Abstract
Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has led to the modern era of immunotherapy in cancer treatment. Agents that release these immune brakes have shown activity to recover dysfunctional T cells and regress various cancer. Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death-1 (PD-1) play their role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family; it mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. Ipilimumab is the first and only FDA-approved CTLA-4 inhibitor; PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). Programmed Death-Ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy. PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are in the current list of the approved agents in addition to ipilimumab. In this review paper, we discuss the role of each immune checkpoint inhibitor (ICI), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their daily practice.
Highlights
Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US
We discuss the mechanism of check-point inhibitors (Figure 1), the role of each drug in various solid tumors (Figure 2), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their clinical practice
In renal cell carcinoma (RCC) with clear cell histology, the FDA approved the use of ipilimumab with nivolumab for previously untreated advanced renal cell cancer (RCC), with intermediate- or poor-risk RCC, regardless of Programmed Death-Ligand 1 (PD-L1) status based on CheckMate-214, an open-label, randomized (1:1) study [32,33]
Summary
In some nations, cancer has overtaken heart disease as the leading cause of mortality. T-cell signals, which generally prevent aberrant or chronic activation of the immune mechanism, may have been opted by the cancerous cell to dampen immunity. In some solid tumors (e.g., metastatic melanoma and non-small-cell lung cancer), immunotherapy is the first line of treatment. We discuss the mechanism of check-point inhibitors (Figure 1), the role of each drug in various solid tumors (Figure 2), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their clinical practice
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