Checkpoint inhibitor

Cell surface checkpoint inhibitors CTLA-4 inhibitors The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma. It blocks the immune checkpoint molecule CTLA-4. Clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs. However, patients treated with check-point blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of suffering from immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions. These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the blood stream. Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood. 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. • Pembrolizumab (brand name Keytruda) is another PD-1 inhibitor that was approved by the FDA in 2014 and was the second checkpoint inhibitor approved in the United States. Keytruda is approved to treat melanoma and lung cancer and is produced by Merck. PD-L1 inhibitors In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer. 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. Relatlimab blocks a protein on immune cells called LAG-3. Intracellular checkpoint inhibitors Other modes of enhancing [adoptive] immunotherapy include targeting so-called intrinsic checkpoint blockades. Many of these intrinsic regulators include molecules with ubiquitin ligase activity, including CBLB, and CISH. CISH 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. The deletion of CISH in effector T cells has been shown to dramatically augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. Surprisingly there was no changes in activity of Cish's purported target, STAT5. CISH knock out in T cells increased PD-1 expression and the adoptive transfer of CISH knock out T cells synergistically combined with PD-1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. Thus, Cish represents a new class of T-cell intrinsic immunologic checkpoints with the potential to radically enhance adoptive immunotherapies for cancer. == Adverse effects ==

Immune-related adverse events may be caused by checkpoint inhibitors. Altering checkpoint inhibition can have diverse effects on most organ systems of the body. Colitis (inflammation of the colon) occurs commonly. The precise mechanism is unknown, but differs in some respects based on the molecule targeted. Thyroiditis with resulting hypothyroidism is a common Immune-related adverse event especially with use of combinations of different ICIs. The underlying mechanism of ICI induced thyroiditis may differ from other forms of thyroiditis. Hypophysitis seems to be more specific to CTLA-4 inhibitors. A lower incidence of hypothyroidism was observed in a trial of combined B cell depletion and immune checkpoint inhibitor treatment compared with studies of immune checkpoint inhibitor monotherapy. 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 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. Severe immune-related adverse events do not spontaneously subside and (with some exceptions) require immunosuppressive treatment. High-dose corticosteroids are usually used in first-line therapy, while selective immunosuppression may be required in steroid-resistant toxicities. Biomarkers for prediction of steroid resistance are topic of research. Enhanced type 1/type 17 immune responses may be associated with immune-related adverse events that do not respond to corticosteroids. == See also ==