Dataset Information

Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence.

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.

SUBMITTER: Vaddepally RK

PROVIDER: S-EPMC7140028 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence.

Vaddepally Raju K RK Kharel Prakash P Pandey Ramesh R Garje Rohan R Chandra Abhinav B AB

Cancers 20200320 3

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 cy ...[more]

PMID: 32245016

Similar Datasets

Project description:BackgroundImmune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients.MethodsirAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software.ResultsirAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. 'Respiratory, thoracic and mediastinal disorders' and 'gastrointestinal disorders' were the two most common groups of disorders caused by the seven ICIs studied. 'Cardiac disorders' was the main type of disorders caused by these ICIs in cancer patients aged 65-85, while 'reproductive system and breast disease' was the main type of disorder in cancer patients aged 18-64. 'Respiratory, thoracic, mediastinal diseases' and 'reproductive system and breast diseases' were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively.ConclusionTissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies.

Project description:Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high-throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca2+ channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses.IMPORTANCE No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant.

Dataset Information

Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence.

Publications

Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets