Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibody-drug conjugates (ADCs) are complex immunoconjugates designed to selectively deliver toxic small molecules preferentially to cancer cells. These immunoconjugates consist of a monoclonal antibody - directed to a tumor antigen - and a cytotoxic agent that is conjugated to the antibody via a molecular linker. Following the binding to a specific antigen on the surface of cancer cells, the conjugate is internalized and releases its cytotoxic payload to kill the malignant cell. ADCs that have gained regulatory approval from the US Food and Drug Administration (FDA) include brentuximab vedotin for CD30-positive Hodgkin's lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several other agents are in advanced stages of clinical development, including sacituzumab govitecan for breast cancer, mirvetuximab soravtansine for ovarian cancer, rovalpituzumab tesirine for lung cancer, depatuxizumab mafodotin for glioblastoma, and oportuzumab monatox for bladder cancer. This review provides an overview of the recent clinical experience with the approved, most advanced, and other promising candidates of ADCs for solid tumors, including a description of biology and chemistry of ADCs, drug resistance and biomarkers, and the future perspective on combination strategies with these new immunoconjugates.
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PMID:Antibody-Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments. 2911 96

Over the last two decades, molecular-targeted agents have become mainstream treatment for many types of malignancies and have improved the overall survival of patients. However, most patients eventually develop resistance to these targeted therapies. Recently, immunotherapies such as immune checkpoint inhibitors have revolutionized the treatment paradigm for many types of malignancies. Immune checkpoint inhibitors have been approved for treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, bladder cancer and gastric cancer. However, oncologists have been faced with immune-related adverse events caused by immune checkpoint inhibitors; these are generally mild but can be fatal in some cases. Because immune checkpoint inhibitors have distinct toxicity profiles from those of chemotherapy or targeted therapy, many oncologists are not familiar with the principles for optimal management of immune-related adverse events, which require early recognition and appropriate treatment without delay. To achieve this, oncologists must educate patients and health-care workers, develop checklists of appropriate tests for immune-related adverse events and collaborate closely with organ specialists. Clinical questions that remain include whether immune checkpoint inhibitors should be administered to patients with autoimmune disease and whether patients for whom immune-related adverse events lead to delays in immunotherapy should be retreated. In addition, the predicted use of combination immunotherapies in the near future means that oncologists will face a higher incidence and severity of immune-related adverse events. This review provides an overview of the optimal management of immune-related adverse events attributed to immune checkpoint inhibitors.
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PMID:Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update. 2951 16

Renal transplantation is associated with an increased risk of cancers at multiple sites; however, the relationships between increased cancer risk and participant characteristics remain unclear. We searched PubMed, Embase, and the Cochrane Library to identify prospective observational studies performed up to July 2017. Totally 11 prospective studies reported data on 79,988 renal transplant recipients were included. Renal transplant recipients were found to display a higher risk of all cancers (standard incidence ratio [SIR]: 2.89; 95% CI: 2.13-3.91; P < 0.001), gastric cancer (SIR: 1.93; 95% CI: 1.60-2.34; P < 0.001), colon cancer (SIR: 1.85; 95% CI: 1.53-2.23; P < 0.001), pancreatic cancer (SIR: 1.53; 95% CI: 1.23-1.91; P < 0.001), hepatocellular carcinoma (SIR: 2.45; 95% CI: 1.63-3.66; P < 0.001), lung cancer (SIR: 1.68; 95% CI: 1.29-2.19; P < 0.001), thyroid cancer (SIR: 5.04; 95% CI: 3.79-6.71; P < 0.001), urinary bladder cancer (SIR: 3.52; 95% CI: 1.48-8.37; P = 0.004), renal cell cancer (SIR: 10.77; 95% CI: 6.40-18.12; P < 0.001), non-melanoma skin cancer (SIR: 12.14; 95% CI: 6.37-23.13; P < 0.001), melanoma (SIR: 2.48; 95% CI: 1.08-5.67; P = 0.032), Hodgkin's lymphoma (SIR: 4.90; 95% CI: 3.09-7.78; P < 0.001), non-Hodgkin lymphoma (SIR: 10.66; 95% CI: 8.54-13.31; P < 0.001), lip cancer (SIR: 29.45; 95% CI: 17.85-48.59; P < 0.001), breast cancer (SIR: 1.11; 95% CI: 1.00-1.24; P = 0.046), and ovarian cancer (SIR: 1.60; 95% CI: 1.23-2.07; P < 0.001). However, renal transplantation did not significantly influence the risks of uterine cancer (P = 0.171), and prostate cancers (P = 0.188). Our findings suggest that patients who receive renal transplantation have an increased risk of cancer at most sites, apart from uterine and prostate cancers patients.
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PMID:Cancer risks in recipients of renal transplants: a meta-analysis of cohort studies. 2963 51

Checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1) monoclonal antibodies have changed profoundly the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, and bladder cancer. Currently, they are tested in various tumor entities as monotherapy or in combination with chemotherapies or targeted therapies. However, only a subgroup of patients benefit from checkpoint blockade (combinations). This raises the question, which all mechanisms inhibit T cell function in the tumor environment, restricting the efficacy of these immunotherapeutic approaches. Serum activity of lactate dehydrogenase, likely reflecting the glycolytic activity of the tumor cells and thus acidity within the tumor microenvironment, turned out to be one of the strongest markers predicting response to checkpoint inhibition. In this review, we discuss the impact of tumor-associated acidity on the efficacy of T cell-mediated cancer immunotherapy and possible approaches to break this barrier.
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PMID:Targeting tumor-associated acidity in cancer immunotherapy. 2997 96

Immune checkpoint inhibitors are most striking among the clinical development of immu- notherapy. These monoclonal antibodies (mAb) restore and augment the anti-tumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies in a variety of cancers. Nivolumab and pembrolizumab, humaznized monoclonal antibodies which block pro- grammed death-1 (PD-1) molecule, were approved for advanced melanoma in 2014 and for advanced NSCLC in 2015 and 2016 in Japan. And, nivolumab was also done for advanced re- nal cell cancer and Hodgkin lymphoma in Japan in 2016. And more, phase III trials of anti-PD- 1 mAb and anti-PD-Li mAb for head and neck cancer, ovarian cancer, bladder cancer, gastric cancer, esophageal cancer etc. are ongoing. Several clinical trials have investigated new agents, alone and in combination, for various cancers. In this chapter the history of development of immne checkpoint inhibitors from basic re- search to clinical trial is overviewed.
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PMID:Anti-PD-1 antibody and anti-PD-Li antibody -from basic and clinic-. 3056 53

A greater understanding of anti-tumor immunity has resulted in rapid development of immunotherapy for a wide variety of cancers. Antibodies targeting the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1), or its ligand (PD-L1) have demonstrated clinical activity and are approved for treatment of melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, head and neck cancers, esophageal cancer, hepatocellular carcinoma, and Hodgkin lymphoma, among others. Treatment is generally well tolerated with relatively few adverse events compared with standard treatments such as chemotherapy. However, immune activation can potentially affect any organ system and a small fraction of patients are at risk for developing severe immune-related adverse events. Immune checkpoint inhibitors (ICIs) and other immunotherapeutic modalities such as cancer vaccines are in nascent stages of development for treatment of thymic epithelial tumors (TETs). Since the thymus plays a key role in the development of immune tolerance, thymic tumors have a unique biology which can influence the risk-benefit balance of immunotherapy. Indeed, early results from clinical trials have demonstrated clinical activity, albeit at a cost of a higher incidence of immune-related adverse events, which seem to particularly affect skeletal and cardiac muscle and the neuromuscular junction. In this paper we describe the effects of thymic physiology on the immune system and review the results of clinical trials that have evaluated immunotherapy for treatment of relapsed thymoma and thymic carcinoma. We review ongoing efforts to mitigate the risk of immune-related complications in patients with TETs receiving immunotherapy and offer our thoughts for making immunotherapy a feasible alternative for treatment of thymic tumors.
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PMID:Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk? 3160 20

The introduction of immunotherapy into the treatment of cancer patients has revolutionised the oncological approach and significantly improved patient survival. The key drugs are immune checkpoint inhibitors (CPIs), whose mechanism of action is to elicit immune response against cancer cell antigens. Three types of CPIs are currently used and approved: an anti-CTLA-4 antibody, ipilimumab; anti-PD-1 antibodies, nivolumab and pembrolizumab; and anti-PD-L1 antibodies: atezolizumab, avelumab and durvalumab. CPIs have been widely used in metastatic and adjuvant melanoma settings, metastatic lung cancer, Hodgkin's lymphoma, renal cancer, bladder cancer, head and neck tumours, and Merkel cell carcinoma. However, side effects of CPIs differ from toxicities of other oncological drugs. According to literature data, in 10-30% of patients CPIs are responsible for immune-related adverse events (irAE) associated with excessive activation of the immune system. Systemic irAEs include enterocolitis, pneumonitis, hepatitis, nephritis, hypophysitis, and autoimmune thyroid disease. However, the most common irAEs of checkpoint inhibitors are dermatologic toxicities ranging from pruritus and mild dermatoses to severe reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Each irAE can become serious if not early diagnosed and appropriately treated. In the article we present different types of skin irAEs related to CPIs together with the recommended therapies.
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PMID:Principles of prophylactic and therapeutic management of skin toxicity during treatment with checkpoint inhibitors. 3161 10


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