PD-1 inhibitors

PD-1 is an inhibitory receptor that plays a role in T-cell activation.

PD‐1 is a cell‐surface receptor expressed on multiple immune cell types, including T cells, B cells, and NK cells, and binds to the ligands PD‐L1 and PD‐L2.

PD-1 is expressed at the activated T-cell surface, PD-1 modulates T-cell effective activities, including proliferation, cytokineproduction, and survival on PD-ligand and (PD-L1) or PD-L2-mediated activation.

PD-1 is a transmembrane receptor present on T cells, which interacts with the PD-1 ligand, PD-L1, present on multiple cell types , including tumor cells and PD-L2.

PD-L1 and PD-L2 signaling disruption by monoclonal antibodies regenerates T-cell mediated antitumor immunity, producing durable anti-cancer effects in a subset of patients.

PD-1 receptor function when a T-cell encounters antigen-presenting cell bearing foreign antigens, which engage the T-cell receptor.

PD-1 receptor is an immune checkpoint inhibitor expressed on active B and T cells, natural killer cells, an some myeloid cells that normally down modulates excessive immune responses.

PD-1 singling inhibits AKT phosphorylation by preventing the CD28-mediated activation of phosphoinoside 3-kinase (PI3K).

Pathway terminates immune response after T cell activation.

In chronic exposure, PD-1 and its ligands, PD-L1 and PD-L2, control immune activity by causing a transient downregulation of T-cell function.

Binding to PD-1 inhibits the activation of T-cell receptor proximal kinases, changing the balance in activation and inhibition of downstream signaling pathways and altering cell cycle progression, gene transcription, metabolism, and epigenetic programs in T cells.

The binding of PD-1 to its ligands PD-L1 and PD-L2 on tumor cells suppresses T cells to a negative feedback loop, leading to evasion of the immune response.

PD-L1 is normally express by macrophage cells and is inducible on activated T cells.

Tumors may acquire the ability to express PD-L1 aberrantly.

PD-1 receptor secondarily signals T-cell activation switching the cell on, involving interaction between the CD28 receptor on the T-cell and a costimulaatory molecule on the surface of the antigen presenting cell.

The second step can involve a coinhibitory signal that inactivates T-cell activity.

PD-1 blocking antibodies undo T-cell inhibition at the effector step of the antitumor immune response, activating or resurrecting exhausted T cells in the tumor microenvironment.

PD-1 has 2 ligands, ligand-1 and ligand-2, which regulate the effector phase of the T-cell response.

When PD-1 is engaged with its ligands, the kinases involved in T-cell activation are exhibited, and the duration of T-cell contact with APCs were targeted cells can be modified.

It is hypothesized that PD-1/PD-L1 check Inhibitors function within the tumor microenvironment.

Infiltrating T cells drive expression of PD -L1 in tumor cells via interferon gamma secretion, which can inhibit infiltrating T cellslls via the PD-L1 receptor.

Chronic exposure to tobacco carcinogens and accumulation of mutations overtime can lead to T-cell exhaustion and trigger T Cells to turn it off and this may be manifested through the upregulation of the programmed death ligand (PD-L1) on tumor cells, which can inhibit T cell function by binding to programmed death 1 (PD-1) on T cells.

By expressing the PD-1 protein on the tumor cell, tumor cells are able to engage the PD-1 receptor to switch of T-cells that enter the tumor environment.

Targeting PD-1 with monoclonal antibodies enable engagement of the anti-tumor immune response by boosting activity of tumor infiltrating T-cells.

PD-1 is highly expressed on T regulatory cells and is induced on immune cells other than T cells, including B cells and natural killer cells limiting their lytic activity.

Programmed cell death (PD-1) is a negative costimulatory receptor expressed mainly on the surface of activated T cells.

Binding of PD-1 tone of its ligands PD-L1 or PD-L2, can inhibit a cytotoxic T-cell response.

Tumors can co-open this pathway and escape T-cell -induced antitumor activity.

Cancer cells of many types have upregulated program cell death ligand-1.

Includes Nivolumab and Pembrolizumab and Atezolizumab, duralumab, and avelumab.

The above drugs can disrupt the engagement PD-1 with its ligands and impede inhibitory signals into cells, with tumor recognition by cytotoxic T cells.

PD-1 assay-Dako 22C3 immunohistocemistry assay for pembrolizumab.

PD-1 assay-Dako 28-8 assay for nivolumab

PD-1 assay-Ventanna SP142 assay for atezolizumab.

Immunohistochemistry testing for PT-L1 is inherently flawed because the PD-L1 present in the tumor environment is dynamic.

The presence of PD-L1 fluctuates according to which tumor is biopsied, when the test is performed, and have how the assay is reproduced.

Biology dictates results for PD-L1 will be wrong some of the time.

Anti-PD-1 and anti-PD-L1 antibodies produce durable responses in approximately 20% of patients with advanced non-small cell lung cancer.

PD-L1 expression is not been validated as a biomarker in tumor tissue.

Effective in metastatic bladder cancer.

Five-year survival for metastatic melanoma is approximately 35%.

Overall incidence of pneumonitis for monotherapy is 2.7%.for all grades and 0.8% for grade 3 or higher.

Patients with non-small cell lung cancer have a 43% higher risk of developing all-grade pneumonitis than patients with melanoma.

The incidence of pneumonitis is higher in patients with non-small cell lung cancer and renal cell cancer than in patients with melanoma.

Patients with renal cell cancer have a 59% higher chance of all-grade pneumonitis than those with melanoma.

Patients on combination therapy have higher incidence of developing pneumonitis than patients on monotherapy.

In a meta-analysis of 20 studies involving 4496 patients the overall incidence of pneumonitis was 2.7% for monotherapy and 6.6% for combination therapy.

3-6% of lung cancer patients have treatment discontinued due to treatment immune related adverse events.

Neurologic toxicities occur in less than 5% of cases and can range from neuropathies to aseptic meningitis, myasthenia gravis, and Guillain-Barre syndrome.

After adequate treatment of immune related adverse events, resumption of immunotherapy can be undertaken if the patient returns to baseline conditions in the absence of other immunosuppressive drugs, other than low-dose prednisone.

Patients with PD-L1 positive NSCLC demonstrated a 45.5% objective response rate to pembrolizumab compared to 29.8% with chemotherapy in the phase III KEYNOTE-24 trial.

Patients with MSI-H phenotype or a dMMR immunohistochemistry colorectal cancer seem to derive the most benefit from PD-1/PD-L1 inhibitors.

Mismatch repair deficient, locally advanced rectal cancer is highly sensitive to single agent PD-1 blockade (Cercek A).

Tocilizumab may be beneficial in patients adverse events refractory to steroids.

PD-1 inhibitor responses in melanoma are related to gut microbiome, with response rate much higher in patients with a diversity of of bacteria in their gut and a different composition of gut bacteria with more Faecalibacterium, Ruminococcacaceae and Clostridiales.

Patients with melanoma treated with PD-1 inhibitors and who failed to respond to therapy had a higher level of Bacteroides.

Contraindicated in patients with allograft and concomitant cancer as it greatly increases the risk of graft rejection.

A meta-analysis of 19 randomized clinical trials involving 11,379 patients, anti-PD1 exhibits significantly greater overall survival compared with anti-PD-L 1 with a comparable  safety profile in patients with solid tumors (Duan J).

Leave a Reply

Your email address will not be published. Required fields are marked *