checkpoint blockade

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checkpoint blockade 

ONCOLOGY

An evolving therapeutic strategy in which antitumour immunity is activated by preventing cells from passing through immune checkpoints*.

*Which may require excitatory costimulatory signals or avoidance of negative or coinhibitory signals that act to dampen or end immune activity (tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, especially against T cells specific for tumour antigens). 

checkpoint blockade image from New Medical Terms

checkpoint blockade: schematic of immune checkpoint interactions on T cells and effect of monoclonal antibody inhibition.

The accompanying image is from http://www.discoverymedicine.com/James-L-Godwin/2014/12/immune-checkpoint-blockade-as-a-novel-immunotherapeutic-strategy-for-renal-cell-carcinoma-a-review-on-clinical-trials/

a) CTLA-4 pathway inhibition: The TCR on an inactivated or activated T cellinteracts with a presented antigen to start the process of immune activation and proliferation towards antigen in question. CD28 co-stimulation is required to complete activation, but CTLA-4 mediated inhibitory signals after binding with its ligands CD80 or CD86 dampens the immune response to prevent over-activation. Inhibition of CTLA-4 by a targeted monoclonal antibody precludes inhibition allowing for unregulated T cell activation.

b) PD-1/PD-L1 pathway inhibition: Similar to above, the TCR of an activated T cell binds an antigen expressed on a tumor cell to initiate the T cell selection process. PD-1 has an analogous inhibitory role, primarily through its interaction with PD-L1 on the tumor cell. By blocking this interaction, with either monoclonal antibodies to PD-1 or PD-L1, the inhibitory stimulus is again down-regulated, resulting in a more robust targeted anti-tumor immune response. Note: APC, antigen presenting cell; MHC, major histocompatibility complex; Ag, antigen; CTLA-4, cytotoxic leukocyte antigen 4; TCR, T-cell receptor; PD, programmed cell death.

Synonym Checkpoint pathway blockade 

References Nat Rev Cancer. 2012 Mar 22;12(4):252-64.

doi: 10.1038/nrc3239

Adv Immunol. 2006;90:297-339 

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