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Archive for the ‘Cancer and Therapeutics’ Category


One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Author: Marzan Khan, B.Sc

 

A team of mechanical engineers at Worcester Polytechnic Institute (WPI) have developed a fascinating technology – a liquid biopsy chip that captures and detects metastatic cancer cells, just from a small blood sample of cancer patients(1). This device is a recent development in the scientific field and holds tremendous potential that will allow doctors to spot signs of metastasis for a variety of cancers at an early stage and initiate an appropriate course of treatment(1).

Metastasis occurs when cancer cells break away from their site of origin and spread to other parts of the body via the lymph or the bloodstream, where they give rise to secondary tumors(2). By this time, the cancer is at an advanced stage and it becomes increasingly difficult to fight the disease. The cells that are shed by primary and metastatic cancers are called circulating tumor cells (CTCs) and their numbers lie in the range of 1–77,200/m(3). The basis of the liquid biopsy chip test is to capture these circulating tumor cells in the patient’s blood and identify the cell type through specific interaction with antibodies(4).

The chip is comprised of individual test units or small elements, about 3 millimeters wide(4). Each small element contains a network of carbon nanotube sensors in a well which are functionalized with antibodies(4). These antibodies will bind cell-surface antigens or protein markers unique for each type of cancer cell. Specific interaction between a cell surface protein and its corresponding antibody is a thermodynamic event that causes a change in free energy which is transduced into electricity(3). This electrical signature is picked up by the semi-conducting carbon nanotubes and can be seen as electrical spikes(4). Specific interactions create an increase in electrical signal, whereas non-specific interactions cause a decrease in signal or no change at all(4). Capture efficiency of cancer cells with the chip has been reported to range between 62-100%(4).

The liquid biopsy chip is also more advanced than microfluidics for several reasons. Firstly, the nanotube-chip arrays can capture as well as detect cancer cells, while microfluidics can only capture(4). Samples do not need to be processed for labeling or fixation, so the cell structures are preserved(4). Unlike microfluidics, these nanotubes will also capture tiny structures called exosomes spanning the nanometer range that are produced from cancer cells and carry the same biomarkers(4).

Pancreatic cancer is the fourth leading cause of cancer-associated deaths in the United states, with a survival window of 5 years in only 6% of the cases with treatment(5). In most patients, the disease has already metastasized at the time of diagnosis due to the lack of early-diagnostic markers, affecting some of the major organs such as liver, lungs and the peritoneum(5,6). Despite surgical resection of the primary tumor, the recurrence of local and metastatic tumors is rampant(5). Metastasis is the major cause of mortality in cancers(5). The liquid biopsy chip, that identifies CTCs can thus become an effective diagnostic tool in early detection of cancer as well as provide information into the efficacy of treatment(3). At present, ongoing experiments with this device involve testing for breast cancers but Dr. Balaji Panchapakesan and his team of engineers at WPI are optimistic about incorporating pancreatic and lung cancers into their research.

REFERENCES

1.Nanophenotype. Researchers build liquid biopsy chip that detects metastatic cancer cells in blood: One blood sample can be tested for a comprehensive array of cancer cell biomarkers. 27 Dec 2016. Genesis Nanotechnology,Inc

https://genesisnanotech.wordpress.com/2016/12/27/researchers-build-liquid-biopsy-chip-that-detects-metastatic-cancer-cells-in-blood-one-blood-sample-can-be-tested-for-a-comprehensive-array-of-cancer-cell-markers/

2.Martin TA, Ye L, Sanders AJ, et al. Cancer Invasion and Metastasis: Molecular and Cellular Perspective. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

https://www.ncbi.nlm.nih.gov/books/NBK164700/

3.F Khosravi, B King, S Rai, G Kloecker, E Wickstrom, B Panchapakesan. Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells. 23 Dec 2013. IEEE Nanotechnology Magazine 7 (4), 20-26

Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells

4.Farhad Khosravi, Patrick J Trainor, Christopher Lambert, Goetz Kloecker, Eric Wickstrom, Shesh N Rai and Balaji Panchapakesan. Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip. 29 Sept 2016. Nanotechnology. Vol 27, No.44. IOP Publishing Ltd

http://iopscience.iop.org/article/10.1088/0957-4484/27/44/44LT03/meta

5.Seyfried, T. N., & Huysentruyt, L. C. (2013). On the Origin of Cancer Metastasis. Critical Reviews in Oncogenesis18(1-2), 43–73.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597235/

6.Deeb, A., Haque, S.-U., & Olowoure, O. (2015). Pulmonary metastases in pancreatic cancer, is there a survival influence? Journal of Gastrointestinal Oncology6(3), E48–E51. http://doi.org/10.3978/j.issn.2078-6891.2014.114

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397254/

Other related articles published in this Open Access Online Scientific Journal include the following:

 

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute, Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/28/liquid-biopsy-chip-detects-an-array-of-metastatic-cancer-cell-markers-in-blood-rd-worcester-polytechnic-institute-micro-and-nanotechnology-lab/

 

Trovagene’s ctDNA Liquid Biopsy urine and blood tests to be used in Monitoring and Early Detection of Pancreatic Cancer

Reporters: David Orchard-Webb, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/06/trovagenes-ctdna-liquide-biopsy-urine-and-blood-tests-to-be-used-in-monitoring-and-early-detection-of-pancreatic-cancer/

 

Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/06/liquid-biopsy-assay-may-predict-drug-resistance/


New insights in cancer, cancer immunogenesis and circulating cancer cells

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2016/04/15/new-insights-in-cancer-cancer-immunogenesis-and-circulating-cancer-cells/

 

Prognostic biomarker for NSCLC and Cancer Metastasis

Larry H. Bernstein, MD, FCAP, Curato

https://pharmaceuticalintelligence.com/2016/03/24/prognostic-biomarker-for-nsclc-and-cancer-metastasis/

 

Monitoring AML with “cell specific” blood test

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2016/01/23/monitoring-aml-with-cell-specific-blood-test/

 

Diagnostic Revelations

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/02/diagnostic-revelations/

 

Circulating Biomarkers World Congress, March 23-24, 2015, Boston: Exosomes, Microvesicles, Circulating DNA, Circulating RNA, Circulating Tumor Cells, Sample Preparation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/03/03/circulating-biomarkers-world-congress-march-23-24-2015-boston-exosomes-microvesicles-circulating-dna-circulating-rna-circulating-tumor-cells-sample-preparation/

 

 

 

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Projected Sales in 2020 of World’s Top Ten Oncology Drugs

Reporter: Aviva Lev-Ari, PhD, RN

 

 

Top Oncology Medicines

Projected Sales in 2020

Revlimid (Celgene)

Generic Name: Lenalidomide

$10,110 Million

 

Imbruvica (AbbVie/J&J)

Generic Name: Ibrutinib

$8,213 Million

 

Avastin (Roche)

Generic Name: Bevacizumab

$ 6,733 Million

 

Opdivo (BMS)

Generic Name: Nivolumab

$ 6,201 Million

 

Xtandi (Medivation & Astellas)

Generic Name: Enzalutamide

$5,700 Million

 

Rituxan (Roche)

Generic Name: Rituximab

$5,407 Million

 

Ibrance (Pfizer)

Generic Name: Palbociclib

$4,722 Million

 

Perjeta (Roche)

Generic Name: Pertuzumab

$4,669 Million

 

Herceptin (Roche)

Generic Name: Trastuzumab

$4,573 Million

 

Keytruda (Merck)

Generic Name: Pembrolizumab

$3,560 Million


SOURCE

https://igeahub.com/2016/04/01/worlds-top-ten-cancer-drugs-by-2020/

World’s Top Ten Cancer Drugs by 2020

Igea gives professionals, patients and investors interested in pharmaceuticals, biotechnology, healthcare technology, diagnostics and medical devices the most relevant, actionable news, information and analysis available anywhere. Our goal is to provide expert insights, analysis and information from industry leaders with a deep understanding of life sciences, medicine and healthcare. Created and curated by Luca Dezzani, MD, Global Medical Director at Novartis Oncology*, Igea offers an insider’s view on the most important developments in life sciences, healthcare technology, digital health and more.


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Prostate Cancer Patient: Consider Monitoring vs Surgery or Radiation, only if Life Expectancy is less than a Decade

Reporter: Aviva Lev-Ari, PhD, RN

Boldface by ALA

 

Rethinking Prostate Cancer, in THE MOST NOTABLE MEDICAL FINDINGS OF 2016

For many years, American physicians have screened their older male patients for prostate cancer by looking at the level of a particular protein in the blood. The protein, called prostate-specific antigen (P.S.A.), can indicate the presence of a tumor long before any symptoms materialize. Recently, though, there has been a movement within the medical community against P.S.A. testing; since prostate cancers typically grow very slowly and rarely cause discomfort, the thinking goes, early screening may not be all that useful. The U.S. Preventive Services Task Force, based on data from two large clinical trials, currently recommends against routine screening, but other expert groups (using the same evidence) have countered that men should be allowed to choose for themselves.

Now the dispute has become even more fraught. In October, The New England Journal of Medicine published a study by a group of British researchers that examined three classes of prostate-cancer patients: those who had received surgery, those who had received radiation therapy, and those whose disease had been carefully monitored without intervention. After ten years, there was no difference in survival rates among the three groups. Active treatment does not change the over-all risk of death, and this was the headline in most news reports. But largely overlooked in the press was that metastases, meaning spread of the cancer beyond the prostate gland to tissues in the pelvis and to bone, occurred three times more frequently in those being monitored than in those who received surgery or radiation. Not surprisingly, the cancer also progressed more quickly in these men.

In an editorial that accompanied the study, Anthony D’Amico, a radiation oncologist at Boston’s Dana-Farber Cancer Institute, argued that men should be informed of the risk of metastasis and of its consequences, particularly pelvic tumors and bone pain and fracture. D’Amico advises that men who wish to avoid metastases should consider monitoring, rather than surgery or radiation, only if their life expectancy is less than a decade. Having cared for many men with prostate cancer that metastasized—an incurable situation often marked by severe suffering—I strongly concur.

SOURCE

http://www.newyorker.com/tech/elements/the-most-notable-medical-findings-of-2016?mbid=nl_TNY%20Template%20-%20With%20Photo%20(122)&CNDID=22119822&spMailingID=10139434&spUserID=MTMzMTc5ODE3NDQwS0&spJobID=1062494562&spReportId=MTA2MjQ5NDU2MgS2

 

REFERENCES

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer

Freddie C. Hamdy, F.R.C.S.(Urol.), F.Med.Sci., Jenny L. Donovan, Ph.D., F.Med.Sci., J. Athene Lane, Ph.D., Malcolm Mason, M.D., F.R.C.R., Chris Metcalfe, Ph.D., Peter Holding, R.G.N., M.Sc., Michael Davis, M.Sc., Tim J. Peters, Ph.D., F.Med.Sci., Emma L. Turner, Ph.D., Richard M. Martin, Ph.D., Jon Oxley, M.D., F.R.C.Path., Mary Robinson, M.B., B.S., F.R.C.Path., John Staffurth, M.B., B.S., M.D., Eleanor Walsh, M.Sc., Prasad Bollina, M.B., B.S., F.R.C.S.(Urol.), James Catto, Ph.D., F.R.C.S.(Urol.), Andrew Doble, M.S., F.R.C.S.(Urol.), Alan Doherty, F.R.C.S.(Urol.), David Gillatt, M.S., F.R.C.S.(Urol.), Roger Kockelbergh, D.M., F.R.C.S.(Urol.), Howard Kynaston, M.D., F.R.C.S.(Urol.), Alan Paul, M.D., F.R.C.S.(Urol.), Philip Powell, M.D., F.R.C.S., Stephen Prescott, M.D., F.R.C.S.(Urol.), Derek J. Rosario, M.D., F.R.C.S.(Urol.), Edward Rowe, M.D., F.R.C.S.(Urol.), and David E. Neal, F.R.C.S., F.Med.Sci., for the ProtecT Study Group*

N Engl J Med 2016; 375:1415-1424 October 13, 2016 DOI: 10.1056/NEJMoa1606220

 

Treatment or Monitoring for Early Prostate Cancer

Anthony V. D’Amico, M.D., Ph.D.

N Engl J Med 2016; 375:1482-1483 October 13, 2016 DOI: 10.1056/NEJMe1610395

CITING ARTICLES

  1. Matthew R. Cooperberg. . (2016) Re: 10-Year Outcomes After Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. European Urology.
    CrossRef

  2. Jean-Jacques Mazeron. . (2016) Cancer de la prostate : to treat or not to treat ?. Bulletin du Cancer.
    CrossRef

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Reduction in Mortality in Breast Cancer Patients: Outcome of Drug Interactions

 Reporter: Aviva Lev-Ari, PhD, RN

Drug interactions using gene-expression data: common molecular pathways that might account for drug pairs with apparent synergistic effects, searching for drug-protein interactions in the twoXAR company’s database.
“This is a holistic look at the data — EHR, gene expression, protein targets of drugs — all in one analysis,”

Study reveals drug interactions that may reduce mortality in breast cancer patients

Stanford researchers found that certain drug combinations were associated with lower mortality rates among breast cancer patients, pointing to potential drug targets and new ways of thinking about known diseases.

DEC 9 2016

Nigam Shah

Nigam Shah

Patient health records revealed two drug combinations that may reduce mortality rates in breast cancer patients, according to a study led by researchers at the Stanford University School of Medicine.

The drugs involved were commonly used noncancer drugs that turned out to be associated with a longer average survival rate in breast cancer patients.

The study was published online Dec. 9 in the Journal of the American Medical Informatics Association. The lead author is Stanford postdoctoral scholar Yen Low, PhD. The senior author is Nigam Shah, MBBS, PhD, associate professor of medicine and of biomedical data science.

“So we ran the analysis, and we found a few drug combinations that seemed to associate with better survival,” said Shah.

‘How do we know it’s true?’

Specifically, there were three pairs of drug types. The two combinations in Red are impplicated with improved survivability.

  • anti-inflammatory drugs, such as aspirin or naproxen, and blood-lipid modifiers, such as statins;
  • lipid modifiers and drugs such as fluticasone used to treat asthma like conditions; and
  • anti-inflammatories and anti cancer hormone antagonists — typically, drugs that suppress the synthesis of estrogen.

SOURCE

http://med.stanford.edu/news/all-news/2016/12/study-reveals-drug-interactions-that-may-reduce-mortality.html

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The Parker Institute in SF – A Collaboration of 6 centers, over 40 labs, and over 300 of the nation’s top researchers, all working together to cure Cancer

Reporter: Aviva Lev-Ari, PhD, RN

 

The Parker Institute an unprecedented collaboration between the country’s leading immunologists and cancer centers:  Memorial Sloan Kettering Cancer Center, Stanford University, University of California, Los Angeles, University of California, San Francisco, the University of Pennsylvania, and the University of Texas MD Anderson Cancer Center

Our network brings together the world’s best. We are 6 centers, over 40 labs, and over 300 of the nation’s top researchers, all working together to cure cancer.

Stanford Cancer Institute funding opportunity webpage: http://med.stanford.edu/cancer/research/funding.html

More information about the Parker Institute for Cancer Immunotherapy can be found at: http://www.parkerici.org

Memorial Sloan Kettering Cancer Center: A world-renowned center for cancer treatment and research, pioneering immunotherapy research since the 19th century.

Stanford Medicine: A world class leader in research and information technologies empowering the development of the next generation of immunotherapies.

University of California, Los Angeles: Renowned for cancer research treatment & prevention.

University of California, San Francisco: A basic-research powerhouse – the genetic drivers of cancer were discovered here – and home to one of the world’s top medical centers.

University of Pennsylvania: One of America’s foremost academic medical centers, and the world leader in T cell-based cancer immunotherapy.

The University of Texas MD Anderson Cancer Center:One of the world’s most respected cancer centers, instrumental in the development of cancer immunotherapy based on checkpoints, blockades.

SOURCE

http://www.parkerici.org/institute/overview

Parker Institute for Cancer Immunotherapy and Cancer Research Institute Launch Collaboration on Cancer Neoantigens

Researchers at 30 organizations to test algorithms that predict tumor markers from DNA in hunt for new personalized cancer treatments

Parker Institute and CRI Launch a Neoantigen Alliance

 

SAN FRANCISCO AND NEW YORK – Dec. 1, 2016 – The Parker Institute for Cancer Immunotherapy and the Cancer Research Institute (CRI) today announced a major collaboration focused on neoantigens. The search for these unique cancer markers has become a robust area of research as scientists believe they may hold the key to developing a new generation of personalized, targeted cancer immunotherapies.

This new collaboration, the Tumor neoantigEn SeLection Alliance (TESLA), includes 30 of the world’s leading cancer neoantigen research groups from both academia and industry. Because these tumor markers are both specific to each individual and unlikely to be present on normal healthy cells, neoantigens represent an optimal target for the immune system and make possible a new class of highly personalized vaccines with the potential for significant efficacy with reduced side effects.

“Bringing together the world’s best neoantigen research organizations to accelerate the discovery of personalized cancer immunotherapies is exactly the type of bold research collaboration that I envisioned when launching the Parker Institute,” said Sean Parker, Silicon Valley entrepreneur and founder of the Parker Institute for Cancer Immunotherapy. “This alliance will not only leverage the immense talents of each of the researchers but will also harness the power of bioinformatics, which I believe will be critical to driving breakthroughs.”

The goal of the initiative is to help participating groups test and continually improve the mathematical algorithms they use to analyze tumor DNA and RNA sequences in order to predict the neoantigens that are likely to be present on each patient’s cancer and most visible to the immune system. In support of this, Parker Institute and CRI have partnered with renowned open science nonprofit, Sage Bionetworks, to manage the bioinformatics and data analysis.

Initially, the project is expected to focus on cancers such as advanced melanoma, colorectal cancer and non-small cell lung cancer that tend to have larger numbers of mutations and thus more neoantigens. Over time, the initiative will seek to broaden the relevance of neoantigen vaccines to a wide range of cancers.

Participants come from universities, biotech, the pharmaceutical industry and scientific nonprofits. The researchers represent a wide swath of scientific fields, including immunology, data science, genomics, molecular biology, and physics and engineering.

“This project embodies the spirit of collaboration and partnership between academia, industry and nonprofits that the Parker Institute strives to foster,” said Jeffrey Bluestone, Ph.D., president and CEO of the Parker Institute for Cancer Immunotherapy. “It is a great example of how we are breaking down traditional barriers to conduct groundbreaking, multidisciplinary science to get cancer treatments to patients faster.”

“The Cancer Research Institute and the Parker Institute share a belief that the immune system is a platform technology that can be harnessed to turn all cancers into a curable disease,” said Adam Kolom, Parker Institute vice president of business development and strategic partnerships and CRI’s Clinical Accelerator program director. “We believe that by bringing together the top laboratories in the world that are developing neoantigen prediction software, we will be able to unlock the promise of this next generation of personalized cancer immunotherapies sooner.”

This marks the first major collaboration between the San Francisco-based Parker Institute for Cancer Immunotherapy, launched in April 2016, and the Cancer Research Institute, founded in 1953 in New York City.

“We’re proud to join the Parker Institute in this collaboration, which demonstrates the vital role that nonprofits can play in bringing together stakeholders from across sectors to work alongside one another to advance the field of cancer immunotherapy,” said Jill O’Donnell-Tormey, Ph.D., Cancer Research Institute CEO and director of scientific affairs.

Participating researchers said they looked forward to working collaboratively through the alliance to solve one of immunotherapy’s most complex problems.

“This experiment is truly remarkable because of its potential to help us more precisely identify abnormal proteins in an individual’s tumor that can be used as targets for personalized cancer immunotherapy,” said professor Robert D. Schreiber, Ph.D., director of the Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs at Washington University School of Medicine in St. Louis. “We believe that this type of precision medicine, used alone or with other forms of immunotherapy, will significantly improve our capacity to treat cancer patients more effectively and with fewer side effects than current treatments.”

About Neoantigens

Neoantigens are markers present on the surface of cancer cells but absent on normal tissue, making them attractive drug target candidates. They commonly arise from mutations that occur as tumor cells rapidly divide and multiply. The immune system can recognize these markers as “foreign,” and as a result, target the cancer cell for destruction. In order to predict which neoantigens will be present on a patient’s tumor, researchers have developed software programs to analyze tumor DNA and output the unique set of markers that the immune system is most likely to recognize.

What the Alliance Will Do

Participating research groups will receive genetic sequences from both normal and cancerous tissues. Using each laboratory’s own algorithms, each group will output a set of predicted neoantigens that are anticipated to be present on the tumor cells and recognizable by the immune system. The predictions will then be validated through a series of tests to assess which predictions are most likely to be correct and recognizable by T-cells. Through this effort, each participant will be provided with data to inform and to further improve their algorithms and therefore the potential effectiveness of personalized neoantigen vaccines for cancer.

Participating Organizations

Currently, the research institutions taking part include the Broad Institute of MIT and Harvard, Caltech, the Dana-Farber Cancer Institute, the La Jolla Institute for Allergy and Immunology, the Ludwig Institute for Cancer Research, Roswell Park Cancer Institute, The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, the University of California, Santa Cruz, The Carole and Ray Neag Comprehensive Cancer Center at UConn Health and Washington University School of Medicine. Internationally, scientists from the Fondazione Network Italiano per la Bioterapia dei Tumori, National Cancer Centre Singapore, the National Center for Tumor Diseases at Heidelberg University Hospital and the Netherlands Cancer Institute have also stepped forward to join the project.

Participants from industry include Advaxis; Agenus; Amgen; BioNTech; Bristol-Myers Squibb; Genentech, a member of the Roche Group; ISA Pharmaceuticals; MedImmune, the global biologics research and development arm of AstraZeneca; Neon Therapeutics and Personalis, Inc.

The six academic research centers that make up the core of the Parker Institute are also expected to participate, including: Memorial Sloan Kettering Cancer Center, Stanford Medicine, the University of California, Los Angeles (UCLA), the University of California, San Francisco, the University of Pennsylvania and The University of Texas MDAnderson Cancer Center. Initial tissue samples are expected to be provided by Memorial Sloan Kettering Cancer Center, National Cancer Centre Singapore, Roswell Park Cancer Institute, UCLA, the University Hospital of Siena in Italy and the John Theurer Cancer Center at Hackensack University Medical Center, a member of Hackensack Meridian Health. As the project progresses, the alliance will add to its growing roster of participants.

About the Parker Institute for Cancer Immunotherapy

The Parker Institute for Cancer Immunotherapy brings together the best scientists, clinicians, and industry partners to build a smarter and more coordinated cancer immunotherapy research effort.

The Parker Institute is an unprecedented collaboration between the country’s leading immunologists and cancer centers: Memorial Sloan Kettering Cancer Center, Stanford Medicine, the University of California, Los Angeles, the University of California, San Francisco, the University of Pennsylvania and The University of Texas MD Anderson Cancer Center. The Parker Institute was created through a $250 million grant from The Parker Foundation.

The Parker Institute’s goal is to accelerate the development of breakthrough immune therapies capable of turning cancer into a curable disease by ensuring the coordination and collaboration of the field’s top researchers, and quickly turning their findings into patient treatments. The Parker Institute network brings together six centers, more than 40 industry and nonprofit partners, more than 63 labs and more than 300 of the nation’s top researchers focused on treating the deadliest cancers.

About the Cancer Research Institute

The Cancer Research Institute (CRI), established in 1953, is the world’s leading nonprofit organization dedicated exclusively to transforming cancer patient care by advancing scientific efforts to develop new and effective immune system-based strategies to prevent, diagnose, treat, and eventually cure all cancers. Guided by a world-renowned Scientific Advisory Council that includes three Nobel laureates and 26 members of the National Academy of Sciences, CRI has invested $336 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities, and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment. To learn more, go to cancerresearch.org.

Contact Information:

Shirley Dang
Science Communications Manager
Parker Institute for Cancer Immunotherapy
sdang@parkerici.org
415-930-4385

Brian Brewer
Director of Marketing and Communications
Cancer Research Institute
bbrewer@cancerresearch.org
212-688-7515 x242

SOURCE

http://www.parkerici.org/media/2016/parker-institute-for-cancer-immunotherapy-cri-neoantigen-alliance

 

Parker Institute for Cancer Immunotherapy (PICI) @ Stanford Medicine Bedside to Bench Grant Program Call for Proposals 

The Parker Institute for Cancer Immunotherapy (PICI) @ Stanford Medicine Bedside to Bench Grant Program supports early stage projects that will enhance interdisciplinary basic and translational research among the Stanford scientific community in Cancer Immunotherapy.

The PICI Bedside to Bench Grant will support collaborations between basic scientists and clinical researchers that lead to fundamental discoveries and advance the field of cancer immunotherapy. These awards are targeted to faculty with early-stage, high-risk ideas that would not be funded by traditional sources.  We are particularly interested in the following areas of study:  

  • T-Cell Therapies,
  • Checkpoint Non-Responders,
  • Antigen Discovery and
  • the Tumor Microenvironment.

All proposals must involve at least one basic science and one clinical investigator.    We encourage applications from scientists across a broad array of disciplines whose combined perspectives will help to accelerate the pace of discovery.

We are particularly interested in proposals that seek to identify correlative biomarkers of response to immunotherapy or that will enable discovery of new targets or pathways that could be leveraged for therapeutic gain using immune based therapies.

SOURCE

http://www.parkerici.org

 

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p53 mutation – Li-Fraumeni Syndrome – Likelihood of Genetic or Hereditary conditions playing a role in Intergenerational incidence of Cancer

 

Reporter: Aviva Lev-Ari, PhD, RN

 

THIS ARTICLE IS RECOMMENDED READING TO ALL OUR e-Readers

because it is a REAL story of a high school student fighting Brain Cancer, glioblastoma multiforme (GBM)

it presents the FRONTIER OF GENOMICS, PRECISION MEDICINE, Interventional Radiology and Interventional ONCOLOGY at

Stanford University, Canary Center at Stanford for Early Cancer Detection, Stanford Medical Center and Lucile Packard Children’s Hospital

I was exposed to Li-Fraumeni Syndrome in the following article:

‘And yet, you try’ – A father’s quest to save his son

http://stanmed.stanford.edu/2016fall/milan-gambhirs-li-fraumeni-syndrome.html

 

Li-Fraumeni syndrome

Other Names for This Condition

  • LFS
  • Sarcoma family syndrome of Li and Fraumeni
  • Sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome
  • SBLA syndrome

LFS is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.

The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called

Soft tissue sarcoma forms in soft tissues of the body, including muscle, tendons, fat, blood vessels, lymph vessels, nerves, and tissue around joints.


(small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.

A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.

Genetic Changes

The CHEK2 and TP53 genes are associated with Li-Fraumeni syndrome.

More than half of all families with Li-Fraumeni syndrome have inherited mutations in the gene. TP53 is a tumor suppressor gene, which means that it normally helps control the growth and division of cells. Mutations in this gene can allow cells to divide in an uncontrolled way and form tumors. Other genetic and environmental factors are also likely to affect the risk of cancer in people with TP53 mutations.

A few families with cancers characteristic of Li-Fraumeni syndrome and Li-Fraumeni-like syndrome do not have TP53 mutations, but have mutations in the CHEK2 gene. Like the TP53 gene, CHEK2 is a tumor suppressor gene. Researchers are uncertain whether CHEK2 mutations actually cause these conditions or are merely associated with an increased risk of certain cancers (including breast cancer).

Inheritance Pattern

Li-Fraumeni syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing cancer. In most cases, an affected person has a parent and other family members with cancers characteristic of the condition.

Diagnosis and Management

These resources address the diagnosis or management of Li-Fraumeni syndrome:

References on LFS

SOURCE

https://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome

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Meeting report: Cambridge Healthtech Institute’s 4th Annual Immuno-Oncology SUMMIT: Oncolytic Virus Immunotherapy Stream – 2016

Reporter: David Orchard-Webb, PhD

 

Cambridge Healthtech Institute’s 4th Annual Immuno-Oncology SUMMIT took place August 29-September 2, 2016 at the Marriott Long Wharf Boston, MA. The following is a synthesis of the Oncolytic Virus Immunotherapy stream.

 

Biomarkers

 

Biomarkers for patient selection in clinical trials is an important consideration for developing cancer therapeutics and immunotherapeutics such as oncolytic viruses in particular. Howard L. Kaufman, M.D., discussed the development of biomarkers for oncolytic virus efficaciousness and patient selection focusing on Imlygic (HSV-1). An important consideration for any viral therapy is the presence or absence of the receptors that the virus uses to gain entry to the cell. For example HSV-1 utilises Nectin and HVEM cell surface receptors and their expression levels on a patient’s tumour will influence whether Imlygic can gain entry and replicate in tumours. In addition he reported that B-RAF mutation facilitates Imlygic infection and that MEK inhibitors sensitise melanoma cell lines to Imlygic. Stephen Russell also presented data on the mathematical modelling of Vesicular Stomatitis Virus (VSV) tumour spread and the development of a companion diagnostic based on gene expression profiling to predict patients whose tumours will be readily infected.

 

The immune reaction triggered by oncolytic viruses is important to monitor. Howard L. Kaufman discussed immunogenic cell death and stated that oncolytic viruses trigger immunity through the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). He reported that immunosuppressive Tregs, PDL1 and IDO expression were associated with anti-cancer CD8+ T cell infiltration. Imlygic also promoted the tumour infiltration of monocytes which depending on the context may either be immunosuppressive or beneficial through recruiting natural killer (NK) cells. This highlights the importance of combining Imlygic with other immune modulating therapeutics that can modulate the immunosuppressive cells and messengers that are present in the tumour environment. He discussed the finding that high mutation burden is a marker for response to immune checkpoint inhibition (such as CTLA and PD1) and suggested that due to the fact that oncolytic viruses release tumour associated antigens (TAA) during cell lysis this may also be a predictive marker for oncolytic viral therapy immune response. Supporting this notion Stephen Russell reported that a patient that underwent complete remission of multiple myeloma plasmacytomas in response to a measles virus oncotherapy had a very high mutational burden.

 

Targeting the tumour stroma with adenoviral vectors

 

VCN Biosciences SL is a privately-owned company focused in the development of new therapeutic approaches for tumors that lack effective treatment”. Manel Cascalló presented data from an ongoing phase I, multi-center, open-label dose escalation study of intravenous administration of VCN-01 oncolytic adenovirus with or without intravenous gemcitabine and Abraxane® in advanced solid tumors. Patients were selected based on low anti-Ad levels. Manel highlighted the problems of the pancreatic cancer matrix which limit intratumoral virus spread and also reduces chemotherapy uptake and tumour lymphocyte infiltration. VCN-01 expresses hyaluronidase to degrade the extracellular matrix and is administered intravenously. Liver tropism is reduced by replacement of the heparan sulfate glycosaminoglycan putative-binding site KKTK of the fiber shaft with an integrin-binding motif RGDK. VCN-01 replicates only in Rb tumour suppressor pathway dysregulated cancers, achieved through genetic modification of the E1A protein. In previous mouse xenograft studies of pancreatic and melanoma tumours VCN-01 showed efficaciousness in intratumoral spread, degradation of hyaluronan, and evidence of sensitisation to chemotherapy. The mouse models suggested that strategies that further target other major components of the ECM such as collagen and stromal cells may increase VCN-01 efficaciousness further [1]. The phase I trial supported safety and demonstrated that when administered intravenously VCN-01 reached the pancreatic tumour and replicated. In combination with gemcitabine and Abraxane® neutropenia was observed earlier than with chemotherapy alone. This is suggestive of increased efficaciousness of the chemotherapeutics as would be expected if a greater effective concentration reached the tumour. Biopsies suggested that VCN-01 shifted the balance of immune cells towards CD8+ T cells and away from immunosuppressive Treg.

 

Adenovirus tumor-specific immunogene (T-SIGn) Therapy

 

PsiOxus Therapeutics Ltd develops novel therapeutics for serious diseases with a particular focus upon cancer”. Brian Champion discussed the application EnAd a chimeric Ad11p/Ad3 adenovirus which retains the Ad11 receptor usage (CD46 and DSG2). PsiOxus are developing Membrane-integrated T-cell Engagers (MiTe) proteins delivered via EnAd. These MiTe proteins are expressed at the cancer cell surface and engage with and activate T-cells. Their lead candidate NG-348 showed promising T-cell activation in vitro.

 

Vaccinia virus – overcoming the immunosuppressive cancer microenvironment

 

David Kirn provided a recent history of the oncolytic virus field and provided an overview of the validation of vaccinia virus over the period 2007-14 stating that it can produce cancer oncolysis, induce an immune response, and result in angiogenic ablation.

 

Western Oncolytics develops novel therapies for cancer”. Steve Thorne discussed strategies to mitigate the immunosupressive environment encountered by oncolytic viruses. He presented data from models of tumours resistant to vaccinia oncolytic virus that Treg, and myeloid-derived suppressor cell (MDSC) numbers were higher whereas CD8+ T-cell levels were lower than in a sensitive model. He elaborated on a strategy of targeting the PGE2 pathway in order to reduce MDSC numbers entering the tumour microenvironment. He demonstrated that vaccinia virus expressing HPGD has reduced levels of MDSC in target tumours.

 

Transgene (Euronext: TNG), part of Institut Mérieux, is a publicly traded French biopharmaceutical company focused on discovering and developing targeted immunotherapies for the treatment of cancer and infectious diseases”. Eric Quéméneur presented preclinical data on Transgene’s oncolytic vaccinia virus TG6002 which expresses a chimeric bifunctional enzyme which converts the nontoxic prodrug 5‐FC into the toxic metabolites 5‐FU and 5‐FUMP. This allows systemic delivery of the non-toxic prodrug chemotherapy with activation at tumours infected with the Vaccinia oncolytic virus. The virus plus prodrug combination was effective against all of the solid tumour cell lines tested. In addition the combination was effective against glioblastoma cancer stem-like cells. In pancreatic and colorectal cancer cell line models the vaccinia prodrug combination was synergistic or additive when combined with additional chemotherapeutics. In immunocompetent mouse models TG6002 increased the Tumour Teff/Treg ratio indicative of a shift from an immunosuppressive to an immunocompetent microenvironment. Furthermore in mouse models TG6002 induced an abscopal response.

 

Vesicular Stomatitis Virus (VSV) – A single shot cure for cancer?

 

Vyriad strives to develop potent, safe and cost-effective cancer therapies in areas of unmet need”. Stephen Russell presented his position that oncolytic viruses could be a single shot cure for cancer. He emphasised the point that in oncolytic viral therapy the initial dose will be the most effective due to the relatively low levels of neutralising antibodies present and therefore defining the optimal dose is critical. The trend is for increased initial dose. Two IND’s have been accepted by the FDA, one for measles virus and the other for VSV.

 

John Bell described using VSV to deliver Artificial microRNAs (amiRNAs) to tumours. It was demonstrate that a VSV delivering ARID1A amiRNA was synthetic lethal when combined with EZH2 (methyl transferase) inhibition. He postulated that oncolytic viruses can be used to create factories of therapeutic amiRNAs transmitted throughout the tumour by exosomes.

 

HSV-1 an update on immune checkpoint combinations

 

Amgen was the first company to launch an FDA approved (October 2015) oncolytic virus, trade name Imlygic, which was developed by the UK based company Biovex. Jennifer Gansert gave a background on Imlygic and presented new data on combination with the CTLA4 inhibitor Ipilimumab. In mouse models abscopal response in contralateral tumours was 100% when a single tumour was treated with Imlygic combined with systemic delivery of anti-CTLA4. A Phase 1b clinical trial to test the combination in unresectable melanoma patients was completed and published in 2016. Fifty percent of the patients had durable response for greater than 6 months and 20% of the patients had ongoing complete response after a year of follow-up. Overall 72% of patients has controlled disease (no progression). In addition Amgen is recruiting for a phase III trial of the anti-PD1 Pembrolizumab in combination with Imlygic for unresectable stage IIIB to IVM1c melanoma.

 

Virttu is a privately held biotechnology company, which has pioneered the development of oncolytic viruses for treating cancer”. Joe Connor discussed Seprehvir an oncolyic virus based on HSV-1 like Imlygic which is in clinical trials for which 100 patients have been treated to date. The trial data indicate that Seprehvir induces CD8+ T cell infiltration and activity as well as a novel anti-tumour immune response against select antigens such as Mage A8/9. Preclinical investigations focus on combination with checkpoint inhibitor antibodies, CAR-T targeted to GD2, and synergies with targeted therapies on the mTOR/VEGFR signalling axes.

 

Reovirus – an update

 

Oncolytics Biotech Inc. is a clinical-stage oncology company focused on the development of oncolytic viruses for use as cancer therapeutics in some of the most prevalent forms of the disease”. Brad Thompson provided an update on REOLYSIN®, Oncolytics Biotech’s proprietary T3D reovirus. Highlights included concluding the first checkpoint inhibitor and REOLYSIN® study in patients with pancreatic cancer and preparing for registration study in multiple myeloma.

 

Maraba virus – privileged antigen presentation in splenic B cell follicles

 

Turnstone Biologics is developing “a first-in-class oncolytic viral immunotherapy that combines a bioselected and engineered oncolytic virus to directly lyse tumors with a potent vaccine technology to drive tumor-antigen specific T-cell responses of unprecedented magnitude”. Caroline Breitbach described Maraba MG1 Oncolytic Virus which was isolated from Brazilian sand flies. Their lead candidate is an MG1 virus expressing the tumour antigen MAGE-A3. In mouse models a combination of adenovirus-MAGE-A3 and MG1-MAGE-A3 in a prime-boost regimen produced extremely robust CD8+ T cell responses. It is thought that a privileged antigen presentation in splenic B cell follicles maximizes the T cell responses. A phase I/II trial is enrolling patients to test the adenovirus-MAGE-A3 and MG1-MAGE-A3 prime-boost regimen in patients with MAGE‐A3 positive solid tumours for which there is no life prolonging standard therapy.

 

Oncolytic virus manufacturing

 

Anthony Davies of Dark Horse Consulting Inc. reviewed the manufacturing hurdles facing oncolytic viruses and pointed out that thus far adenovirus is the gold standard. He discussed isoelectric focusing for virus manufacturing, process flow and the procurement of key raw materials. He emphasized the importance of codifying analytical methods, and the statistical design of experiments (DOE) for optimal use of finite resources.

 

Mark Federspiel described the difficulties associated with measles virus manufacturing which include the large pleomorphic size (100-300nm) which cannot be filter sterilized efficiently due to shear stress. As a result aseptic conditions must be maintained throughout the manufacturing process. There are also issues with genomic contamination from infected cells. He described improved manufacturing bioprocesses to overcome these limitations using the HeLa S3 cell line. Using this cell line resulted in less residual genomic DNA than the standard however it was still relatively high compared to vaccine production. There is still much room for improvement.

 

REFERENCES
Rodríguez-García A, Giménez-Alejandre M, Rojas JJ, Moreno R, Bazan-Peregrino M, Cascalló M, Alemany R. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res. 2015 Mar 15;21(6):1406-18. Doi: 10.1158/1078-0432.CCR-14-2213. Epub 2014 Nov 12. PubMed PMID: 25391696.

 

Other Related Articles Published In This Open Access Online Journal Include The Following:

https://pharmaceuticalintelligence.com/2016/07/15/agenda-for-oncolytic-virus-immunotherapy-unlocking-oncolytic-virotherapies-from-science-to-commercialization-chis-4th-annual-immuno-oncology-summit-august-29-30-2016-marriott-lo/

Real Time Coverage and eProceedings of Presentations on August 29 and August 30, 2016 CHI’s 4th IMMUNO-ONCOLOGY SUMMIT – Oncolytic Virus Immunotherapy Track

https://pharmaceuticalintelligence.com/2016/09/01/real-time-coverage-and-eproceedings-of-presentations-on-august-29-and-august-30-2016-chis-4th-immuno-oncology-summit-oncolytic-virus-immunotherapy-track/

LIVE Tweets via @pharma_BI and by @AVIVA1950 for August 29 and August 30, 2016 of CHI’s 4th IMMUNO-ONCOLOGY SUMMIT – Oncolytic Virus Immunotherapy Track, Marriott Long Wharf Hotel – Boston

https://pharmaceuticalintelligence.com/2016/09/01/live-tweets-via-pharma_bi-and-by-aviva1950-for-august-29-and-august-30-2016-of-chis-4th-immuno-oncology-summit-oncolytic-virus-immunotherapy-track-marriott-long-wharf-hotel/

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