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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:

 

 

AGENDA for Oncolytic Virus Immunotherapy Unlocking Oncolytic Virotherapies: From Science to Commercialization CHI’S 4TH ANNUAL IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

 


What's The Big Data?

America's Entrepreneurs

Source: U.S. Census Bureau

Among the 5.4 million U.S. firms with paid employees, 481,981, or 8.9 percent, had been in business for less than two years in 2014, according to findings from the U.S. Census Bureau’s inaugural Annual Survey of Entrepreneurs.

In contrast to the employer firms that had been in business for less than two years, there were 167,917, or 3.1 percent, that had been in business for 16 years or more. More than 4 in 10 employer firms (2.4 million, or 44.1 percent) have been in business between 11 and 15 years.

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The complexity of the technologies involved in development of mRNA Therapies is demonstrated by the Platform components and the ecosystem put in place by Moderna Therapeutics Inc., the leading venture in the mRNA Therapeutics Sector of the Biotech Industry

 

Moderna Therapeutics Inc.Corporate Facts

The Moderna Ecosystem

Messenger RNA (mRNA) Therapeutics™ hold the potential to transform medicine across multiple drug modalities and therapeutic areas. As the first mover and leading company in the space, our responsibility is to simultaneously advance promising internal development programs, while also mobilizing an entire ecosystem capable of propelling the field forward for patients.

Moderna Ventures

We form wholly-owned ventures to focus dedicated resources and staff in key disease areas where high unmet medical needs demand safe, efficacious and innovative therapies.

  • Onkaido, the first of Moderna’s ventures, formed as a wholly-owned subsidiary to develop mRNA drugs in oncology, is utilizing all of the tools and modalities developed at Moderna.
  • Valera, Moderna’s second venture, is focused on the advancement of vaccines and therapeutics for the prevention and treatment of viral and bacterial infectious diseases.
  • Elpidera, Moderna’s third venture, is focused exclusively on the advancement of mRNA-based treatments for rare diseases.
  • Caperna, Moderna’s fourth venture, is focused exclusively on the advancement of personalized vaccines for the treatment of cancer.

We are incubating additional ventures in diverse therapeutic areas, leveraging a cross-section of relevant modalities.

External Partnerships

Moderna is working with world leaders in key therapeutic areas where our mRNA Therapeutics™ can potentially have a profound impact on patients’ lives. We enjoy close and productive strategic agreements with:

  • AstraZeneca — mRNA Therapeutics focused on cardiovascular, metabolic and renal diseases as well as cancer;
  • Alexion Pharmaceuticals — mRNA Therapeutics for rare diseases;
  • Merck — mRNA-based vaccines and passive immunity treatments against viral diseases, as well as mRNA-based personalized cancer vaccines for multiple types of cancer;
  • Vertex — mRNA Therapeutics for the treatment of cystic fibrosis;
  • DARPA (the Defense Advanced Research Projects Agency) — mRNA-based antibody-producing drugs to protect against known and unknown emerging infectious diseases and engineered biological threats;
  • Bill & Melinda Gates Foundation — Combination of mRNA-based antibody therapeutics to help prevent HIV;
  • Karolinska Institutet and Karolinska University Hospital — mRNA Therapeutics to treat serious diseases; and
  • Institut Pasteur — mRNA-based drugs and vaccines to fight infectious diseases.

SOURCE

http://www.modernatx.com/our-business-model

Drug Modalities

Building from our mRNA core expression platform, we have created a new scale of drug discovery and development that enables a series of new drug modalities. Each modality represents a distinct approach to using the mRNA platform to encode proteins that achieve a therapeutic benefit, enabling us to develop numerous drug candidates across a wide array of therapeutic areas.

Vaccines

Vaccines are substances that teach the immune system to rapidly recognize and destroy invading pathogens such as bacteria or viruses, preparing the body’s adaptive immunity for future exposure to the pathogen. Historically, vaccines have introduced immune-activating markers from pathogens into the body. Conversely, Moderna is developing mRNA-based vaccines that enable the body to produce and present immunogenic proteins to the immune system.

Moderna is also developing mRNA-based personalized cancer vaccines to prime the immune system to recognize cancer cells and mount a strong, tailored response to each individual patient’s cancer. Moderna’s technology allows for a rapid turn-around time in production of these unique mRNA vaccines.

Intracellular/Transmembrane

Many diseases are caused by defects in proteins that function inside cells. Existing methods of protein-based therapy do not allow for proteins to reach the intracellular space, and as such are unable to replace the defective, disease-causing proteins within cells. Moderna’s platform allows for the development of mRNA therapies that can stimulate production of intracellular proteins as well as transmembrane proteins. This could potentially lead to a novel approach to treating a vast array of rare genetic and other diseases caused by intracellular protein defects.

Intratumoral

Many targets for the treatment of cancer have been identified but their therapeutic potential has been limited by either the inability to access these targets, or by systemic toxicities. Moderna’s platform allows for localized expression of therapeutic proteins within the tumor microenvironment.

Secreted antibodies

Antibodies are secreted proteins that bind to and inhibit specific targets. Moderna’s platform has the potential to stimulate the body’s own cells to produce specific antibodies that can bind to cellular targets.

Secreted proteins

Proteins are large, complex molecules that have many critical functions both inside and outside of cells. Moderna’s platform stimulates cells to produce and secrete proteins that can have a therapeutic benefit through systemic exposure.

SOURCE

http://www.modernatx.com/about-our-pipeline/drug-modalities

Moderna’s mRNA Platform

At Moderna, we are pioneering the development of a new class of drugs made of messenger RNA (mRNA). This novel drug platform builds on the discovery that modified mRNA can direct the body’s cellular machinery to produce nearly any protein of interest, from native proteins to antibodies and other entirely novel protein constructs that can have therapeutic activity inside and outside of cells.

Our efforts are helping Moderna and the industry to flatten the mRNA learning curve across the full breadth of competencies needed to drive the platform forward, including chemistry, mRNA biology, formulation, process development, automation and high-throughput production, quality, and Good Manufacturing Practice (GMP) manufacturing.

SOURCE

http://www.modernatx.com/our-mrna-platform


Can some types of fat protect us from brain disease?

Drugs that activate this novel stress response pathway, which they call the mitochondrial-to-cytosolic stress response, protected both nematodes and cultured human cells with Huntington´s disease from protein-folding damage.

Reporter: Aviva Lev-Ari, PhD, RN

 

“Maybe there is a way to use one drug to alter the mitochondrial signal and another drug to alter the communciation signal from the brain,” he said. “You would never see these two effects if you were studying protein folding in a tissue culture dish, because you don’t have the whole organism, C. elegans, in which you can look at the signals being communicated.”

Co-authors of the fat study include Hyun-Eui Kim, Ana Rodrigues Grant, Milos Simic, Rebecca Kohnz, Daniel Nomura, Jenni Durieux, Celine Riera, Melissa Sanchez, Erik Kapernick and Suzanne Wolff at UC Berkeley. The second study was co-authored by Kristen Berendzen, Jenni Durieux, Ye Tian, Hyun-eui Kim and Suzanne Wolff of UC Berkeley, in collaboration with Li-Wa Shao and Ying Liu of Peking University in Beijing.

The studies are supported by the Howard Hughes Medical Institute, National Institutes of Health, Glenn Foundation for Medical Research, and Jane Coffin Childs Memorial Fund for Medical Research.

RELATED INFORMATION

SOURCE

Can some types of fat protect us from brain disease?

 


Real Time Coverage of the AGENDA for Powering Precision Health (PPH) with Science, 9/26/2016, Cambridge Marriott Hotel, Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

Boston Marriott Cambridge – September 26, 2016

@PPHSUMMIT

7:00-8:15         Coffee & Registration

8:30-9:30         Opening
                         Kevin Hrusovsky
                         PPH Summit Founder and Chair, CEO Quanterix    

LIVE @ Marriott, Cambridge Aviva Lev-Ari streaming live from Powering Precision Health Summit

Apple and Steve Jobs – Returned to Apple after Pixar – Jobs has teamed up with Microsoft.

Innovations @Apple: iPhone, iPad, iPod, TV Apple,

Innovations @High Tech Industry in the World: Uber, Facebook, Robots,

Science – leads the revolution and DISRUPTIVE innovations

Medicine – Cardiology, Neurology, Oncology: INFLAMMATION markers

  • Speakers Affiliations
  • Collaborations
  • Leaders in the field
  • 5% Patient Advocacy; 10% Investors, 20% Providers, SCIENTISTS

PRECISION HEALTH: DIGITAL REVOLUTION AND HEALTH

  • lower costs on HC 40%, shift to prevention, 60% better access
  • Sick care: Japan and France HC more productive – Life expectency is 8 yrs hight than the US
  • Cancer, diabetes, In the US 31 out of 100,ooo reaches +100 yrs of age
  • Cancer Women: BRCA
  • Cancer Men: Prostate Cancer: PSA >10 – riskhigher
  • Sugar consumption in the USA  – 216 Liters/person
  • Obesity and Diabetes
  • Food addiction: Salt, fat, sugar: 2/3 of the populations are obese
  • Omega 6 overload – inflammation
  • Neurological disease:
  1. AD starts at 50 in some cases
  2. Concussions in Sports 5-10% – leading to neurodegenerative diseases
  3. Bicycle accidents at kids: no monitoring
  4. Drug as environmental factor – TOXICITY: depression, Schisophrenia, cardiac Arythmia
  • Digitizing biomarkers & Analytics: extreme specificity and sensitivity of Inflammation markers: Lowest DETECTION marker levels
  • LIQUID BIOPSY – ACCURATE NON-INVASIVE – 20B THE MARKET FOR LIQUID BIOPSY
  • Epigenetics: Twin Studies: Proteins – detections –
  1. Suppression Inflammation Surveilence
  2. Braf mutations – therapy
  3. Cardiology: Mediteranean diet
  4. Troponin-I: Can be seen before symptoms emerges
  5. WEARABLE DEVICES: Detection >> Prevention >> Treatment Sick Care >>> HealthCare
  6. unique opportunity to REVOLUTIONIZE MEDICINE – help patients sooner

Powering Precision Health with Science                          
Compelling technological and scientific advances are fueling a proposition that today’s healthcare can be radically improved and made more effective, accessible and economical by deploying disruptive technologies to carefully guide healthy living.  The potential for shifting our innovation focus from disease diagnostics and treatment (sick care) to early detection and disease prevention (precision healthcare) will be explored in oncology, neurology and cardiology as well as their underlying inflammation pathways.  Mobilizing this transformation requires the democratization of health assessments with digital technology, big data and wellness studies coupled with comprehensive policy and provider reconfiguration that incentivizes healthy living and “accountable” care.  Significant precision health advances are being realized in certain parts of the world and providing a credible blueprint for its potential.   Catalyzing our Precision Health initiative requires scientists, innovators, physicians, providers, regulators, investors and patient advocates to unite and build a collective vision for Precision Health.

Oncology                                         
9:30-10:45
9:30- 9:40       Introductions: Oncology Innovator Panel
                        Kevin Hrusovsky PPH Summit Founder and Chair, CEO Quanterix

 David Walt, PhD, Tufts University

Infectious disease 

  1. Single molecule array (simoa) – digitization of signals beads in Alisas – beads loaded on disc array
  2. Serum Cytokines – IL-10 and IL-8: at sub-femtomolar concentrations

Vaccination study: injection of these Cytokines: Human serum cytokine, baseline – COntrol Healthy Samples

Variation inter subjects in cytokine levels: Day One response evolution of th eImmune response

  • day reported illness
  • cytokine fluctuation
  • cytokine expression levels
  • IgG Simoa sensitivity (secondary infection); IgM (primary infection)

ONCOLOGY: Early Detection of Breast Cancer

Future technology:

  • sensitive detection for BRCA
  • 6-12% false positive in Mamography
  • Breast cancer Biomarkers: Singleplex Simeo assays
  • 8X-1000X improved sensitivity
  • Assay tested in commercial kits
  • SimOa for miRNA detection: 66 patients tested, prior to therapy: Marker 1,2,3

Individual protein assay were multiplexed

  1. Three protein Signature: PLS-DA Classification: 84% precision Health vs BRCA Stage II
  2. Sensitivity/specificity: on Biomarkers in BLOOD: 95.9% accuraccy Health vs. diagnosed BRCA

Protein Biomarkers in serum samples – cells secret, cells are invovled with mutations

  • find binding agents

                                                   

Robert Weinberg, PhD,  MIT /Whitehead Institute

  •  Early detection in colonoscopy is significant
  • Breast CA – early detection  and effect on mortality: 705 OF WOMEN AT 85 have BRCA
  • response to drugs in Cancer; diagnosis of relapse
  • reduce Cancer Mortality ONLY by reduction of inscidence not early detection which – DX and TX does not change mortality – acquired somatic mutation
  • Circulating tumor Cells & CIrculating DNA – Sequencing is very limited in its applicability for BRCA
  • Genomics data integration iwth gene expression
  • Reincentivise the young  – Pharma and Diagnostics — need to fund Postdocs in Academia

John Houston, PhD
                         Formerly SVP Bristol Myers Squibb   

  • What is real and what is doable
  • Advanced   Melanoma: markable accomplishments
  • why some patients respond and why others do not – Biomarkers
  • Combination drug  therapy in Oncology
  • signature for response and non-response is critical
  • Platform to capture data in retrospect

Phil Stephens, PhD
Foundation Medicine

  1. 10,000 patients with cancer mutations
  2. biomarkers for Target Therapy
  3. combinations need be Target and immuno
  4. Bladder Cancer is example were sequencing did help
  5. RNA and DNA and beyond: making sequencing data on metastatic disease
  6. diagnostic Industry needs regulation – Some Texts are not accurate and do not assists

Discussion Moderator: Kevin   – Biomarkers other Technologies mRNA, Liquid Biopsy                                      
                                                                                                                
9:40-10:00       Keynote Address Oncology:
                         David Walt, PhD
                         Tufts University

Beyond Genomics: Disruptive Approaches to Cancer and Infectious Disease Diagnostics
We have used the single molecule array  technology to screen dozens of potential biomarkers for their ability to diagnose various diseases and predict clinical outcomes.  The single molecule array technology has been used primarily for protein detection but is also applicable to the detection of nucleic acids, including DNA, mRNA, and microRNA, without any amplification.  Ultra-high sensitivity enables the detection of both protein and nucleic acid biomarkers at concentrations previously undetectable in blood. After measuring the candidate biomarkers, we employ classification algorithms to down-select the most informative biomarkers that correlate with the clinical information.  We have employed this approach to discover serum biomarkers for monitoring individuals over extended periods for infectious disease and for early detection of breast cancer.

10:00-10:45     Oncology Innovator Panel Discussion
Revolutionizing Oncology with Disruptive Technologies to Prevent, Detect, and Treat Cancer

10:45-11:15      Coffee break

Neurology                                       
11:15-12:30     Introductions: Neurology Innovator Panel
                      Kevin Hrusovsky
                      PPH Summit Founder and Chair, CEO Quanterix

Robert Stern, PhD
Boston University, School of Medicine, BU Alzheimer’s Disease and CTE Center
                                               

Doug Cole, MD – Neurologist and investor – Flagship Ventures
                                              

  1. no powerful tools to understand AD 20 years ago,
  2. Tools are now available – in 5-20 years tools will allow for Treatment development
  3. Societal issue – leadership at University Presidents, Sports organization – grass root pressure like with No Smoking
  4. commonality needs be explore across diseases to establish syndroms shared that will enable development of disease management and treatment

 

Jesse M. Cedarbaum, MD – Biogen 
                                                

  1. Neurologist – worked with MS, Parkinson, AD – did not work with CTE
  2. Soccer – Contact with the ball  – effect the structure of exon, synapsis, beta protein
  3. TOOLS: Genetic risk allowing to play short or long durations
  4. Football, soccer, baseball and tennis
  5. WE NEED LARGE POOLS OF NEUROLOGICAL DISEASES IN PATIENTS – BECAUSE  there are common proteins involved and comorbidities vs present participation in clinical trials by diagnosis
  6. all studies for Parkinson are not analysed in the context of AD
  7. PCP needs tool to diagnose AD better than today the diagnosis is done
  8. in Military training vibrations that causes CTE
                                                 

Tim Fox
                                               Former NFL Safety, Sports Commentator                                                  
           Peter Cronin
                                               Former NFL Linebacker                                       

11:15-11:25     Tim Fox
                       Former NFL Safety, Sports Commentator  
                       Personal Perspective on The Impact of Repeated Concussions and CTE                 

11:25-11:45      Keynote Address Neurology:
                        Robert Stern, PhD
                        Boston University, School of Medicine, BU Alzheimer’s Disease and CTE Center

Diagnosing Chronic Traumatic Encephalopathy (CTE) During Life: Potential Fluid and Neuroimaging Biomarkers                           
Chronic Traumatic Encephalopathy (CTE) is a unique neurodegenerative disease associated with a history of repetitive head impacts, including concussive and sub-concussive trauma, such as that experienced by contact sport athletes (e.g., American football players, boxers). Currently CTE can only be diagnosed through postmortem neuropathological examination demonstrating the pathognomonic lesions of perivascular phosphorylated tau (p-tau) at the depths of the cortical sulci. The ability to diagnose CTE during life is critically important to understanding the epidemiology of the disease, as well as the examination of specific risk factors (e.g., head impact exposure, genetics) and the ability to conduct clinical trials for treatment and prevention. This talk will describe recent findings in the development of possible in vivo biomarkers for CTE, including Simoa plasma total tau, plasma exosomal tau, as well as tau PET imaging.

LIVE @PPHSUMMIT 

  • $60Million NIH Grants
  • Awareness, Prevention, Management
  • Repetitive Head Impacts vs Concussions
  1. effect on neuronal functioning
  2. even one season causes cognitive, physiological changes in the brain
  3. Boxing for long time
  4. long time consecquences – Neuropathology
  5. CTE – brain trauma, leads to progressive neuro-degeneration
  • post consussion disease without symptoms of concussion
  • like AD, microtubule-Associated Protein Tau – misfolded hyperphosphorilated form of tau (p-tau): Perivascular and Depth of Solci — >>>> Spread of areas with distruction
  • Why it was not commonly observed ??
  • CTE and Public Health: Contact Sports – REPETITIVE IMPACT
  • Exposure: Severity and type of trauma
  • rest between hits
  • CTE vs PTSD, other injuries
  • Diagnose during life: develop in vivo biomarkers
  • How to create Biomarkers: DETECT Study: 100 NFL players vs Control – no sport involvement
  • All imaging were not specific to Tau detection –
  • Brain PET Tau Imaging developed: Invasive, expensive, we need a blood test
  • Tau deposits
  • Blood based Biomarkers for CTE – high sensitivity — FOllow up blood screening
  • Plasma Exosomal Tau: Exosomes are cell-derived nanovescicles: Blood, saliva, urine
  • generation of Neuronal Exosomes – extracellular space
  • Exosomes isolation required – Measure Tau in Blood
  • Quanterix_ Plasma total Tau – simoa HD-1
  • Results: plasma T-Tau – difference NFL and control – NFL – Extreme T-Tau COncentration
  • How to refine and validate Plasma T-Tau?
  • relevance to AD – modify early predict sympthoms – Using DIgital Biomarkers
  • Precision Health: Prevention and Tx of CTE:
  • Concussions & subconclusive Hits >>> PreClinical, >>> Clinical CTE not dimented >> CTE Dementia= synaptic loss

11:45-11:55        Peter Cronin
Former NFL Linebacker
Personal Perspective on The Urgent Need For Detection and Treatment of CTE

  • concussion with memory loss, mood changes,

11:55-12:30     Neurology Innovator Panel Discussion
Revolutionizing Neurology with Disruptive Technologies: Prevent, Detect and Treat
Concussions/CTE

  • AD – we know what the proteins are, subtype of diseases – tools and technology
  • Advancement when a test will allow to discern

 

 

12:30-1:15       Buffet style lunch

1:15-3:30         Scientific Tracks

Track 1 – Neurology – not attended
1:15-1:40         Jessica Gill, PhD, RN                 The Role of Proteomic Biomarkers of Brain Injuries
                         National Institute of Health
1:40-2:05         Danielle Graham, PhD               Accelerating exploratory fluid biomarker assay development in
Biogen                                       Neurodegenerative Disease
2:05-2:25         Alison Joyce, PhD                      Development of a Sensitive Homebrew Simoa Assay to Detect
Pfizer Inc                                    Leucine-Rich Repeat Kinase 2 (LRRK2)
2:25–3:00         Cheryl Wellington, PhD              Toward Precision Medicine in Canada: Two vignettes
                         University of British Columbia                   
3:00-3:25         Miriam Moscovitch-Lopatin       An Ultra-Sensitive Simoa Immunoassay for Quantifying BDNF
                          MGH                                          Levels in CSF in Early Huntington Disease: A Longitudinal PRE-
CELL Biomarker Study

Track 2 – Cardiology, Oncology, Inflammation, Infectious Disease

1:30-2:00         Ralph McDade, PhD      Ex-Luminex    Myriad RBM     

Triphase approach to biomarker pattern discovery for cancer immunotherapy and autoimmune disease

  • Bi-Polar vs Depression – Diagnosis
  • nostics for Depression Kit to determine which anti-depressant drug to prescribe
  • xMAP Technology – immuno-assays
  • 96 well plate
  • robotic liquid handling – assay precision and reproducability
  • proprietary matrix blockers
  • Myriad Genetics is the Parent company
  • Validation Parameters
  • CLIA certified ELISA Amono assay
  • Analyte: TNF-alpha, IFN-gamma (no marker in RA), IL-1 beta, IL-6, IL-17A
  • DIsease state samples – RA – IL-1Betta
  • Multiplexing
                                                             

2:00-2:30         John Yan                                     An Ultrasensitive Assay Format for Detecting PD/Biomarkers in
Takeda Pharmaceutical Co          Cell and Xenograft Tumor

  • ULK1 important Autophage Initiating Kinase
  • mTOR – -/+mTor treated with ULK1

                       
2:30-3:00         Rama Boyanapalli, PhD              The long and winding road to a highly sensitive RANKL Assay
                         Shire Company

  • RANKL IS A PART OF THE NECROTIC FACTOR (TNF)
  • PROTEIN BIOMARKER RANKL AND BONE STRENGTH (bone resorption) and bone formation – Vitamin D PGE@
  • Commercial Kits available:Recombinant and Serum based
  • IMOA technology ultrasensitive
  • Antibody Selection: R&D System DUoSet human RANKL ELISA selection-
  1. Capture Ab sonjugate to beads – MOUSE MONCLONAL
  2. Detector Ab – GOAT POLYCLONAL
  3. tested 12 commercially available Abs
  4. Additional assay optimization
  5. Criteria for QUALIFYING AN ASSAY:
  • ASSAY SPECIFICITY
  • MINIMUM REQUIRED DILUTION
  • PRECISION
  • Calibration curves with varying calibrator levels – for precision studies
  • Comparing Simoa to ELISA Kit: RANKL concentration

 

3:00-3:30         Bonnie J. Howell, PhD                 Ultrasensitive Detection of Viral p24 Following Reactivation of
Merck                                          Latent HIV

  • HIV Biology
  • tratment
  • reservoir detection
  • HIV — affects t-Cells — AIDS
  • life cycle of HIV-1
  • Viral RNA, recapaged to virom and start another cycle of infection
  • Treatment of ANtiviral therapies (ART)
  • Persistent replication of the virus
  • HIV Vure Means?
  • Sterilization / eradicated of HIV free
  • Remission/Functional
  • get of ART for few years
  • latent vells survuve deceased activation
  • latent reservoir homeostatic proliferation
  • latent cell reactivation
  • reactivation
  • Where do they hide?
  • HIV – CNS, Gut, GI, GU, Bone marrow,
  • Estimation 1 per million resting CD4 – Quantifying the HIV Rservoir
  1. different PCR- and Culture based assays used to measure reservoir
  2. poor correlation between assay
  3. >95% provirus is defective – does not produce Vyron
  4. Quanterix SImoa digital ELISA for ultrasensitive HIV p24 protein detection
  5. serum convert stage – makes measurement of reservoir difficult
  6. Merck optimized ultrasensitive p24 immunoasay
  7. p24 detectd in gnotypically diverse HIV clinical isolates
  8. HIV-1, CPZ, HIV-2, SIV-MM
  9. Virus to kill strategy: IMMUNO-therapy – measuring protein so importent
  10. Shock and kill
  • Cells with latent HIV with
  • cells with activated HIV
  • Induction in ART-suppresant
  • T-cell activation with stimulation Suppresant p24 Increases with reservoir size in most pt.
  • PMA/Ionomycin, CD4+ T-cell Lysate as measured by TILDA
  • HDACi induces p24 Expression in ART Suppressed HIV + Patients CD4+
  • Latency-Reversing Agents
  • Treatment with Multiple doses of Vorinostat
  • Gag RNA – Assay: Baseline vs Post-VOR – HIV pt received 10 doses VOR administared in 72 hours
  • Two doses of Vorinostat
  • Dilution series

SUMMARY

p24 digital ELISA improves assay sensitivity and selectivity

p24 detected in genotypically diverse HIV clinical isolates
                         
3:30-4:00         Coffee Break

 

Cardiology and Inflammation

                                     
4:00-4:10         Introductions: Cardiology/Inflammation Panel
                         Kevin Hrusovsky
PPH Summit Founder and Chair

                                                  Dennis Ausiello, MD
                                                  Mass General HospitalEmeritus
                                                   Petr Jarolim, MD, PhD
 
Brigham and Women’s HospitalDana Farber Cancer Institute 
Grace Colon, PhD
 InCarda Therapeutics, Inc. and ProterixBio, Inc.                                                            

4:10-4:30        Keynote Address Cardiology/Inflammation
                        Dennis Ausiello, MD
                        Mass General HospitalEmeritus

Mobilizing Precision Health is Within Reach
The data revolution, from genetic to digital, has provided a compelling need to assess wellness and its progression to disease. This is in direct contrast to the long standing approach in medicine of episodic and symptomatic measurement of disease and its progression to morbidity and mortality. Compelling data and science are fueling a proposition that today’s healthcare can be radically improved and made more effective, accessible and economical by deploying disruptive technologies to carefully monitor and guide healthy living.  We will explore the real potential of pre-symptomatic assessment of the human condition independent of time and place, with an improvement in disease prevention. Democratizing health assessments and monitoring with mobile devices, smart phones and community drug stores is an important opportunity for enabling early detection, preventative medicine and precision health.  Establishing disruptive detection technology and sampling strategies across multiple biomarker panels is key to enabling this vision.

4:30 -5:15        Cardiology and Inflammation Innovator Panel Discussion
Revolutionizing Cardiology with Disruptive Technologies: Prevent, Detect and Treat Cardiovascular
Disorders and Diabetes

5:15-5:30         Chair Summary and Summit Close

5:30-7:30         Cocktail Reception

SOURCE