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Nathan Goodyear

Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for No... - 0 views

www.nature.com/...srep13110

PD-1 cancer check point inhibitors PD-L1 CLTA-4 immunotherapy

shared by Nathan Goodyear on 20 Apr 18 - No Cached
  • the lack of immunologic control is recognized as a hallmark of cancer currently
  • Programmed death-1 (PD-1) and its ligand PD-L1 play a key role in tumor immune escape and the formation of tumor microenvironment, closely related with tumor generation and development
  • Blockading the PD-1/PD-L1 pathway could reverse the tumor microenvironment and enhance the endogenous antitumor immune responses.
  • ...4 more annotations...
  • environmental factors, living habits, genetic mutations, dysfunction of the immune system and so on
  • special tumor immune microenvironment
  • cytotoxic T lymphocyte-associated antigen 4 (CLTA-4), Programmed death-1 (PD-1) and its ligands PD-L1 (B7H1) and PD-L2 (B7-DC)
  • CTLA-4 regulates T cell activity in the early stage predominantly, and PD-1 mainly limits the activity of T-cell in the tumor microenvironment at later stage of tumor growth
  • Nathan Goodyear on 20 Apr 18
     
    PD-1 to read.
Nathan Goodyear

Update on Programmed Death-1 and Programmed Death-Ligand 1 Inhibition in the Treatment ... - 0 views

www.ncbi.nlm.nih.gov/...PMC5382272

cancer PD-1 immunotherapy programmed death-1

shared by Nathan Goodyear on 20 Apr 18 - No Cached
  • Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), the first immune checkpoint receptor to be clinically targeted, is exclusively expressed on the surface of CD4+ and CD8+ T cells in lymphatic tissue and is involved in T-cell regulation, proliferation, and tolerance
  • programmed death-1 (PD-1) immune checkpoint inhibitor antibodies, which restores T-cell effector function and augments the host anti-tumor response by blocking the binding of either programmed death-ligand 1 (PD-L1) and/or PD-L2 to PD-1 receptors
  • lung cancer is the first and second cause of cancer mortality in men and women
  • ...1 more annotation...
  • Eighty-five percent of lung cancers are non-small-cell lung cancer (NSCLC)
  • Nathan Goodyear on 20 Apr 18
     
    To read update article on PD-1 and immunotherapy.
Nathan Goodyear

Chemotherapy induces tumor immune evasion by upregulation of programmed cell ... - 0 views

www.ncbi.nlm.nih.gov/...PMC5527486

chemotherapy PD-L1 immune system cancer

shared by Nathan Goodyear on 16 Feb 21 - No Cached
  • upregulation of glycolysis in cancer cells, with subsequent exhaustion of glucose in the microenvironment, leading to the death of T cells from starvation
  • PD‐L1 expression promotes the production of interleukin 10, a cytokine involved in the death of activated T cells
  • PD‐L1 expression in tumor tissue might lead to T‐cell exhaustion and unresponsiveness
  • ...1 more annotation...
  • PD‐L1 on cancer cells could induce T‐cell apoptosis through
  • Nathan Goodyear on 16 Feb 21
     
    Chemotherapy found to increase PD-L1 expression in vitro and in vivo studies.
Nathan Goodyear

PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Com... - 0 views

www.ncbi.nlm.nih.gov/...PMC5572324

cancer PD-1 PDL-1 immune system immunotherapy

shared by Nathan Goodyear on 25 Sep 18 - No Cached
  • Nathan Goodyear on 25 Sep 18
     
    Good review of PD-1 and PDL-1 siganling in the immune system in cancer immunotherapy.
Nathan Goodyear

Oncolytic virotherapy promotes intratumoral T cell infiltration and improves Anti-PD-1... - 0 views

www.cell.com/...S0092-8674(17)30952-2

immunotherapy cancer RIGVIR oncolytic therapy PD-1 check point inhibitors

shared by Nathan Goodyear on 23 Oct 18 - No Cached
  • Nathan Goodyear on 23 Oct 18
     
    Study found that viral oncolytic therapy improved efficacy of PD-1 check point inhibitors by 62%. Increased CD8 expression, interferon-gamma...Interesting, starting CD8 levels played no role in predicting outcome.
Nathan Goodyear

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patie... - 0 views

science.sciencemag.org/...595

immunotherapy gut bacteria melanoma cancer PD-1 gut flora gut microbiota gut microbiome

shared by Nathan Goodyear on 07 Feb 21 - No Cached
  • Nathan Goodyear on 07 Feb 21
     
    Fecal transplant study. Gut microbes improve efficacy of anti-PD-1 therapy immunotherapy.
Nathan Goodyear

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model - 0 views

www.ncbi.nlm.nih.gov/...PMC6983418

check point inhibitors CTL lymphoma cytotoxic T cells PD-1 vitamin C immune check point inhibitors IV vitamin C NK cells NK

shared by Nathan Goodyear on 01 Apr 21 - No Cached
  • Nathan Goodyear on 01 Apr 21
     
    high dose vitamin C shown to augment PD-1 immune check point inhibitors in Lymphoma mouse model.
Nathan Goodyear

Tetraiodothyroacetic acid (tetrac), integrin αvβ3 and disabling of immune che... - 0 views

www.future-science.com/...fmc-2018-0123

cancer T4 tetrac PD-1 immunotherapy

shared by Nathan Goodyear on 07 Feb 21 - No Cached
  • Nathan Goodyear on 07 Feb 21
     
    T4 upregulates PD-1 and tetrac, T4 analog, inhibits.
Nathan Goodyear

Cytokine release syndrome after radiation therapy: case report and review of the litera... - 0 views

jitc.biomedcentral.com/...s40425-017-0311-9

cytokine storm PD-1 radiation

shared by Nathan Goodyear on 20 Aug 20 - No Cached
  • Nathan Goodyear on 20 Aug 20
     
    Radiation in conjunction with PD-1 therapy induced cytokine storm in cancer case study.
Nathan Goodyear

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multi... - 0 views

www.ncbi.nlm.nih.gov/...PMC5809128

cancer anal cancer nivolumab immunotherapy

shared by Nathan Goodyear on 13 Jul 18 - No Cached
  • Patients received a median of six doses of nivolumab
  • four of the first 12 patients had partial responses
  • Nine (24% [95% CI 15–33]) of 37 patients achieved a response (seven partial responses and two complete responses
  • ...16 more annotations...
  • no treatment-related deaths
  • the most common adverse events were anaemia (26 [70%]), fatigue (25 [68%]), and rash
  • hypothyroidism
  • hypothyroidism
  • nivolumab-related autoimmune hypothyroidism, which resolved after a short course of corticosteroids
  • No grade 3 or 4 adverse events occurred
  • Nivolumab resulted in objective responses in 24% of patients with metastatic SCCA
  • Historically, doublet chemotherapy with cisplatin and fluorouracil has been the most common treatment for patients with metastatic SCCA
  • our results suggest that immune checkpoint blockade agents might extend overall survival beyond currently available therapies, especially if provided early in the disease treatment course
  • the dose of nivolumab we used differs from the 2016 recommendation of a fixed 240 mg every 2 weeks
  • 25% of patients develop distant metastases
  • most patients with localised SCCA are cured by chemoradiation
  • More than 90% of cases of SCCA are linked to prior infection with human papillomavirus (HPV)
  • Within tumour cells, HPV oncoproteins are immunogenic and can trigger an anti-tumour host immune response by recruitment of tumour-infiltrating lymphocytes
  • Tumour cells express PD-L1 and, on binding its inhibitory receptor PD-1 on the surface of T cells, downregulate T-cell activation and thwart the local anti-tumour immune response
  • Nivolumab is a humanised monoclonal antibody against PD-1 that disrupts this interaction, enabling T-cell cytotoxicity. It has activity as a monotherapy in advanced solid cancers, such as head and neck cancer, melanoma, non-small-cell lung cancer, and renal cell carcinoma
  • Nathan Goodyear on 13 Jul 18
     
    study finds nivolumab helpful in some patients with surgically unresectable or metastatic anal cancer.  The dose used was 3 mg/kg every 2 weeks. 
Nathan Goodyear

How is the Immune System Suppressed by Cancer - 1 views

www.cancertutor.com/ancer-suppresses-immune-system

iNOS cancer immune system

shared by Nathan Goodyear on 23 May 18 - No Cached
  • nitric oxide (NO) released by tumor cells
  • Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
  • NO from eNOS in cancer cells can travel through membranes and over long distances in the body
  • ...43 more annotations...
  • NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
  • The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
  • nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
  • Inhibition of inducible Nitric Oxide Synthase (iNOS)
  • NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
  • Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
  • tolerance in the immune system that decreases the immune response to antigens on the tumors
  • Freund’s adjuvant
  • increase in kinases in these cells which phosphorylate serine, and tyrosine
  • responsible for activation of many growth factors and enzymes
  • phosphorylated amino acids suppress iNOS activity
  • Hexokinase II
  • Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
  • Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10.  IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
  • Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
  • These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
  • Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
  • Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
  • IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
  • IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
  • nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
  • early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
  • later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
  • cGMP is increased by NO
  • NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
  • the greater the malignancies and the greater the metastatic potential of these tumors
  • The greater the NO production in many types of tumors,
  • gynecological
  • elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
  • The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells.  Histamine alone stimulates many tumor cells.
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
  • T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
  • last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
  • intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
  • In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
  • Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
  • Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
  • Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
  • Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
  • COX 2 inhibitors or all trans-retinoic acid
  • Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      cimetidine is an H2 blocker
  • interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
  • In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
  • these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
  • Nathan Goodyear on 23 May 18
     
    Great review of the immunosuppression in cancer driven by the likes of NO.
Nathan Goodyear

Approved Drugs > Modification of the Dosage Regimen for Nivolumab - 0 views

www.fda.gov/...ucm520871.htm

immunotherapy cancer nivolumab monoclonal antibodies

shared by Nathan Goodyear on 13 Jul 18 - No Cached
  • Nathan Goodyear on 13 Jul 18
     
    FDA recommends nivolumab, PD-1 inhibitor immunotherapy, at 240 mg IV Q2 weeks.
Nathan Goodyear

Immunosuppressive Myeloid Cells Induced by Chemotherapy Attenuate Antitumor CD4+ T-Cell... - 0 views

cancerres.aacrjournals.org/...3441

MDSC chemotherapy myeloid-derived suppressor cells

shared by Nathan Goodyear on 15 Nov 20 - No Cached
  • Nathan Goodyear on 15 Nov 20
     
    This study points to the increase in immunosuppression as a result of chemotherapy induced increase in MDSCs and T reg. This effect is dose dependent.
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