RESEARCH
Email: Steve
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General Resources
About CCA
Targeting CholangiocarcinomaFDA priority review for bile ductAbbreviations
- AE, adverse events;
- APCs, antigen presenting cells;
- ASPH, aspartate-β-hydroxylase;
- BTC, biliary tract cancers;
- CCA, cholangiocarcinoma;
- cDC, classical DCs;
- CR, complete response;
- CSF1R, colony stimulating factor 1 receptor;
- CTLA-4, cytotoxic T-lymphocyte-associated protein 4;
- CTLs, cytotoxic T lymphocytes;
- dCCA, distal cholangiocarcinoma;
- DCs, dendritic cells;
- DCR, disease control rate;
- DoR, duration of response;
- ECM, extracellular matrix;
- EVs, extracellular vesicles;
- FDA, food and drug administration;
- GM-CSF, granulocyte macrophage colony-stimulating factor;
- HCC, hepatocellular carcinoma;
- ICB, immune checkpoint blockade;
- iCCA, intrahepaticcholangiocarcinoma;
- IDO, indoleamine 2,3-dioxygenase;
- IHC, immunohistochemistry;
- IL-interleukin;
- iNOS, inducible nitric oxide synthase;
- KC, Kupffer cells;
- MDSCs, myeloid-derived suppressor cells;
- M-MDSC, monocyte-MDSCs;
- MUC1, mucin 1;
- NLR, neutrophil-lymphocyte ratio;
- NK, natural killer;
- NKG2D, natural killer group 2D;
- ORR, objective response rate;
- OS, overall survival;
- pCCA, perihilar cholangiocarcinoma;
- PD-1, programmed death 1;
- pDC, plasmacytoid DCs;
- PD-L1, programmed death ligand 1;
- PFS, progression free survival;
- PMN, polymorphonuclear;
- PMN-MDSCs, polymorphonuclear-MDSCs;
- PR, partial response;
- PSC, primary sclerosing cholangitis;
- TAMs, tumor-associated macrophages;
- TILs, tumor-infiltrating lymphocytes;
- TIME, tumor immune microenvironment;
- TMB, tumor mutational burden;
- TGFβ, transforming growth factor β;
- TNF, tumor necrosis factor;
- Treg, regulatory T cells;
- VEGF, vascular endothelial factor;
- WT1, Wilms tumor 1
Keywords
- Distal cholangiocarcinoma,
- immune checkpoint blockade,
- immune cold CCA,
- immune hot CCA,
- intrahepatic cholangiocarcinoma,
- perihilar cholangiocarcinoma
Targeting Mismatch Repair
Future Looks Brighter for Treatment of Cholangiocarcinoma
AS WITH OTHER gastrointestinal cancers, about 2.5% of cholangiocarcinomas have mismatch repair (MMR) deficiency, which makes them a target for programmed cell death protein 1 (PD-1) inhibitors. In small subsets of cholangiocarcinoma in two KEYNOTE trials, outcomes of treatment with pembrolizumab (Keytruda) were positive.
Among 86 patients in KEYNOTE-016 with mismatch repair– deficient tumors, 4 patients had cholangiocarcinoma; the overall response rate was 53%, with 21% being complete responses; 2-year overall survival was 64%.6 Among 94 patients with mismatch repair–deficient tumors enrolled in KEYNOTE-158, there were 9 patients with cholangiocarcinoma; the overall response rate was 37%, and as of the latest report, the median duration of response had not been reached. Testing for MMR deficiency is now indicated in cholangiocarcinoma, Dr. Kelley said.
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WHERE WE ARE AT NOW WITH CCA
A Science Direct Article
Helen highlights table 3 – Clinical trials image within in the Doc.
Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common primary hepatic malignancy after hepatocellular carcinoma (HCC). CCAs are heterogeneous biliary epithelial tumors that are classified into intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) subtypes based on their anatomic location within the biliary tree.
The overall incidence of CCA, particularly iCCA, has increased over recent decades. Unfortunately, the 5-year overall survival (OS) for CCA remains less than 10%. Surgical resection or liver transplantation following neoadjuvant chemoradiation are potentially curative treatment options for the subset of patients who present with early-stage disease.2 However, diagnosing CCA at an early stage remains a significant challenge, and the majority of patients present with advanced stage disease.
PDF link
London
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Education
Patient Stories
Surgery
Oncology
Surgery
Oncology
Study: Chemotherapy
Study: Immunotherapy
Study: Combination Treatments
Clinical Trials – Immuno
Kate Kelly – Patient ONE
KEYNOTE-028 Trial Unveils Biomarkers Linked to Pembrolizumab Efficacy
KEYNOTE-028 trial is a single-arm, phase Ib basket trial
“This interesting study adds to the growing body of literature regarding potential biomarkers for response to immune checkpoint inhibitors,
Anti–PD-1/PD-L1 Antibodies
ASCO Post Article 2016
Source Originated from Patient Story
KEYTRUDA – WHAT A 40% RESPONSE RATE HAS MEANT TO ME.
Posted by: TCF Blog Team on Tuesday, February 14th, 2017
Bill Drake
Refers to Keynote Trial 028 Results
“In relapsed/refractory metastatic esophageal cancer, the KEYNOTE-028 trial evaluated pembrolizumab at 10 mg/kg every 2 weeks.3 The study restricted enrollment to patients who stained positive for the PD-1 ligand, PD-L1, defined as expression in at least 1% of tumor or inflammatory cells or positive bands in the stroma.”
Keytruda Side Effects
List
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. Check with your doctor or nurse immediately if any of the following side effects occur:
This is a high quality lecture
Bullet Points
- Immunotherapy teaches the T Cells -if the cancer comes back the T Cells will remember
- Some patients who have completed other chemo trials maybe very weakened immune and may not respond as well
- Colorectal Cancers tend to be high TMB which yields Msi-High and better PD-L1 expression and PD-1 response Approx 30 mins in on the video
- CTLA- 4 Cured 20%
- PD-L1 was much higher
- Cure and Cancer in the same sentence
Beyond the Blockade
UW Video
Published on May 19, 2018
A seismic shift has occurred recently in cancer therapy. Multiple agents that unleash the adaptive immune response against tumors have been FDA-approved and found to induce remarkable results in a subset of patients with advanced cancers. The mechanistic basis for these checkpoint inhibitor therapies and new agents in development that could augment their activity will be discussed. After viewing this lecture, participants should be able to: 1. List the 4 main steps involved in inducing a durable and effective adaptive immune response. 2. Explain how checkpoint blockade enhances immune responses to tumors. 3. List at least 3 effects that IL-15 has or doesn’t have on lymphocytes that make it an attractive immunotherapy agent. Chihiro Morishima, MD Director, Research Testing Services Co-Director, Clinical Immunology Laboratory Associate Professor, Department of Laboratory Medicine University of Washington
Steve Notes for highlight
- 38 mins: Who will respond? – CD8 + T Cell Infiltration in tumours is a sign for successful Immunotherapy
- 38:30 – Whilst PD-L1 is a great biomarker it turns out the patients who do not have PD-l1 can still respond to Check point Inhibitors
Clinical Trials – Chemo
Clinical Trials: Combo
Grants, Fellowships and Researchers
Psyhcology
Microbiome & Food
Presentations
Caregivers & Advocates
Orgs, Groups and Govt
Survival Stats and Updates
Early Detection
IHC Testing
Genomic Profiling
dMMR
ICI – Checkpoint Pathway
Biomarkers
Mutations
FGF in Action
Targeting FGFR Alterations
44mins:
Dr. Randi Isaacs
From the Cholangiocarcinoma Foundation’s 2015 Annual Conference.
Lon video -did not watch much
- There are 4 receptors and 22 ligands in the FGF family
- looking foe a molecule inhibitor molecule
- FGFR2 = GI and Breast
- BGJ398 is exciting -it is a potent “Pan-FGFR Inhibitor
Targeted Oncology
Published on Jun 21, 2019
A discussion regarding the role of fibroblast growth factor receptors in tumor development and the frequency at which it occurs. For more resources and information regarding anticancer targeted therapies: http://targetedonc.com/
Gold Biotechnology, Inc.
Published on Jun 1, 2015
This video provides an overview about fibroblast growth factors (FGFs) and their receptors (FGFRs). Here, Dr. David Ornitz, a professor of developmental biology at Washington University in St. Louis, School of Medicine, will address what FGFs and their receptors are, how the FGF-FGFR signal is regulated and how FGFs and their receptors regulate biological functions.
Part two of this video will be published in July, and will provide more information about diseases resulting from FGF and FGFR mutations.
Dr. Ornitz has published 168 scientific papers and 27 book chapters and reviews. You can visit his website at http://ornitzlab.wustl.edu
To access Dr. Ornitz’s paper “The Fibroblast Growth Factor Signaling Pathway,” visit http://onlinelibrary.wiley.com/doi/10….
Crushing Once-Untreatable Cancers
By Targeting Each Patient’s Unique Tumor, Precision Medicine Is Crushing Once-Untreatable Cancers. But Only a Fraction of Patients Currently Benefit. Can Medicine Close the Gap?
Linda Boyed, for example, an energetic 52-year-old occupational therapist, was thrilled to be on vacation with her family in Hawaii, hitting the beaches and taking long walks. But she couldn’t shake a constant feeling of fatigue. By the time she returned home, near Columbus, Ohio, her skin had yellowed.
What is
Fibroblast Growth Factor Receptor (FGFR)? Tagline
Oncology.TV
Published on Apr 29, 2014
Dr. Joel Neal from Stanford University Medical School talks about FGFR,
FGFR2
Shomu on FGFR2
fgf signaling pathway – This lecture explains about fibroblast growth factor signaling using fibroblast growth factor receptor during cell cycle and cell division. Fibroblast growth factor acts like a growth hormone that adheres to the fibroblast growth factor receptor and helps to send the chemical signal inside the cell and activates the required transcription factor through a cell signaling pathway and it finally relay the signal inside the cell nucleus and helps in the transcription of the desired gene the product of which helps in the cell cycle and cell division.
For more information, log on to- www.shomusbiology.com/
BTC constitute epithelial malignancies of the biliary tree
Current knowledge, clinical candidates and future challenges
Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1.
Immune check point inhibitors are currently being used across various poor prognostic tumor groups with good results; however, there is some association of programmed cell death protein ligand-1 (PD-L1), expression and effectiveness of these treatments.127,128 Expression of PD-L1 in BTC shows a wide range from 29% to 100%,129,130 and the full analysis of the KEYNOTE-028 study is still awaited. This Phase Ib trial is evaluating the effects of treatment with a monoclonal antibody against human immune cell check point programmed death 1 (PD-1), pembrolizumab in patients with previously pretreated advanced BTC who have PD-L1 expression.131 BTCs are infrequently associated with Lynch syndrome, a genetic disorder thatpredisposes to mic-rosatellite instability (MSI) and mismatch repair deficiency (MMR).17With the food and drug association (FDA) approval of pembrolizumab132 for MSI- and MMR-deficient tumors, in patients who have BTC associated with Lynch syndrome, there may be an option for treating them with immune check point inhibitors, where available..133
The role of immunomodulating treatments in BTC is still an area of exploration, and none of the current immune investigational drugs have been approved in this disease group. The expression of PD-L1 is a predictive biomarker in other tumor sites, such as non-small-cell lung cancer (NSCLC), for the efficacy of these immunotherapies. Apart from this biomarker, another recently emerging predictor of response is the human microbiome, where certain bacterial species are associated with clinical efficacy of immunotherapies.141
Primary End Point Achieved
Explore IDH Mutations
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EGFR is found on the surface of some normal cells and is involved in cell growth. It may also be found at high levels on some types of cancercells, which causes these cells to grow and divide. Blocking EGFR may keep cancer cells from growing. Some EGFR inhibitors are used to treat cancer.
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