[1] The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.
[15] At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.
[15] Initial clinical trial results with IgG4 PD-1 antibody nivolumab (under the brand name Opdivo and developed by Bristol-Myers Squibb) were published in 2010.
[21] LAG-3 Inhibitors In 2022, the FDA approved a combination of relatlimab and nivolumab (Opdivo) to be marketed under the name Opdualag for people aged 12 or older with previously untreated melanoma that cannot be removed surgically or has spread (metastasized) within the body.
More recently, CISH (cytokine-inducible SH2-containing protein), another molecule with ubiquitin ligase activity, was found to be induced by T cell receptor ligation (TCR) and negatively regulate it by targeting the critical signaling intermediate PLC-gamma-1 for degradation.
Thus, Cish represents a new class of T-cell intrinsic immunologic checkpoints with the potential to radically enhance adoptive immunotherapies for cancer.
[30] This holds promise for combining check point inhibitor therapy with immunosuppressive drugs to achieve anti-cancer effects with less toxicity.
Studies are beginning to show that intrinsic factors, such as species of the genus Bacteroides that inhabit the gut microbiome [31] prospectively modify risk of developing immune related adverse events.
Further evidence of this can be found in patients that saw reversal of immune toxicity following fecal microbiome transplant from healthy donors.