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HIV Cure Drugs Safety Issues - ART Interruption Brain Affects. HDAC Gene Changes Long Term Affects / Immune Checkpoint Cancer Drugs: cardiac toxicity
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Cure Studies/ART Interruption & Brain Affects, Vorinostat - (10/13/17).....nine participants presented a compartmentalized HIV RNA rebound within the CSF after interruption of ART, even when sampled within 2 weeks from viral rebound......After 500 days of viral suppression animals were treated with two cycles of latency reversing agents and increases in viral transcripts were examined..Increases in activation markers and plasma and CSF viral loads were observed in one animal treated with latency reversing agents, despite ongoing ART. [ what about inflammation affects of ART interruption?]
HDAC Cure Drugs Safety Issues -Cardiac Toxicity of Immune Checkpoint Inhibitors /HDAC inhibitors Upregulate gene expression which in long term can cause immune dysregulation...."The majority of studies on ICIs have underestimated cardiotoxicity....Myocarditis was diagnosed at a median of 17 days after the first treatment, suggesting the presence of early cardiotoxicity"
HDAC inhibitors Upregulate gene expression which in long term can cause immune dysregulation & serious adverse affects, their long term affects are not known.
Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell......https://www.ncbi.nlm.nih.gov/m/pubmed/18289048/
Divergent effects of HDAC inhibition on the global gene expression profiles have been described when testing various cancer cells, and this is further complicated by altered HDAC expression induced by HDAC inhibitors
The toxicity profiles of HDACIs can be compared between the different types, with side effects mainly consisting of diarrhea, myelosuppression and cardiac QT persistence. Most HDACIs have a half-life of 2-8 hours in plasma and will undergo hepatic metabolization and subsequent intestinal excretions.80,102,115-118
https://pdfs.semanticscholar.org/447f/48f9c2adbf3b8456d829d6d2d2400fc18e9b.pdf
Furthermore, the use of HDACIs in nononcological models, such as heart disease including cardiac hypertrophy and myocardial ischemia/reperfusion, has been investigated with the therapeutic potential remaining controversial.119-121 Investigations from our laboratory aiming to explore the combinatorial effects of the broad-spectrum HDACI trichostatin A with chemotherapy using the anthracycline doxorubicin to induce hypertrophy in rat cardiac myocytes also suggested detrimental effects caused by the HDACI.122,123 We reported that trichostatin A augmented doxorubicin-induced hypertrophy by altering the expression of hypertrophy-associated genes.122 In addition, further investigations indicated that pretreatment but not posttreatment of cardiac myocytes exposed to trichostatin A and the short-chain fatty acids, VPA, and sodium butyrate augmented DNA damage induced by doxorubicin....https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584656/
Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors....about 40% of noncoding microRNAs are upregulated or downregulated
Histone deacetylase inhibitors: molecular mechanisms of action...HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence.....http://www.nature.com/onc/journal/v26/n37/full/1210620a.html
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Cardiac Toxicity of Immune Checkpoint Inhibitors....."The majority of studies on ICIs have underestimated cardiotoxicity.....Two cases of fulminant myocarditis after treatment with ipilimumab plus nivolumab for melanoma have been recently described.Hypertension was their only cardiovascular risk factor. Histological analysis demonstrated lymphocytic infiltrates within the myocardium, the cardiac sinus, and the atrioventricular nodes.Patients who received combination therapy (nivolumab plus ipilimumab) had more severe and frequent myocarditis than those who received nivolumab alone (0.27% versus 0.06%).Myocarditis was diagnosed at a median of 17 days after the first treatment, suggesting the presence of early cardiotoxicity. Finally, severe and even fatal cardiovascular events have occurred.All cases of cardiotoxicity associated with ICIs reported so far occurred immediately after the infusion or during the first year of therapy,3,5 but prospective studies should assess whether late-onset chronic cardiotoxicity can occur."
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Cardio-Oncology Meets Immunology
Circulation. 2017 -Gilda Varricchi, Maria Rosaria Galdiero, Carlo G. Tocchetti
Cardiotoxicity caused by chemotherapeutics such as anthracyclines is well recognized. In recent years, immunotherapy has been successfully introduced in cancer treatment. Unfortunately, cardiotoxicity seems to have emerged as an issue in recent reports.1
Stimulating Antitumoral Immune Responses
For decades, immunologists and oncologists have attempted to stimulate antitumor immune responses to fight cancer. Initial attempts displayed marginal success because several inhibitory pathways such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) dampen the antitumor functions of T lymphocytes. Tumors exploit these pathways to escape T cell-mediated tumor-specific immunity. Monoclonal antibodies targeting CTLA-4 (ipilimumab), PD-1 (nivolumab and pembrolizumab), and PD-L1 (atezolizumab, avelumab, durvalumab), called immune checkpoint inhibitors (ICIs), have revolutionized cancer treatments. However, dramatic responses are currently confined to few patients, presumably because of the complex network of immunosuppressive pathways in tumor microenvironments. Combined anti-CTLA-4 and anti-PD-1 blockade further enhances antitumor activity (Figure, A). ICIs are being tested in HIV-infected patients, characterized by overexpression of immune checkpoints and T-cell exhaustion.
Immune-Related Adverse Events Associated With Checkpoint Inhibitors
As a result of the role played by immune checkpoints in the maintenance of self-tolerance, their therapeutic blockade can cause immune-related adverse events (IRAEs). IRAEs associated with ipilimumab were already evident in phase I studies. IRAEs are common, usually reversible, and not severe in most patients.1,2 PD-1- and PD-L1-blocking agents display different IRAEs (eg, renal and endocrine effects and cardiomyopathy) that resemble the autoimmune manifestations of PD-1-deficient mice.3 IRAEs associated with the ipilimumab/nivolumab combination require discontinuation of therapy in nearly 40% of patients. It is unclear whether the use of immunosuppressive agents (eg, tumor necrosis factor-α inhibitors) is more appropriate than high-dose glucocorticoids in the treatment of severe IRAEs.
Cardiotoxicity of Checkpoint Inhibitors in Patients With Cancer
The majority of studies on ICIs have underestimated cardiotoxicity3; however, occasional cases have been reported. Two cases of fulminant myocarditis after treatment with ipilimumab plus nivolumab for melanoma have been recently described.3 Both patients died after receiving the first doses despite intensive treatment. Hypertension was their only cardiovascular risk factor. Histological analysis demonstrated lymphocytic infiltrates within the myocardium, the cardiac sinus, and the atrioventricular nodes. This observation can explain the complete heart block that can occur in these patients. PD-L1 was expressed on injured cardiomyocytes and on infiltrating CD8+ T cells (Figure, B). Overexpression of PD-L1 on the injured myocardial cell is consistent with the constitutive expression of PD-L1 in human hearts and its upregulation in T cell-mediated myocarditis in mice.4 Johnson et al3 also assessed the frequency of myocarditis and myositis in the safety databases of Bristol-Myers Squibb to identify the occurrence of these events in patients treated with nivolumab, ipilimumab, or both. Among 20 594 patients treated with these ICIs, 18 drug-related myocarditis cases (0.09%) were reported. Patients who received combination therapy (nivolumab plus ipilimumab) had more severe and frequent myocarditis than those who received nivolumab alone (0.27% versus 0.06%).3 Myocarditis was diagnosed at a median of 17 days after the first treatment, suggesting the presence of early cardiotoxicity. Finally, severe and even fatal cardiovascular events have occurred, making analysis of the incidence of cardiotoxicity of ICIs a priority.
Moving Forward: The Integration of Cardio-Oncology and Immunology
Cardiologists and oncologists should be aware of immune-mediated myocarditis because of its fulminant progression.3 The development of myocarditis in patients treated with ICIs has biological plausibility. Deletion of CTLA-4 and PD-1 axes can cause autoimmune myocarditis and dilated cardiomyopathy,4 suggesting that these molecules play a role in the prevention of autoimmunity. In addition, genetic deletion of PD-L1, as well as treatment with anti-PD-L1, can transform transient myocarditis into lethal disease, suggesting that PD-1/PD-L1 and CTLA-4 play important roles in limiting T cell-mediated autoimmune myocarditis. Moreover, isolated ischemic-reperfused rat hearts showed increased expression of PD-1 and PD-L1 in cardiomyocytes. Myocarditis has a wide spectrum of presentations reflecting the many causes and the variable pattern of tissue involvement.
Moreover, patients with autoimmunity can have subclinical or subacute myocarditis. At present, exclusion criteria related to preexisting autoimmune diseases in patients with cancer treated with ICIs are based on personal experience,1,5 but patients with autoimmune disorders are usually excluded from trials with ICIs. Approximately 14% of patients with lung cancer have a concurrent diagnosis of autoimmune disease, indicating that autoimmunity needs to be considered before the initiation of these therapies. Menzies and collaborators5 reported their experience with 2 groups of patients with preexisting autoimmune disease and melanoma treated with ipilimumab or anti-PD-1. Although 20% to 30% of these patients experienced an autoimmune flare, the authors concluded that treatment with either ipilimumab or anti-PD-1 is feasible for patients with certain preexisting autoimmunities. Given the heterogeneity and the wide spectrum of severity of autoimmune disorders, specific guidelines for exclusion criteria and treatment are needed. Similarly, there are no validated guidelines for the treatment of myocarditis in the setting of cancer immunotherapy. Wang and collaborators1 proposed an algorithm that represents an excellent basis for a consensus guideline.
Newer monoclonal antibodies targeting different immune checkpoints and a new generation of cancer therapies (eg, engineered T cells and cancer vaccines), beyond ICIs, are under development for several tumors. Therefore, cardiovascular evaluation appears necessary to detect the potential cardiotoxicity of newer cancer immunotherapies (Table) because these agents are often used in combination with cardiotoxic kinase inhibitors.
All cases of cardiotoxicity associated with ICIs reported so far occurred immediately after the infusion or during the first year of therapy,3,5 but prospective studies should assess whether late-onset chronic cardiotoxicity can occur.
Constitutive expression of PD-1 and PD-L1 in human and murine myocytes and the recent identification of PD-L1 on injured myocytes in patients with fulminant myocarditis treated with checkpoint inhibitors3,4 suggest that cytokines and immune cells can upregulate PD-1/PD-L1 pathways in the human myocardium (Figure, C). Additional in vitro and in vivo research is needed to further understand the mechanisms of these cardiotoxicities (Table).
With a growing number of patients treated immune ICIs, a tight collaboration among cardiologists, oncologists, and immunologists appears necessary for better management of ICI cardiotoxicity.
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