regression in about 25% of patients with lung cancer (1,2,3)
    
    
  • PD-1 is expressed on the surface of activated macrophages, T-lymphocytes, B lymphocytes, NK cells, and on some myeloid cells, where it inhibits the survival, proliferation and function through its interaction with PD-L1 and L2
    
  • evidence suggests that the tumor microenvironment can lead to up-regulation of PD-1 on tumor-reactive T cells and contribute to impaired antitumor immune responses (4)
    
    
    • the interaction of PD-1 with its ligands attenuates immune responses and protects tumour cells from cytotoxic T-cell attack, leading to immune system evasion
    • immune checkpoint inhibitors are antibodies that target co-inhibitory molecules, such as PD-1/PD-L1, to improve anti-tumour immune responses
  • checkpoint blockade immunotherapies are so named because they remove the blockade imposed by molecules such as programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PDL-1) on checkpoints required for T-cell activity
    • binding of programmed death-1 (PD-1) with its ligands (PD-L1/2) transmits a co-inhibitory signal in activated T-cells that promotes T-cell exhaustion, leading to tumor immune evasion
    • transformed cells can evade immune system elimination by decreasing the expression of antigen presentation molecules and co-stimulatory molecules or, by increasing the expression of co-inhibitory molecules such as programmed cell death protein 1 (PD-1)
      
      
  • nivolumab is the first-in-human immunoglobulin G4 (IgG4) PD-1 immune checkpoint inhibitor antibody that disrupts the interaction of the PD-1 receptor with its ligands PD-L1 and PD-L2 (5)
    • the anti-PD-1 antibody nivolumab was approved by the US Food and Drug Administration (FDA) for the treatment of melanoma in 2014 and renal cell carcinoma in 2015

Pulmonary tuberculosis and immune checkpoint inhibitors (6)

• study of FDA adverse event reporting system found 74 cases pulmonary tuberculosis associated with immune checkpoint inhibitors (ICIs)
  • authors recommend identifying risk factors associated with ICIs-related pulmonary tuberculosis in order to improve safety

Immune checkpoint inhibitors and cardiotoxicity (7)

• study evidence noted ~1% of patients experienced immune checkpoint inhibitor–induced cardiotoxicity, with myocarditis having a mortality rate of 38%
  

Reference:

1. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013; 342: 1432–1433
2. Topalian, S.L., Hodi, F.S., Brahmer, J.R. et al. Safety, activity, and immune correlates of anti-antibody in cancer. N Engl J Med. 2012; 366: 2443–2454
3. Karachaliou N, Cao MG, Teixido C, Viteri S, Morales-Espinosa D, Santarpia M, Rosell R. Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints. Cancer Biol Med. 2015;12:79-86
4. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537-4
5. Guo L, Zhang H, Chen B. Nivolumab as Programmed Death-1 (PD-1) Inhibitor for Targeted Immunotherapy in Tumor. J Cancer. 2017 Feb 10;8(3):410-416.
6. Zhu J, He Z, Liang D, et al. Pulmonary tuberculosis associated with immune checkpoint inhibitors: a pharmacovigilance study. Thorax Published Online First: 11 March 2022. doi: 10.1136/thoraxjnl-2021-217575
7. Nielsen DL, Juhl CB, Nielsen OH, Chen IM, Herrmann J. Immune Checkpoint Inhibitor–Induced Cardiotoxicity: A Systematic Review and Meta-Analysis. JAMA Oncol. Published online August 22, 2024.