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Archive for the ‘Genome Biology’ 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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Four patents and one patent application on Nanopore Sequencing and methods of trapping a molecule in a nanopore assigned to Genia, is been claimed in a Law Suit by The Regents of the University of California, should be assigned to UCSC

Reporter: Aviva Lev-Ari, PhD, RN

 

The university claims that while at UCSC Roger Chen’s research focused on nanopore sequencing, and that he along with others developed technology that became the basis of patent applications filed by the university. However, when Chen left the university in 2008 and cofounded Genia, he was awarded patents for technology developed while he was at UCSC, but those patents were assigned to Genia and not the university, according to the suit.

In the suit, the university notes four patents and one patent application assigned to Genia that it claims should be assigned to UCSC: US Patent Nos., 8,324,914; 8,461,854; 9,041,420; and 9,377,437; and US Patent Application 15/079,322. The patents and patent applications all relate to nanopore sequencing and specifically to methods of trapping a molecule in a nanopore and characterizing it based on the electrical stimulus required to move the molecule through the pore.

Genia was founded in 2009, and in 2014, Roche acquired the startup for $125 million in cash and up to $225 million in milestone payments. Earlier this year, the company published a proof-of-principle study of its technology in the Proceedings of the National Academy of Sciences.

Roche’s head of sequencing solutions, Neil Gunn, said that Roche would announce a commercialization timeline in 2017.

It’s unclear how the lawsuit will impact that commercialization, but Mick Watson, director of ARK-Genomics at the Roslin Institute in the UK, speculated in a blog post that if the suit is decided in favor of UCSC, it could result in a very large settlement and potentially even the end of Genia.

 

SOURCE

https://www.genomeweb.com/sequencing/university-california-files-suit-against-genia-cofounder

http://www.opiniomics.org/university-of-california-makes-legal-move-against-roger-chen-and-genia/

 

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Dr. Doudna: RNA synthesis capabilities of Synthego’s team represent a significant leap forward for Synthetic Biology

Reporter: Aviva Lev-Ari, PhD, RN

 

Synthego Raises $41 Million From Investors, Including a Top Biochemist

Synthego also drew in Dr. Doudna, who had crossed paths with the company’s head of synthetic biology at various industry conferences. According to Mr. Dabrowski, the money from her trust represents the single-biggest check from a non-institutional investor that the start-up has raised.

Synthego’s new funds will help the company take its products to a more global customer base, as well as broaden its offerings. The longer-term goal, Mr. Dabrowski said, is to help fully automate biotech research and take care of much of the laboratory work that scientists currently handle themselves.

The model is cloud technology, where companies rent out powerful remote server farms to handle their computing needs rather than rely on their own hardware.

“We’ll be able to do their full research workflow,” he said. “If you look at how cloud computing developed, it used to be that every company handled their server farm. Now it’s all handled in the cloud.”

SOURCE

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

UPDATED – Status “Interference — Initial memorandum” – CRISPR/Cas9 – The Biotech Patent Fight of the Century: UC, Berkeley and Broad Institute @MIT

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/06/status-interference-initial-memorandum-crisprcas9-the-biotech-patent-fight-of-the-century/

 

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SBI’s Exosome Research Technologies

Reporter: Aviva Lev-Ari, PhD, RN

Welcome to the Fascinating World of Exosomes and Microvesicles

Just learning about exosomes?

The team at SBI has put together this brief overview to help get you started in the growing field of exosome research.

 

Why are exosomes important?

Once thought to be little more than a way for cells to offload waste, the past decade has seen a huge shift in the way we think about exosomes. We’ve begun to recognize that exosomes are deliberately released from the cell, functioning as signal carriers and tissue reshapers through their cargo of RNA, proteins, lipids, and DNA. Involved in a wide range of healthy and pathogenic processes such as cancer, inflammation, immunity, CNS function, cardiac cell function, to name a few – exosomes are being studied for their role in these basic biological processes as well as for their use as biomarkers (see Applications) and even as tools for targeted delivery of biomolecules such as therapeutics (see Engineering).

What are exosomes?

Exosomes are 60 – 180 nm membrane vesicles secreted by most cell types in vivo and in vitro. These extracellular vesicles are endocytic in origin, produced by the inward budding of multivesicular bodies (MVBs). They are released from the cell into the microenvironment following fusion of MVBs with the plasma membrane.

What aren’t exosomes?

Exosomes are not the only small, membrane-bound extracellular vesicle that can be found. They are distinct in origin from apoptotic blebs or apoptotic bodies, which are 50 nm to 5 um in size, carry DNA, RNA, and histones, and display surface markers targeting them for clearance by macrophages. And they are also different from microparticles (also known as microvesicles, ectosomes, shedding vesicles, microparticles, plasma membrane-derived vesicles, and exovesicles), which can range from 50-1000 nm in size and are derived directly from the plasma membrane rather than endocytic bodies within the cell.8 These distinctions and labeling conventions are not always used consistently in the literature and between different groups, leading to some ambiguity in the literature. When isolating exosomes, it’s important to remember that these other types of vesicles may also be present and interpret results accordingly.

What else are exosomes called?

Adding to the confusion, exosomes are sometimes referred to by the source of the sample material. For example, dendritic cell exosomes are also called dexosomes, and cancer cell exosomes may be called oncosomes. Researchers are starting to move towards more standardized nomenclature, but those searching through older literature should be aware of other names for exosomes.

Where are exosomes normally found?

Exosomes have been found in blood, urine, amniotic fluid, breast milk, malignant ascites fluids, and seminal fluid. They contain distinct subsets of molecules depending upon the cell type from which they are secreted, making them useful for biomarker discovery.

How do I study exosomes?

SBI is the only vendor to offer reagents and kits that support all apsects of exosome research-covering isolation, detection and measurement, discovery (characterization and analysis), and even exosome engineering. With a comprehensive set of tools and services to accelerate the study of exosomes and exosome RNA biomarkers, SBI puts the power of exosomes into researchers’ hands.

SBI’s Exosome Research Technologies

ISOLATION

DETECTION

DISCOVERY

ENGINEERING

ExoQuick

Exosome FACS

Purified exosomes

Package miRNAs into exosomes

Exosome FACS and IP

Antibodies and ELISAs

RNA-Seq NGS kit

Transfect exosomes

Exosome depleted FBS

EXOCET assay

Mass Spec library kit

Engineer Exosome Protein Cargo

Label exosome cargo

miRNA qPCR kits

 

SOURCE

https://www.systembio.com/exosome-knowledge

https://www.systembio.com/products

https://www.systembio.com/services

 

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Evaluating the Genetic Profiles of Tumor Cells circulating in the Bloodstream could transform Cancer Care: A Blood Test for managing Lung Cancer @Stanford University Medical School

Reporter: Aviva Lev-Ari, PhD, RN

 

A Legacy of Innovation @Stanford University Medical School

  1. 1967

    First synthesis of biologically active DNA in test tube

  2. 1968

    First adult human heart transplant in the United States

    Norman Shumway successfully transplants a heart into 54-year-old steelworker Mike Kasperak, who survives for 14 days.

     

  3. 1973

    First expression of a foreign gene implanted in bacteria by recombinant DNA methods

  4. 1981

    First successful human combined heart/lung transplant in the world (fourth attempted worldwide)

  5. 1984

    Isolation of a gene coding for part of the T-cell receptor, a key to the immune system’s function

  6. 1988

    Isolation of pure hematopoietic stem cells from mice

  7. 2002

    First use of gene expression profiling to predict cancer outcomes

  8. 2007

    Application and expansion of optogenetics, a technique to control brain cell activity with light

SOURCE

Evaluating the Genetic Profiles of Tumor Cells circulating in the Bloodstream could transform Cancer Care: A Blood Test for managing Lung Cancer @Stanford University Medical School

The approach that the team developed could be used to look at mutations in three or four genes, and it requires no more than 2 milliliters of blood — about half a teaspoon. The test can be completed in about five hours, the researcher said, and costs less than $30. For comparison, a single state-of-the art biopsy of lung tissue with DNA sequencing costs about $18,000 and takes as long as three weeks to furnish results. Johnson & Johnson’s CellSearch — another blood test, already approved by the FDA — costs about $900 and takes a week to deliver results.

The researchers created a system for isolating circulating tumor cells from the blood of cancer patients and reading a handful of genes from inside each tumor cell. Thus, they were able to obtain genetic information about the original cancer tumor that resides deep in the lungs without doing a biopsy, which can be dangerous for the patient.

“We are trying to make minimally invasive technology that allows us to continuously monitor one person’s health over time,” said radiology instructor Seung-min Park, PhD, a lead author of the new study, which was published online Dec. 12 in the Proceedings of the National Academy of Sciences. Park shares lead authorship of the study with former Stanford graduate students Dawson Wong, PhD, and Chin Chun Ooi.

A MagSifter chip, shown here fastened to an acrylic holder, can purify circulating tumor cells from the blood of cancer patients.

The MagSifter is an electromagnetic sieve that can be turned on and off. When the MagSifter is on, it pulls the nanoparticle-labeled CTCs from the blood sample and allows the rest of the blood to flow through the sifter. The CTCs pulled from the blood are then deposited into a flat array of tiny wells, each large enough for only one cell. Now the tumor cells are ready for genetic analysis. Each flat of 25,600 wells looks like a miniature muffin tin, with room for a lot of tiny muffins.

SOURCE

http://med.stanford.edu/news/all-news/2016/12/blood-test-could-provide-cheaper-way-to-evaluate-lung-tumors.html

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Translation of whole human genome sequencing to clinical practice: The Joint Initiative for Metrology in Biology (JIMB) is a collaboration between the National Institute of Standards & Technology (NIST) and Stanford University.

Reporter: Aviva Lev-Ari, PhD, RN

 

JIMB’s mission is to advance the science of measuring biology (biometrology). JIMB is pursuing fundamental research, standards development, and the translation of products that support confidence in biological measurements and reliable reuse of materials and results. JIMB is particularly focused on measurements and technologies that impact, are related to, or enabled by ongoing advances in and associated with the reading and writing of DNA.

Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.

Genome in a Bottle
Authoritative Characterization of
Benchmark Human Genomes


The Genome in a Bottle Consortium is a public-private-academic consortium hosted by NIST to develop the technical infrastructure (reference standards, reference methods, and reference data) to enable translation of whole human genome sequencing to clinical practice. The priority of GIAB is authoritative characterization of human genomes for use in analytical validation and technology development, optimization, and demonstration. In 2015, NIST released the pilot genome Reference Material 8398, which is genomic DNA (NA12878) derived from a large batch of the Coriell cell line GM12878, characterized for high-confidence SNPs, indel, and homozygous reference regions (Zook, et al., Nature Biotechnology 2014).

There are four new GIAB reference materials available.  With the addition of these new reference materials (RMs) to a growing collection of “measuring sticks” for gene sequencing, we can now provide laboratories with even more capability to accurately “map” DNA for genetic testing, medical diagnoses and future customized drug therapies. The new tools feature sequenced genes from individuals in two genetically diverse groups, Asians and Ashkenazic Jews; a father-mother-child trio set from Ashkenazic Jews; and four microbes commonly used in research. For more information click here.  To purchase them, visit:

Data and analyses are publicly available (GIAB GitHub). A description of data generated by GIAB is published here. To standardize best practices for using GIAB genomes for benchmarking, we are working with the Global Alliance for Genomics and Health Benchmarking Team (benchmarking tools).

High-confidence small variant and homozygous reference calls are available for NA12878, the Ashkenazim trio, and the Chinese son with respect to GRCh37.  Preliminary high-confidence calls with respect to GRCh38 are also available for NA12878.   The latest version of these calls is under the latest directory for each genome on the GIAB FTP.

The consortium was initiated in a set of meetings in 2011 and 2012, and the consortium holds open, public workshops in January at Stanford University in Palo Alto, CA and in August/September at NIST in Gaithersburg, MD. Slides from workshops and conferences are available online. The consortium is open and welcomes new participants.

SOURCE

Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.

JIMB World Metrology Day Symposium

JIMB’s mission is to motivate standards-based measurement innovation to facilitate translation of basic science and technology development breakthroughs in genomics and synthetic biology.

By advancing biometrology, JIMB will push the boundaries of discovery science, accelerate technology development and dissemination, and generate reusable resources.

 SOURCE

VIEW VIDEO

https://player.vimeo.com/video/184956195?wmode=opaque&api=1″,”url”:”https://vimeo.com/184956195″,”width”:640,”height”:360,”providerName”:”Vimeo”,”thumbnailUrl”:”https://i.vimeocdn.com/video/594555038_640.jpg”,”resolvedBy”:”vimeo”}” data-block-type=”32″>

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

“Genome in a Bottle”: NIST’s new metrics for Clinical Human Genome Sequencing

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/06/genome-in-a-bottle-nists-new-metrics-for-clinical-human-genome-sequencing/

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CHI’s Combination Immunotherapy Design Models, February 20-22, 2017, Moscone North Convention Center, San Francisco, CA – part of the 24th International Molecular Medicine Tri-Conference

Reporter: Aviva Lev-Ari, PhD, RN

 

Cambridge Healthtech Institute’s Fifth Annual

Combination Immunotherapy Design Models

Preclinical Approaches and Biomarkers to Bring Combination Therapies to the Clinic

February 20-22, 2017 | Moscone North Convention Center | San Francisco, CA
Part of the 24th International Molecular Medicine Tri-Conference

Despite tremendous progress in our understanding of cancer biology, the majority of novel anticancer therapies fail in clinical trials, which indicates deficiencies in conventional translational approaches. In most cases preclinical data have overpredicted clinical efficacy in oncology. With the rise of immuno-oncology the challenge of in vivo pharmacology was enhanced by the differences in mouse and human immune systems that further damages the predictiveness of preclinical data. The phenomenon of cancer heterogeneity and subsequent drug resistance add another dimension to the preclinical cancer research warranting active work on combination cancer regimens. Better models and approaches are clearly in high and urgent demand and has been worked on by industry and academia scientists. Cambridge Healthtech Institute’s Fifth Annual Translational Models in Oncology and Immuno-Oncology conference is designed to highlight cutting edge advances in in vivo, in vitro and in silico modeling and to facilitate a discussion about effective translational approaches in cancer research.

 

 

MONDAY, FEBRUARY 20

10:30 am Conference Program Registration Open

TRANSLATIONAL IMMUNO-ONCOLOGY

11:50 Chairperson’s Opening Remarks

Terri McClanahan, Ph.D., Executive Director, Molecular Discovery, Biologics, Merck Research Laboratories

12:00 pm KEYNOTE PRESENTATION: Rational Development of Combination Therapies in Immuno-Oncology

Michael Kalos, M.D., CSO, Cancer Immunobiology, Eli Lilly

Treatment of patients with combinations of agents, such as CTLA4 and PD1, has provided additional benefit to patients, along with increased toxicity, highlighting the value for developing combination therapies. In this session, we will discuss preclinical and translational strategies and approaches to support the rational development of more effective combination strategies that lead to increased clinical benefit for patients.

12:30 Biomarker Development for the Era of Combination Cancer Immunotherapy

Terri McClanahan, Ph.D., Executive Director, Molecular Discovery, Biologics, Merck Research Laboratories

Keytruda® (pembrolizumab), a PD-1-specific monoclonal antibody, is approved in the U.S. for advanced melanoma, NSCLC and SCCHN, and is being studied in >30 cancers. Efforts are now underway to extend the benefit of cancer immunotherapy to more patients through the use of anti PD-1-based combination regimens. However, significant challenges remain to identify the best combinations that provide true immune synergy, and to target the right combinations to the right patients who will experience unambiguous clinical benefit. Biomarker and translational research-driven strategies can guide the future state of the field, ultimately allowing for the development of precision medicine approaches to combination cancer immunotherapy.

1:00 Session Break

1:10 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

2:10 Session Break

TRANSLATIONAL IMMUNO-ONCOLOGY (CONT.)

2:30 Chairperson’s Remarks

Christian Gerdes, Ph.D., Head, Pharmacology, Roche Pharma Research & Early Development, Roche

2:40 Immunocompetent Mouse Models as a Tool for Cancer Immunotherapy Pipeline Advancement

Christian Gerdes, Ph.D., Head, Pharmacology, Roche Pharma Research & Early Development, Roche

As immunotherapy gains more and more traction, the need for more predictive preclinical models grows as well. It is widely recognized that immunocompetent mice are used to assess the anti-tumor efficacy of cancer immunotherapies. This presentation will discuss the uses of mouse models and how they can advance drug pipelines.

3:10 Designing and Executing Cancer Immunotherapy Clinical Trials

Pamela N. Munster, M.D., Professor, Medicine, Program Leader, Development Therapeutics, Director, Early Phase Clinical Trials Program, Helen Diller Cancer Center, University of California, San Francisco

A breakdown in immune tumor surveillance plays a crucial role in the development of metastatic cancer. Targeting the programmed death receptor (PD-1) and its ligand (PD-L1) have been major breakthroughs in certain cancers such melanoma, lung and other cancers. However, many cancers, including breast cancers, appear less responsive. We are exploring the roles of tumor lymphocyte infiltration, T cell differential, epigenetic modifiers and the co-operative involvement of other immune pathways to induce responses in immune silent tumors. Translating preclinical findings into early phase clinical studies, we will describe recent advances in how to determine safety, feasibility and efficacy of integrating immunotherapy into targeted therapy and chemotherapy.

3:40 Talimogene Laherparepvec in Combination with Checkpoint Inhibitors: From Bench to Bedside

Pedro J. Beltran, Ph.D., Research Director, Oncology Research, Amgen, Inc.

Checkpoint inhibitors and viral immunotherapy with talimogene laherparepvec have shown significant therapeutic benefit in melanoma patients when used as monotherapies. As these two forms of approved immunotherapy act mostly on different parts of the immunity cycle, studying their combination pre-clinically and clinically informs their future development. We have used 3 syngeneic murine models to study the pharmacodynamic and efficacy changes driven by the combination of talimogene laherparepvec and blockade of CTLA-4 or PD-1/PD-L1. Clinical trials testing these combinations in the clinic are currently ongoing.

4:10 Presentation to be Announced

 

4:25 Sponsored Presentation (Opportunity Available)

4:40 Refreshment Break and Transition to Plenary Session

5:00 Plenary Keynote Session

6:00 Grand Opening Reception in the Exhibit Hall with Poster Viewing

7:30 Close of Day

TUESDAY, FEBRUARY 21

7:30 am Registration Open and Morning Coffee

8:00 Plenary Keynote Session

9:00 Refreshment Break in the Exhibit Hall with Poster Viewing

TUMOR MODELS FOR CANCER IMMUNOTHERAPY

10:05 Chairperson’s Remarks

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

10:15 Mouse Models to Test Human Cancer Immuno-Therapeutics

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

Preclinical in vivo tumor models are essential to test anti-tumor activity and side-effect profiles of novel immunotherapeutics. However, antibody-based therapies often do not cross-react with the corresponding murine targets, making such tests difficult. We have utilized Regeneron’s capabilities in murine genetic engineering to develop several approaches of combining functional immune cells with preclinical tumor models. We have used these approaches for preclinical testing of both checkpoint inhibiting antibodies and T cell-engaging bispecific antibodies.

10:45 Characterization of Molecular and Cellular Properties of Murine Syngeneic Models to Aid Model Selection and Biomarker Discovery for Immune-Oncology Programs

Wenyan Zhong, Ph.D., Senior Principal Scientist, Oncology R&D Group, Pfizer

Preclinical in vivo models for most immuno-oncology (IO) programs require the use of immunocompetent mice bearing syngeneic tumors. To facilitate model selection for use in preclinical efficacy studies, we characterized a panel of mouse tumor cell lines and syngeneic tumor tissues. In this talk, we will discuss molecular and cellular properties of these models.

11:15 Case Study: Blockade of Phosphatidylserine-Mediated Tumor Immune Suppression to Enhance Immune Checkpoint Therapies

Michael Gray, Ph.D., Senior Research Scientist, Peregrine Pharmaceuticals

Phosphatidylserine (PS) exposure in tumors induces non-inflammatory signals which contribute to an immunosuppressive environment. Antibody blockade of PS activates immune responses by promoting M1 macrophages, maturation of dendritic cells and inducing adaptive T-cell responses. PS targeting antibodies enhance the anti-tumor activity of checkpoint antibodies in preclinical tumor models.

MIBioresearch11:45 Methods and Models for Preclinical Immuno-Oncology

Dylan Daniel, Ph.D., Director, Scientific Development, MI Bioresearch

MI Bioresearch has characterized an array of syngeneic immuno-oncology models to support in vivo pharmacology drug discovery. Our characterization includes comprehensive lymphoid and myeloid flow cytometry immune profiling, and model responses to checkpoint inhibitors and focal beam radiotherapy combinations.

12:00 pm Exemplar_GeneticsGenetically Engineered Miniswine Models of Cancer

John Swart, Ph.D., President, Exemplar Genetics

Current preclinical models of cancer fail to accurately recapitulate human disease and do not effectively translated to the clinic. Recently, Exemplar Genetics has developed a genetically engineered miniature swine model that contains a conditional KRAS mutation on the background of TP53-targeted pigs, the ExeGen® TP53+/R167H& KRAS+/G12D miniswine model. This model should allow for the inducement of human-like tumors in a tissue specific manner. Initial characterization of induced tumors demonstrates the transformative nature of this model.

12:30 Session Break

 Mitra Biotech12:35 Luncheon Presentation to be Announced

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing

ADVANCING TRANSLATION WITH NOVEL APPROACHES AND INDUSTRY-ACADEMIA PARTNERSHIPS

2:00 Chairperson’s Remarks

Lawrence B. Schook, Ph.D., Gutsgell Professor, Animal Sciences and Radiology, University of Illinois

2:10 Collaboration for Translation: Academic-Industry Partnerships to Explore Novel Opportunities in the Area of Immuno-Oncology

Joseph Dal Porto, Ph.D., Director, Pfizer Center for Therapeutic Innovation

The Center for Therapeutic Innovation (CTI) -San Francisco is a direct partnership between Pfizer and leading academic institutions, including UC San Francisco, UC San Diego, Stanford University and others, to establish open collaborations designed to rapidly identify targets and develop therapeutic NMEs. The long-term goal is to substantially reduce the time required to translate promising bio-medical research into new medications and therapies. Most recently, CTI has joined with academic oncology and immunology researchers to understand the translatability of emerging targets in the Immuno-Oncology therapeutic arena.

2:40 An Example of a Collaboration between Industry and Academia for Testing Combination Therapies in Preclinical Patient-Derived Xenograft Models of Glioblastoma

Anderson Clark, Ph.D., Director, Translational in vivo Pharmacology, Oncology, EMD Serono Research & Development Institute

John De Groot, Associate Professor, Chair Ad Interim, Neuro-Oncology, The University of Texas MD Anderson Cancer Center

The use of patient-derived xenograft (PDX) models of cancer has increased over the past decade, both in industry and academia, providing preclinical data to support both drug development and basic oncology research.

3:20 The Oncopig Cancer Model (OCM): A Platform for Transitional, Translational and Transformative Advances in Cancer Research

Lawrence B. Schook, Ph.D., Gutsgell Professor, Animal Sciences and Radiology,

University of Illinois

Mammalian models are integral components of basic, translational, and clinical cancer research. Recently, there have been advances in creating large animal transitional porcine cancer models, for use in preclinical and translational research studies with transformational impact for human clinical trials. Pigs, due to their anatomy, physiology, metabolism, and genetics, provide an ideal investigational transitional platform for human clinical trials and offer a critical pathway to narrow gaps in cancer therapy.

3:40 Presentation to be Announced

 

4:10 Hollywood Oscar Dessert Reception in the Exhibit Hall with Poster Viewing

5:00 Breakout Discussions in the Exhibit Hall

These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion. Pre-registration to sign up for one of the topics will occur a week or two prior to the Event via the App.

Humanized Mouse Models

Gavin Thurston, Vice President, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals

  • Appropriate applications of humanized mouse models in immuno-oncology
  • Limitations of current models
  • Areas of future development

Next Generation Cellular Models

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech Inc.

  • Cancer cell line profiling
  • Large-scale genomic and drug response screening
  • Future directions

Biomarkers for Cancer Combination Design

Jianda Yuan, M.D., Ph.D., Director, Translational Immuno-Oncology Research, Early Clinical Oncology Development, Merck & Co., Inc.

  • Validation of biomarkers before use in clinical care
  • Using prognostic and predictive biomarkers for enrichment and stratification factors in drug development
  • Challenges and Implementation of biomarkers into clinical practice

6:00 Close of Day

WEDNESDAY, FEBRUARY 22

7:00 am Registration Open

7:00 Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

8:00 Plenary Keynote Session

10:00 Refreshment Break and Poster Competition Winner Announced in the Exhibit Hall

TRANSLATIONAL BIOMARKERS IN CANCER IMMUNOTHERAPY DEVELOPMENT

10:50 Chairperson’s Remarks

Jianda Yuan, M.D., Ph.D., Director, Translational Immuno-Oncology Research, Early Clinical Oncology Development, Merck & Co., Inc.

11:00 Next Generation Biomarkers for the Era of Combination Cancer Immunotherapy

Jianda Yuan, M.D., Ph.D., Director, Translational Immuno-Oncology Research, Early Clinical Oncology Development, Merck & Co., Inc.

Sarah Javaid, Ph.D., Senior Scientist, Discovery Pharmacogenomics, Genetics and Pharmacogenomics, Merck & Co., Inc.

Combination approaches are the keys to improving clinical response. From preclinical immune-oncology mouse models to patients enrolled on clinical trials, novel high throughput technologies enable us to understand the mechanisms underlying the complex interactions between the immune system and cancer, identify predictive biomarkers for the patients who will most likely benefit from current immunotherapies, avoid immune-related adverse events and guide the future combination cancer immunotherapy.

11:30 High-Content Molecular Profiling in Preclinical Immuno-Oncology Research

Ruslan Novosiadly, Senior Research Advisor, Cancer Immunobiology, Biomarkers, Eli Lilly

Recent clinical data have revealed the remarkable potential for T cell modulating agents to induce potent and durable responses in a subset of cancer patients. In this presentation, we discuss molecular approaches, platforms and strategies that enable a broader interrogation of the activity of agents that modulate the activity of tumor-specific T cells as well as examples of data sets generated in preclinical studies that have provided important insights into the biological activity of T cell therapies and support further rational development of this exciting treatment modality.

12:00 pm Utility of Quantifying Circulating Lymphocyte Populations as Pharmacodynamic Biomarkers in Trials of Immune Oncology Therapeutics

Nathan Standifer, Ph.D., Scientist II, Clinical Pharmacology and DMPK, MedImmune

Immune oncology (IO) therapeutics are directed at inducing immune responses against tumor cells. Intrinsic to this mechanism of action is the activation of circulating immune cells, which can be most effectively monitored using flow cytometry-based assays. In this presentation, aspects of assay development, validation, implementation and analysis of clinical flow cytometry datasets will be discussed. Results from clinical trials of IO as single agents or in combination with other IO will be shown and strategies for interpretation and post-hoc analyses will be detailed.

12:30 Session Break

Cellecta 12:40 Luncheon Presentation to be Announced

 

1:10 Refreshment Break in the Exhibit Hall and Last Chance for Poster Viewing

CELLULAR MODELS FOR COMBINATION THERAPY DESIGN

1:50 Chairperson’s Remarks

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech

2:00 Understanding and Predicting Cellular Response through Chemical and Functional Genomic Profiling of Well-Characterized Cancer Cell Lines

Scott Martin, Senior Scientific Manager, Group Lead, Functional Genomics, Discovery Oncology, Genetech

Determining relationships between genomic features and drug sensitivity is central to the concept of personalized medicine and indication selection. Many studies have highlighted the value of integrating omics data with drug activity across cell lines to identify predictors of response. Here we extend upon these studies with numerous chemical and genetic perturbations to explore such relationships. Data reveals both known and novel correlations, and was also used to explore best experimental and computational practices.

2:30 Beyond Genomics: Identifying Treatment Options for Refractory Cancer Patients Using Real Time Functional Assays and FDA Approved Drug Combinations

Matthew De Silva, CEO, Founder, Notable Labs

Refractory cancer patients often have resistant disease that does not respond to single agent therapy. Combination strategies are promising, but patient heterogeneity makes clinical trial design difficult. Next generation functional phenotypic assays using a patient’s cancer cells can identify potentially synergistic treatments in a matter of days, but the combinatorial space is often larger than the available cells. In silico models that employ ‘omic data from a patient can prioritize which combinations to test ex vivo. If the agent(s) of choice are approved, physicians can then prescribe them

3:00 Generation of ex vivo Tumor Models from PDX Tumors as a Platform for Clinically Relevant Anticancer Drug Discovery

Geoffrey A. Bartholomeusz, Ph.D., Associate Professor and Director, siRNA Core Facility, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Monolayer cell cultures platforms inadequately represent the complex tumor microenvironment and drugs identified by these systems have failed when translated into the clinics. Clinically relevant PDX systems are both costly and time consuming. We have developed a clinically relevant ex vivo tumor tissue system derived from a PDX tumor, and preliminary data confirms its potential to serve as a platform for clinically relevant drug discovery in a time and cost effective manner.

3:30 Session Break

CRISPR FOR TUMOR MODELING, INTERNATIONAL INITIATIVES

3:40 Chairperson’s Remarks

Monte Winslow, Ph.D., Assistant Professor, Genetics, Stanford University

3:45 Cancer Modeling with in vivo CRISPR/Cas9 Genome Editing

Monte Winslow, Ph.D., Assistant Professor, Genetics, Stanford University

Conventional genetically engineered mouse models of human cancer have been instrumental in our understanding of all aspects of cancer development. However, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately comprehend this disease. I will discuss our ongoing work to employ CRISPR/Cas9-mediated genome editing to generate cancer models and illuminate gene function during cancer progression within the natural in vivo setting.

4:15 Tailored Pre-Clinical Models with CRISPR-Based Genome Editing

Lukas Edward Dow, Assistant Professor, Medicine, Weill Cornell Medicine

CRISPR/Cas9 genome editing has changed the way we design and execute in vivo experiments. We are using CRISPR-based genome editing in stem cells and in adult mice to generate tailored pre-clinical models. This allows both a deeper understanding of the genetic underpinnings of cancer progression and provides a platform to interrogate new therapeutic strategies in specific genetic contexts, which is key for realizing the potential of personalized medicine.

4:45 The Human Cancer Model Initiative

Louis M. Staudt, M.D., Ph.D., Director, Center for Cancer Genomics, Co-Chief, Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health

The Human Cancer Model Initiative (HCMI) aims to generate 1000 new cancer cell lines directly from patient biopsy material using a variety of technologies, including organoids and conditionally reprogrammed cells. Each cell line will be genomically characterized and clinical diagnostic and therapeutic data will be gathered from the participating patients. The new cell lines and their associated data will be made available to the research community to promote a deeper understanding of cancer and its response or resistance to therapy.

5:15 Close of Conference Program

SOURCE

http://www.triconference.com/Pre-Clinical-Oncology-Models/

From: Marina Filshtinsky <pete@healthtech.com>

Date: Wednesday, December 14, 2016 at 10:00 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Combination Immunotherapy Design Models

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