Commentary: Small Molecule Inhibition of PD-1 Transcription is an Effective Alternative to Antibody Blockade in Cancer T

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Commentary: Small Molecule Inhibition of PD-1 Transcription is an Effective Alternative to Antibody Blockade in Cancer Therapy

“The past few years has witnessed exciting progress in the application of “immune check-point inhibitors” (ICI) in the treatment of various human cancers1–3. This involves the use of antibody blockade with monoclonal antibodies (mAbs) that block receptor binding to their natural ligands. Programmed cell death-1 (PD-1) recognises PD ligand (PDL)-1 and PDL-2 on presenting cells and this sends signals that inhibit T-cell activation and effector cytotoxic responses. Through these mechanisms, PD-1 inhibits the immune system and can prevent autoimmune diseases 4. Tumor cells expressing PDL-1/PD-L2 can use this mechanism to evade immune surveillance, allowing disease progression. A therapeutic approach involves administration of mAbs that block the engagement of checkpoint molecules with their ligand. In the case of anti-PD-1, these mAbs block the binding of PD-1 on the T-cell with PDL-1/PDL-2 on the tumor cell, preventing recognition and allowing activation of the T-cell to provide an immune response against the tumor cell. Blockade also reverses T-cell exhaustion and restores T-cell functionality 5, 6. Furthermore, PD-1 expression on tumor-infiltrating CD8+ T-cells correlates with impaired function, while PD-L1 expression on tumors facilitates escape4.

One of the first established immunotherapeutic approaches involved the use of Ipilimumab against CTLA-47, 8. It was the prototypical immunomodulatory antibody first approved by the FDA in 2011 for advanced melanoma based on its survival benefit. This was followed by the highly successful blockade of PD-1 (i.e. Nivolumab and Pembrolizumab), or its ligand (PD-L1) (i.e. Atezolizumab), either alone7, or in combination with anti-CTLA-48. In certain cases, the use of PD-1 mAbs superseded CTLA-4 mAbs, due to their increased response rates9, 10 and the combination of both therapies gave rise to even superior response rates10, 11. However, this success correlated with increased toxic side effects. A substantial proportion of patients receiving ICI develop immune-related adverse events (irAEs) including colitis, endocrinopathies, hepatitis, pneumonitis, cardiotoxicity, nephritis, skin eruptions and vitiligo12–20. These events have been reported at 20-28%, 17-21% and 45-59% for the use of anti-CTLA-4, anti-PD1 or combination therapy, respectively9–11. These drugs are currently being used in the treatment of various cancers including Melanoma, renal cell carcinoma, colorectal cancer and Hodgkin lymphoma21–24 as well as the viral infection HCV25. Immune-modulating agents, such as corticosteroid, infliximab, and mycophenolic acid are being used to manage irAEs26 where possible but in some cases, treatment is discontinued.

Although some success has been seen, the majority of patients are still not cured, some develop resistance and those with immune-resistant cancers such as colon and ovarian are poorly responsive. This poor prognosis highlights a need to improve current or identify alternative clinical interventions”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525092/