Therapeutic importance, general and endocrine adverse effects of immune checkpoint inhibitors I: mechanism of action and therapeutic use

Abstract

The tumor microenvironment has a fundamental role in the escape phenomenon of cancerous cells from the immune surveillance, the immunological protective mechanisms of the host. These cells produce active substances that can bind to and stimulate the inhibitory immune checkpoints (CTLA-4, PD1 etc.) expressed on the cytotoxic T-lymphocytes and other immunocompetenT-cells, thus inhibiting the immune defense. The immune checkpoint inhibitors (ICIs), introduced in therapeutic use in 2011, are human or humanized monoclonal antibodies (mAbs) that block the immune checkpoints, and thus release the inhibition, restoring the antitumoral immune defense. After the description of their mechanism of action, the clinical applications of anti-CTLA-4 mAbs ipilimumab and tremelimumab, anti-PD1-antibodies nivolumab and pembrolizumab, and the anti-PD-L1-antibodies are presented. The ICIs are used mainly in inoperable and advanced tumors, but this fact is not a rigorous rule, and their therapeutic indications have been and will continue to expand. The next section summarizes new research directions that are also needed, because primary and adaptive resistance to ICIs exists, the latter developing during therapy. In an unselected population, ICIs are therapeutically efficient only in about 20-30% of patients, but these will be long-term survivors. Not rarely the therapeutic effect is preceded by a transient pseudoprogression. Tumors with high mutation burden (melanoma, lung, and bladder cancers) respond much better to ICI therapy, because they produce more neoantigens; this is the case in the “hot” tumors, too, because in these tumor-infiltrating immune cells are markedly present. Their application would require reliable predictive biomarkers, but there are few of them so far, e.g., investigation of PD-L1 expression, and diagnostic tests associated to ICIs. This first part of the review ends with problems regarding therapy resistance and their possible solutions.