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Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

 

Reporter: Stephen J. Williams, PhD

 

Follow Live in Real Time using

#AACR20

@pharma_BI

@AACR

 

Register for FREE at https://www.aacr.org/

 

AACR VIRTUAL ANNUAL MEETING II

 

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

 

This Virtual Meeting is Part II of the AACR Annual Meeting.  Part I was held online in April and was centered only on clinical findings.  This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

 

REGISTER NOW

 

 

 

Virtual Educational Session

Prevention Research, Science Policy, Epidemiology, Survivorship

Carcinogens at Home: Science and Pathways to Prevention

Chemicals known to cause cancer are used and released to the environment in large volumes, exposing people where they live, work, play, and go to school. The science establishing an important role for such exposures in the development of cancers continues to strengthen, yet cancer prevention researchers are largely unfamiliar with the data drawn upon in identifying carcinogens and making decisions about their use. Characterizing and reducing harmful exposures and accelerating the devel

Julia Brody, Kathryn Z. Guyton, Polly J. Hoppin, Bill Walsh, Mary H. Ward

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Molecular and Cellular Biology/Genetics, Clinical Research Excluding Trials

EMT Still Matters: Let’s Explore! – Dedicated to the Memory of Isaiah J. Fidler

During carcinoma progression, initially benign epithelial cells acquire the ability to invade locally and disseminate to distant tissues by activating epithelial-mesenchymal transition (EMT). EMT is a cellular process during which epithelial cells lose their epithelial features and acquire mesenchymal phenotypes and behavior. Growing evidence supports the notion that EMT programs during tumor progression are usually activated to various extents and often partial and reversible, thus pr

Jean-Paul Thiery, Heide L Ford, Jing Yang, Geert Berx

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

Tumor Biology, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

One of These Things Is Not Like the Other: The Many Faces of Senescence in Cancer

Cellular senescence is a stable cell growth arrest that is broadly recognized to act as a barrier against tumorigenesis. Senescent cells acquire a senescence-associated secretory phenotype (SASP), a transcriptional response involving the secretion of inflammatory cytokines, immune modulators, and proteases that can shape the tumor microenvironment. The SASP can initially stimulate tumor immune surveillance and reinforce growth arrest. However, if senescent cells are not removed by the

Clemens A Schmitt, Andrea Alimonti, René Bernards

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Molecular and Cellular Biology/Genetics

Recent Advances in Applications of Cell-Free DNA

The focus of this educational session will be on recent developments in cell-free DNA (cfDNA) analysis that have the potential to impact the care of cancer patients. Tumors continually shed DNA into the circulation, where it can be detected as circulating tumor DNA (ctDNA). Analysis of ctDNA has become a routine part of care for a subset of patients with advanced malignancies. However, there are a number of exciting potential applications that have promising preliminary data but that h

Michael R Speicher, Maximilian Diehn, Aparna Parikh

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Methods Workshop

Clinical Research Excluding Trials, Clinical Trials, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Translating Genetics and Genomics to the Clinic and Population

This session will describe how advances in understanding cancer genomes and in genetic testing technologies are being translated to the clinic. The speakers will illustrate the clinical impact of genomic discoveries for diagnostics and treatment of common tumor types in adults and in children. Cutting-edge technologies for characterization of patient and tumor genomes will be described. New insights into the importance of patient factors for cancer risk and outcome, including predispos

Heather L. Hampel, Gordana Raca, Jaclyn Biegel, Jeffrey M Trent

DETAILS

Monday, June 22

1:30 PM – 3:22 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Drug Development, Epidemiology

Under-representation in Clinical Trials and the Implications for Drug Development

The U.S. Food and Drug Administration relies on data from clinical trials to determine whether medical products are safe and effective. Ideally, patients enrolled in those trials are representative of the population in which the product will be used if approved, including people of different ages, races, ethnic groups, and genders. Unfortunately, with few patients enrolling in clinical trials, many groups are not well-represented in clinical trials. This session will explore challenges

Ajay K. Nooka, Nicole J. Gormley, Kenneth C Anderson, Ruben A. Mesa, Daniel J. George, Yelak Biru, RADM Richardae Araojo, Lola A. Fashoyin-Aje

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Cancer Chemistry

Targeted Protein Degradation: Target Validation Tools and Therapeutic Opportunity

This educational session will cover the exciting emerging field of targeted protein degradation. Key learning topics will include: 1. an introduction to the technology and its relevance to oncology; 2. PROTACS, degraders, and CELMoDs; 3. enzymology and protein-protein interactions in targeted protein degraders; 4. examples of differentiated biology due to degradation vs. inhibition; 5. how to address questions of specificity; and 6. how the field is approaching challenges in optimizing therapies

George Burslem, Mary Matyskiela, Lyn H. Jones, Stewart L Fisher, Andrew J Phillips

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Bioinformatics and Systems Biology, Experimental and Molecular Therapeutics, Drug Development, Molecular and Cellular Biology/Genetics

Obstacles and opportunities for protein degradation drug discovery

Lyn H. Jones
  • PROTACs ubiquitin mediated by E3 ligases;  first discovered by DeShaies and targeted to specific proteins
  • PROTACs used in drug discovery against a host of types of targets including kinases and membrane receptors
  • PROTACs can be modular but lack molecular structural activity relationships
  • can use chemical probes for target validation
  • four requirements: candidate exposure at site of action (for example lipophilicity for candidates needed to cross membranes and accumulate in lysosomes), target engagement (ternary occupancy as measured by FRET), functional pharmacology, relevant phenotype
  • PROTACs hijack the proteosomal degradation system

Proteolysis-targeting chimeras as therapeutics and tools for biological discovery

George Burslem
  • first PROTAC developed to coopt the VHL ubiquitin ligase system which degrades HIF1alpha but now modified for EREalpha
  • in screen for potential PROTACS there were compounds which bound high affinity but no degradation so phenotypic screening very important
  • when look at molecular dynamics can see where PROTAC can add additional protein protein interaction, verifed by site directed mutagenesis
  • able to target bcr-Abl
  • he says this is a rapidly expanding field because of all the new E3 ligase targets being discovered

Expanding the horizons of cereblon modulators

Mary Matyskiela

Translating cellular targeted protein degradation to in vivo models using an enzymology framework

Stewart L Fisher
  • new targeting compounds have an E3 ligase binding domain, a target binding domain and a linker domain
  • in vivo these compounds are very effective; BRD4 degraders good invitro and in vivo with little effect on body weight
  • degraders are essential activators of E3 ligases as these degraders bring targets in close proximity so activates a catalytic cycle of a multistep process (has now high turnover number)
  • in enzymatic pathway the degraders make a productive complex so instead of a kcat think of measuring a kprod or productivity of degraders linked up an E3 ligase
  • the degraders are also affecting the rebound protein synthesis; so Emax never to zero and see a small rebound of protein synthesis

 

Data-Driven Approaches for Choosing Combinatorial Therapies

Drug combinations remain the gold standard for treating cancer, as they significantly outperform single agents. However, due to the enormous size of drug combination space, it is virtually impossible to interrogate all possible combinations. This session will discuss approaches to identify novel combinations using both experimental and computational approaches. Speakers will discuss i) approaches to drug screening in cell lines, the impact of the microenvironment, and attempts to more

Bence Szalai, James E Korkola, Lisa Tucker-Kellogg, Jeffrey W Tyner

DETAILS

Monday, June 22

3:45 PM – 5:21 PM EDT

Virtual Educational Session

Tumor Biology

Cancer Stem Cells and Therapeutic Resistance

Cancer stem cells are a subpopulation of cells with a high capacity for self-renewal, differentiation and resistance to therapy. In this session, we will define cancer stem cells, discuss cellular plasticity, interactions between cancer stem cells and the tumor microenvironment, and mechanisms that contribute to therapeutic resistance.

Robert S Kerbel, Dolores Hambardzumyan, Jennifer S. Yu

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Drug Development, Experimental and Molecular Therapeutics

Molecular Imaging in Cancer Research

This session will cover the fundamentals as well as the major advances made in the field of molecular imaging. Topics covered will include the basics for optical, nuclear, and ultrasound imaging; the pros and cons of each modality; and the recent translational advancements. Learning objectives include the fundamentals of each imaging modality, recent advances in the technology, the processes involved to translate an imaging agent from bench to bedside, and how molecular imaging can gui

Julie Sutcliffe, Summer L Gibbs, Mark D Pagel, Katherine W Ferrara

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Immunology, Experimental and Molecular Therapeutics, Drug Development

Tumor Endothelium: The Gatekeepers of Tumor Immune Surveillance

Tumor-associated endothelium is a gatekeeper that coordinates the entry and egress of innate and adaptive immune cells within the tumor microenvironment. This is achieved, in part, via the coordinated expression of chemokines and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. Crosstalk between adaptive immune cells and the tumor endothelium is therefore essential for tumor immune surveillance and the success of immune-based thera

Dai Fukumura, Maria M Steele, Wen Jiang, Andrew C Dudley

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Immunology, Experimental and Molecular Therapeutics

Novel Strategies in Cancer Immunotherapy: The Next Generation of Targets for Anticancer Immunotherapy

T-cell immunotherapy in the form of immune checkpoint blockade or cellular T-cell therapies has been tremendously successful in some types of cancer. This success has opened the door to consider what other modalities or types of immune cells can be harnessed for exert antitumor functions. In this session, experts in their respective fields will discuss topics including novel approaches in immunotherapy, including NK cells, macrophage, and viral oncotherapies.

Evanthia Galanis, Kerry S Campbell, Milan G Chheda, Jennifer L Guerriero

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Drug Development, Immunology, Clinical Research Excluding Trials

Benign Cells as Drivers of Cancer Progression: Fat and Beyond

Carcinomas develop metastases and resistance to therapy as a result of interaction with tumor microenvironment, composed of various nonmalignant cell types. Understanding the complexity and origins of tumor stromal cells is a prerequisite for development of effective treatments. The link between obesity and cancer progression has revealed the engagement of adipose stromal cells (ASC) and adipocytes from adjacent fat tissue. However, the molecular mechanisms through which they stimulate

Guojun Wu, Matteo Ligorio, Mikhail Kolonin, Maria T Diaz-Meco

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Experimental and Molecular Therapeutics, Tumor Biology

Dharma Master Jiantai Symposium on Lung Cancer: Know Thy Organ – Lessons Learned from Lung and Pancreatic Cancer Research

The term “cancer” encompasses hundreds of distinct disease entities involving almost every possible site in the human body. Effectively interrogating cancer, either in animals models or human specimens, requires a deep understanding of the involved organ. This includes both the normal cellular constituents of the affected tissue as well as unique aspects of tissue-specific tumorigenesis. It is critical to “Know Thy Organ” when studying cancer. This session will focus on two of the most

Trudy G Oliver, Hossein Borghaei, Laura Delong Wood, Howard C Crawford

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Clinical Trials

Clinical Trial Design: Part 1: Novel Approaches and Methods in Clinical Trial Design

Good clinical trial design has always had to balance the competing interests of effectively and convincingly answering the question with the limitations imposed by scarce resources, complex logistics, and risks and potential benefits to participants. New targeted therapies, immuno-oncology, and novel combination treatments add new challenges on top of the old ones. This session will introduce these concerns and 1) suggest ways to consider what outcomes are relevant, 2) how we can best

Mary W. Redman, Nolan A. Wages, Susan G Hilsenbeck, Karyn A. Goodman

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Tumor Biology, Drug Development

High-Throughput Screens for Drivers of Progression and Resistance

The sequencing of human cancers now provides a landscape of the genetic alterations that occur in human cancer, and increasingly knowledge of somatic genetic alterations is becoming part of the evaluation of cancer patients. In some cases, this information leads directly to the selection of particular therapeutic approaches; however, we still lack the ability to decipher the significance of genetic alterations in many cancers. This session will focus on recent developments that permit the identification of molecular targets in specific cancers. This information, coupled with genomic characterization of cancer, will facilitate the development of new therapeutic agents and provide a path to implement precision cancer medicine to all patients.

William C Hahn, Mark A Dawson, Mariella Filbin, Michael Bassik

DETAILS

Monday, June 22

3:45 PM – 5:15 PM EDT

Defining a cancer dependency map

William C Hahn

Introduction

William C Hahn

Genome-scale CRISPR screens in 3D spheroids identify cancer vulnerabilities

Michael Bassik

Utilizing single-cell RNAseq and CRISPR screens to target cancer stem cells in pediatric brain tumors

Mariella Filbin
  • many gliomas are defined by discreet mutational spectra that also discriminates based on age and site as well (for example many cortical tumors have mainly V600E Braf mutations while thalamus will be FGFR1
  • they did single cell RNAseq on needle biopsy from 7 gliomas which gave about 3500 high quality single cells; obtained full length RNA
  • tumors clustered mainly where the patient it came from but had stromal cell contamination probably so did a deconvolution?  Copy number variation showed which were tumor cells and did principle component analysis
  • it seems they used a human glioma model as training set
  • identified a stem cell like glioma cell so concentrated on the genes altered in these for translational studies
  • developed multiple PDX models from patients
  • PDX transcriptome closest to patient transcriptome but organoid grown in serum free very close while organoids grown in serum very distinct transcriptome
  • developed a CRISPR barcoded library to determine genes for survival genes
  • pulled out BMI1  and EZH2 (polycomb complex proteins) as good targets

Virtual Methods Workshop

Prevention Research, Survivorship, Clinical Research Excluding Trials, Epidemiology

Implementation Science Methods for Cancer Prevention and Control in Diverse Populations: Integration of Implementation Science Methods in Care Settings

Through this Education Session we will use examples from ongoing research to provide an overview of implementation science approaches to cancer prevention and control research. We draw on examples to highlight study design approaches, research methods, and real-world solutions when applying implementation science to achieve health equity. Approaches to defining change in the care setting and measuring sustained changes are also emphasized. Using real examples of patient navigation prog

Graham A Colditz, Sanja Percac-Lima, Nathalie Huguet

DETAILS

Monday, June 22

3:45 PM – 5:30 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Epidemiology

COVID-19 and Cancer: Guidance for Clinical Trial Conduct and Considerations for RWE

This session will consider the use of real-world evidence in the context of oncology clinical trials affected by the COVID-19 pandemic. Key aspects of the FDA’s recent “Guidance on Conduct of Clinical Trials of Medical Products of Medical Products during COVID-19 Public Health Emergency” will be discussed, including telemedicine, accounting for missing data, obtaining laboratory tests and images locally, using remote informed consent procedures, and additional considerations for contin

Wendy Rubinstein, Paul G. Kluetz, Amy P. Abernethy, Jonathan Hirsch, C.K. Wang

 

 

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eProceedings – Day 1: Charles River Laboratories – 3rd World Congress, Delivering Therapies to the Clinic Faster, September 23 – 24, 2019, 25 Edwin H. Land Boulevard, Cambridge, MA

 

https://events.criver.com/event/9eab0ee1-982e-42c6-a4cd-fb43f9f2f1d0/confirmation:7c68cf9b-c599-469e-b602-42178c77e4f9

 

ANNOUNCEMENT

 

Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover this event in Real Time for pharmaceuticalintelligence.com 

Confirmation Number: 8ZNCBYNGHCK

In attendance generating in realtime event’s eProceeding and social media coverage by

 

Aviva Lev-Ari, PhD, RN

Director & Founder

Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

Editor-in-Chief

http://pharmaceuticalintelligence.com 

e-Mail: avivalev-ari@alum.berkeley.edu

(M) 617-775-0451

https://cal.berkeley.edu/AvivaLev-Ari,PhD,RN

SkypeID: HarpPlayer83          LinkedIn Profile        Twitter Profile

#crlworldcon

@CRiverLabs

@pharma_BI

@AVIVA1950

 

 

Join us this year as we explore novel approaches to drug development that effectively reduce program timelines and accelerate delivery to the clinic. Using a variety of case studies, our speakers will illustrate methods that successfully cut time to market and highlight how artificial intelligence and genomics are expediting target discovery and drug development. In an agenda that includes presentations, panel discussions, and short technology demonstrations, you will learn how the latest science and regulatory strategies are helping us get drugs to patients faster than ever.

AGENDA

Day One, September 23, 2019

  • Novel approaches to silence disease drivers
  • The role of AI in expediting drug discovery

Monday, September 23

8:30 – 9:00 a.m. Introduction and Welcome Remarks James C. Foster, Chairman of the Board, President, and Chief Executive Officer, Charles River
9:00 – 9:30 a.m. 2019 Award Winner: A Silicon Valley Approach to Understanding and Treating Disease Matt Wilsey, Chairman, President, and Co-Founder, Grace Science Foundation
9:30 – 10:15 a.m. Keynote Session Brian Hubbard, PhD, Chief Executive Officer, Dogma Therapeutics
10:15 – 10:30 a.m. Break
10:30 – 11:15 a.m. Novel Approaches to Silence Disease Drivers Systemic Delivery of Investigational RNAi Therapeutics: Safety Considerations and Clinical Outcomes Peter Smith, PhD, Senior Vice President, Early Development, Alnylam Pharmaceuticals
11:15 a.m. – 12:00 p.m. Novel Approaches to Silence Disease Drivers: Considerations for Viral Vector Manufacturing to Support Product Commercialization Richard Snyder, PhD, Chief Scientific Officer and Founder, Brammer Bio
12:00 – 1:00 p.m. Lunch
1:00 – 1:45 p.m. Accelerating Drug Discovery Through the Power of Microscopy Images Anne E. Carpenter, Ph.D., Institute Scientist, Sr. Director, Imaging Platform, Merkin Institute Fellow, Broad Institute of Harvard and MIT
1:45 – 2:30 p.m. The Role of AI in Expediting Drug Discovery Target Identification for Nonalcoholic Steatohepatitis Using Machine Learning: The Case for nference Tyler Wagner PhD, Head of Cardiovascular Research, nference
2:30 – 2:45 p.m. Break
2:45 – 3:30 p.m. Technobite Sessions with Emulate Bio and University of Pittsburgh Drug Discovery Institute

Kyung Jin H Jang, VP of Bio Product development, Emulate, Inc.

Albert Gough, PhD, U Pittsburg School of Medicine

3:30 – 4:15 p.m. Artificial Intelligence Panel Discussion: Real World Applications from Discovery to Clinic Moderated by Carey Goldberg, WBUR
4:15 – 4:45 p.m. Jack’s Journey Jake and Elizabeth Burke, Cure NF with Jack
4:45 – 5:00 p.m. Closing Remarks
5:00 – 6:00 p.m. Networking Reception

 

 

Day Two – September 24, 2019

  • How genomics is expediting drug discovery
  • Accelerating therapies through the regulatory process

Tuesday, September 24

8:45 – 9:00 a.m. Opening Remarks and Recap James C. Foster, Chairman of the Board, President, and Chief Executive Officer, Charles River
9:00 – 9:30 a.m. 2018 Award Winner Update David Hysong, Patient Founder and Chief Executive Officer, Shepherd Therapeutics William Siders, CDO, Shepherd Therapeutics
9:30 – 10:15 a.m. Advances in Human Genetics and Therapeutic Modalities Enable Novel Therapies Eric Green, Vice President of Research and Development, Maze Therapeutics
10:15 – 11:00 a.m. How Genomics is Expediting Drug Discovery Manuel Rivas, Assistant Professor, Department of Biomedical Data Science, Stanford University
11:00 – 11:15 a.m. Break
11:15 a.m. – 12:00 p.m. Genomics Panel Discussion: Signposting Targets That Will Speed the Path to Market Moderated by Martin Mackay, Co-Founder, RallyBio
12:00 – 1:00 p.m. Lunch
1:00 – 1:45 p.m Truly Personalized Medicines for Ultra-rare Diseases: New Opportunities in Genomic Medicine Timothy Yu, Attending Physician, Division of Genetics and Genomics and Assistant Professor in Pediatrics, Boston Children’s Hospital
1:45 – 2:30 p.m. Application of Machine Learning Technology for the Assessment of Bulbar Symptoms in ALS Fernando Vieira, Chief Scientific Officer, ALS Therapy Development Institute
2:30 – 2:45 p.m. Break
2:45 – 3:30 p.m. Accelerating Rare Disease Therapies Through the Regulatory Process Martine Zimmermann, Senior Vice President and Head of Global Regulatory Affairs, Alexion Pharmaceuticals, Inc.
3:30 – 4:00 p.m. Wearing ALL the Hats: From Impossible to Possible Allyson Berent, Chief Operating Officer, GeneTx Biotherapeutics
4:00 – 4:15 p.m. Closing Remarks

 

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  • Find a cause and work with passion
  • CVD increased 53% from 2005 to 2016
  • Cholesterol, LDL receptor and CV disease
  • Genetics  evolution and discovery of PCSK9
  1. A PCSK9 Variant lowers CV risk
  2. complete lack of PCSK9 is safe – protects from CVD
  • LDL receptor
  • Statins do not work on LDL receptor if the mutation exists
  • Antibody and antisense for the PCSK9 mutation – Inexpensive Oral Medications can change Global Diseases
  • Dogma of Drug DIscovery: Approach a Patent vs Approach a Disease
  • Ligands bind within a cryptic binding pocket adjacent to a novel PCSK9 polymorphism

12 years of drug discovery

  1. 2003: PCSK9 mutation discovered
  2. 2005:
  3. 2006:
  4. 2012;
  5. 2012: Dogma Scientists begin
  6. compound found binds to primates
  7. 2015:
  8. 2018: Efficiency DGM-4403 lowers LDL-c by 55% 0ver 14 days
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  • 2014 – @Moderna, mRNA
  • 2017 – Alnylam

RNAi – delivery is the most difficult

  • gene silencing changes medicine and diseases
  • Small Interfeering RNA (siRNA) Therapeutics
  • Delivery challenges – stability and targeting
  • RNA Interference (RNAi) – Onpattro (patisiran)
  • GalNAc-siRNA Conjugates – delivery to the hepatocytes
  • N-Acetyl Galactosamine (GalNACc-siRNA conjugates
  • Hepatocyte specific : Liver across species: ASGPR expression
  • Metabolic Stability: Chemistry to Improve siRNA
  • Platform for genetic diseases
  • Evolution of COnjugate Design: GalNAc-siRNA – enhanced stabilization chemistry
  • ALN-TTRSC02 compared to Revusiran
  • ALN-TTRsc02 (advanced) –  – tetrameric protein binds transports serum retinol binding
  • AL Amyloidosis
  • ApoA1 Amyloidosis
  • ATTR Amyloidosis – manufacture in the Liver: Hereditery vs non-hereditary – Wild-Type
  • Patisiran Therapeutic Hypothesis – siRNA targeting TTR formulated
  • Pharmacology of TTR siRNA in Animal Model
  • V30M TTR Transgenic Mouse Model: Patisiran Phase 1 Study to Phase 3 APOLLA Study Design for any TTR mutation – Prior tetramer stabilizer used permitted
  • hATTR Amyloidosis and APOLLO Assessment: Phase 3 is Global – Cardiomyopathy – potential,
  • Patisiran met all secondary Endpoints: Canadian, Japanese approval – US approved indication, European approved
  • Alnylam Investigational RNAi Therapeutics:
  • Pipeline: Genetic medicines
  • Hepatic Infectious diseases
  • CNS & Ocular
  • Cardiovascular
11:15 AM-12:00 PM
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  • Viral-Vector-mediated in vivo Gene Therapy
  • VVS Viral Vector Platforms:
  1. Adenovirus immunogenicity
  2. Lentivirus
  3. Retrovirus
  4. Herpes
  5. Recombinant Adeno-Associated Viral Vectors: Glybera, Luxturna
  6. Zolgenzma
  • Establish the product specifications based on data (CQAs)
  • Is the vector product: parenteral or anciliary material

Considerations:

  • Large scall vs small
  • lot demand vs platform choice
  • Proof of concept
  • Own/License the manufacturing reagents (portability) vs reliance on providers
  • Process and Analytical Design & Development: Cell line: Mamalian, others
  • Raw materials: Viral clearance steps – cell banks generation
  • impurity profiles
  • Cell Substrates
  • Cell clone screening
  • Preclinical/Clinical, Alachua, FL; Phase III/Commercial: Cambridge & Lexington
  • Biologics Upstream Process Flow: Master cell banks
  • Transient Transfection Process (Lenti and AAV)
  • rAAV Proviral cell line
  • Production Vector-based Process (Baculo or HSV)
  • Product purification: Filtration methods, Chromatography, centrifugal separation: Concentration/filtration
  • Formulation
  • Compatibility wiht vial: Glass, CZ, COP: absorption vs Inactivation
  • Single use
  • Frozen storage
  • Storage, Packing and Distribution
  • Technology Transfer: Research vs Mature Process (Qualified cell bank)
  • Plasmids: E.coli MCB backbone
  • Analytics Design & Development: Testing: Nucleic-acid based, protein-based
  1. AAV Vector Lot Release Assays
  2. Lentivirus
  • QA: QA Management System –
  • Analytical Assays
  • FDA Issues SIX New Draft Guidance Documents in 7/2018
  • Process Validation: Life cycle approach: Process caracterizationProcess performance qualification
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  • assayGene clusterbased on morphological similarity: Express each gene, gene painting Image analysis, cluster morphological profiles
  • identification of allelle that are not constitutively activating mutants.
  • weakly supervised deep learning to extract features
  • identify similarities and differences among treatments at the same population level
  • Predict many distinct expensive assays on a huge compound library using a single cell painting
  1. Test 5,000 compounds in the assay of interest as well as cell painting
  2. Find combination of iamge-based features that predict in the assay of interest
  3. Predict “hit” from existing 1Million compound cell paining data set
The Role of AI in Expediting Drug Discovery Target Identification for Nonalcoholic Steatohepatitis Using Machine Learning: The Case for nference
Tyler Wagner PhD, Head of Cardiovascular Research, nference
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  • Lung-Chip Applications
  • Pulmonary inflammation
  • Intestine-chip Applications
  • Liver-Chip: Building Tissue Complexity: Co-culture, tri-culture, quatro-culture, Transcriptomic Analysis
  • Liver-Chip: Kupffer cells Characterization
  • Stellate Cells
  • parenchymal channel, non-parenchymal channel
  • Liver Chip: Predicting species differences in liver toxicity: Effects of Bosentan on Albumin secretion
  • Acetaminophen Toxicity in Liver-Chip: APAP Metabolism: detected changes in morphology, ATP, GSH – Dosepdependent increase of ROS
  • Steatosis and Stellate Cell Activation: and Species difference in Toxicity Liver chip data correlates with in vivo data
  • Predict Human safety risks with liver chip
Albert Gough, PhD, U Pittsburg School of Medicine
  • Approaches for repurposing drugs:
  1. Integrated, fluidic organ MPD,
  2. cells, 3D structures,
  3. O2 Modulation & Sensing
  4. Biosensors
  5. secretome
  • Higher Biomimetic content Higher throughput
  • regulatory liver-pancreas axis in Type 2 Diabetes model
  • Estradiol-Induced proliferation of mutants in Breast Cancer varies from 2D monoculture to 3D LAMP
  • MPS Models:
  1. celle and organ Structure in MPS
  2. Single organ MPS & Coupled organ
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Carey Goldberg, WBUR
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September 24, 2019

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Digital Therapeutics: A Threat or Opportunity to Pharmaceuticals


Digital Therapeutics: A Threat or Opportunity to Pharmaceuticals

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Digital Therapeutics (DTx) have been defined by the Digital Therapeutics Alliance (DTA) as “delivering evidence based therapeutic interventions to patients, that are driven by software to prevent, manage or treat a medical disorder or disease”. They might come in the form of a smart phone or computer tablet app, or some form of a cloud-based service connected to a wearable device. DTx tend to fall into three groups. Firstly, developers and mental health researchers have built digital solutions which typically provide a form of software delivered Cognitive-Behaviour Therapies (CBT) that help patients change behaviours and develop coping strategies around their condition. Secondly there are the group of Digital Therapeutics which target lifestyle issues, such as diet, exercise and stress, that are associated with chronic conditions, and work by offering personalized support for goal setting and target achievement. Lastly, DTx can be designed to work in combination with existing medication or treatments, helping patients manage their therapies and focus on ensuring the therapy delivers the best outcomes possible.

 

Pharmaceutical companies are clearly trying to understand what DTx will mean for them. They want to analyze whether it will be a threat or opportunity to their business. For a long time, they have been providing additional support services to patients who take relatively expensive drugs for chronic conditions. A nurse-led service might provide visits and telephone support to diabetics for example who self-inject insulin therapies. But DTx will help broaden the scope of support services because they can be delivered cost-effectively, and importantly have the ability to capture real-world evidence on patient outcomes. They will no-longer be reserved for the most expensive drugs or therapies but could apply to a whole range of common treatments to boost their efficacy. Faced with the arrival of Digital Therapeutics either replacing drugs, or playing an important role alongside therapies, pharmaceutical firms have three options. They can either ignore DTx and focus on developing drug therapies as they have done; they can partner with a growing number of DTx companies to develop software and services complimenting their drugs; or they can start to build their own Digital Therapeutics to work with their products.

 

Digital Therapeutics will have knock-on effects in health industries, which may be as great as the introduction of therapeutic apps and services themselves. Together with connected health monitoring devices, DTx will offer a near constant stream of data about an individuals’ behavior, real world context around factors affecting their treatment in their everyday lives and emotional and physiological data such as blood pressure and blood sugar levels. Analysis of the resulting data will help create support services tailored to each patient. But who stores and analyses this data is an important question. Strong data governance will be paramount to maintaining trust, and the highly regulated pharmaceutical industry may not be best-placed to handle individual patient data. Meanwhile, the health sector (payers and healthcare providers) is becoming more focused on patient outcomes, and payment for value not volume. The future will say whether pharmaceutical firms enhance the effectiveness of drugs with DTx, or in some cases replace drugs with DTx.

 

Digital Therapeutics have the potential to change what the pharmaceutical industry sells: rather than a drug it will sell a package of drugs and digital services. But they will also alter who the industry sells to. Pharmaceutical firms have traditionally marketed drugs to doctors, pharmacists and other health professionals, based on the efficacy of a specific product. Soon it could be paid on the outcome of a bundle of digital therapies, medicines and services with a closer connection to both providers and patients. Apart from a notable few, most pharmaceutical firms have taken a cautious approach towards Digital Therapeutics. Now, it is to be observed that how the pharmaceutical companies use DTx to their benefit as well as for the benefit of the general population.

 

References:

 

https://eloqua.eyeforpharma.com/LP=23674?utm_campaign=EFP%2007MAR19%20EFP%20Database&utm_medium=email&utm_source=Eloqua&elqTrackId=73e21ae550de49ccabbf65fce72faea0&elq=818d76a54d894491b031fa8d1cc8d05c&elqaid=43259&elqat=1&elqCampaignId=24564

 

https://www.s3connectedhealth.com/resources/white-papers/digital-therapeutics-pharmas-threat-or-opportunity/

 

http://www.pharmatimes.com/web_exclusives/digital_therapeutics_will_transform_pharma_and_healthcare_industries_in_2019._heres_how._1273671

 

https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/exploring-the-potential-of-digital-therapeutics

 

https://player.fm/series/digital-health-today-2404448/s9-081-scaling-digital-therapeutics-the-opportunities-and-challenges

 

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The second annual PureTech Health BIG (Brain-Immune-Gut) Summit 2019 – By invitation only –

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

 

January 30 – February 1, 2019

The second annual PureTech Health BIG Summit brings together an elite ensemble of leading scientific researchers, investors, and CEOs and R&D leaders from major pharmaceutical, technology, and biotech companies.

The BIG Summit is designed to stimulate ideas that will have an impact on existing pipelines and catalyze future interactions among a group of delegates that represent leaders and innovators in their fields.

Please follow the discussion on Twitter using #BIGAxisSummit

By invitation only; registration is non-transferable.

For more information, please contact PureTechHealthSummit@PureTechHealth.com

 

HOST COMMITTEE

Participants

 

BIG SUMMIT AGENDA

(Subject to Change)

PureTech Health BIG Summit 2019 Agenda_FINALv2_WEBSITE.jpg

“Almost starting to understand immunology at this thought-provoking @PureTechh #BIGAxisSummit. Great Speakers.”

-tweet by Simone Fishburn, BioCentury @SimoneFishburn

SOURCE

https://bigsummit2019.com/agenda/

 

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Gail S. Thornton Selections

Luke Timmerman‏ @ldtimmerman 7h7 hours ago

Back for final sessions at #BIGAxisSummit. @PureTechH Jim Harper of Sonde Health talking about how voice data — pacing, fine motor articulation, oscillation — can point the way to objective, quantitative measures for detecting and monitoring depression.

 

Eddie Martucci

 @EddieMartucci 5h5 hours ago

Paul Biondi at #BIGAxisSummit : What makes big deals happen is financial, and *deep conviction* of a big future fit. Disproportionate valuation from bidders is expected.

Love this. We often reduce everything to mathematical analyses to champion or ridicule deals. Not that simple

 

PureTech Health Plc‏ @PureTechH Jan 31

Bob Langer (@MIT) asks how #lymphatics affected by #aging. Santambrogio: typically blame aging #immune cells for increased disease, but aging affects lymphatics too (less efficient trafficking shown). Rejuvenating these could affect several aging-related diseases #BigAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Viviane Labrie (@VAInstitute) discusses why the appendix has been identified as a potential starting point for #parkinsons #BIGAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Chris Porter (@MIPS_Australia) notes #lymphatics is major route for trafficking #immune cells that surveil gut and respond to immune & #autoimmune stimuli. This is key in #BIGAxis interactions and why lymphatics-targeted therapies could enhance #immunomodulation #BIGAxisSummit

 

Dr. Stephen J. Williams Selections

1.

2.

3.

4.

5.

Dr. Irina Robu Selection

1.

2.

3.

4.

5.

Dr. Sudipta Saha Selection

1.

2.

3.

4.

5.

 

 

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News announced during the 37th J.P. Morgan Healthcare Conference (#JPM19): Dublin medtech HealthBeacon raises $12m in a Series A round

Reporter: Gail S. Thornton

HealthBeacon’s Smart Sharps system helps patients adhere to their medication schedule. The company was founded by Jim Joyce and Kieran Daly in 2013, and opened offices in Boston in 2017. The digital platform, which last year received vital FDA clearance for the US market, not only ensures that patients keep up with their injectable treatments, but also allows them to dispose of medication in a safe way, and keeps carers up to date with the patients’ progress.

Published January 8, 2019 by John Kennedy, Silicon Republic.

Two men in dark jackets sit before a green wall holding a white medical device.

From left: Co-founders Kieran Daly and Jim Joyce. Image: HealthBeacon

With funding and FDA approval under its belt, this Dublin tech start-up has plans to help patients stick to their medication schedule.

Dublin and Boston digital health company HealthBeacon has raised $12m in a Series A investment round that brings total investment in the company to almost $15m.

The round was organised by HealthBeacon and Cantor Fitzgerald, led by Oyster Capital and Elkstone Partners, and the investment syndicate included Quorndon Capital and Cantor Fitzgerald’s private client group. Earlier investors in HealthBeacon include Enterprise Ireland, BVP and a range of angel investors.

‘I know with confidence as to whether my patients are adhering to their treatment strategy’
– DOUG VEALE

“Cantor has a major focus on life sciences and on digital health, and we have every confidence that CEO and co-founder Jim Joyce has created a true sector leader in HealthBeacon,” said Liam Kiely, director of Cantor Fitzgerald.

The announcement was made in San Francisco at the JPMorgan Chase Biotech Showcase. The funding comes on the back of rapid global expansion of the FDA-cleared HealthBeacon Smart Sharps technology.

The right stuff

Dublin-based HealthBeacon’s Smart Sharps system helps patients adhere to their medication schedule. The company was founded by Jim Joyce and Kieran Daly in 2013, and opened offices in Boston in 2017.

The digital platform, which last year received vital FDA clearance for the US market, not only ensures that patients keep up with their injectable treatments, but also allows them to dispose of medication in a safe way, and keeps carers up to date with the patients’ progress.

The funding from this Series A will be used to launch its Smart Sharps system in the US and to develop its portfolio of medical adherence tools for high-value medications.

In 2017, HealthBeacon revealed plans to create 20 new jobs in Dublinin roles spanning IT, software development, project management and customer service. As of today, HealthBeacon operates in 10 markets and has tracked more than 200,000 home-based injections, making it one of the largest global deployments of a medical adherence device. Today, HealthBeacon employs more than 30 people and plans to double the team over the next 18 months.

The addressable market for injectable medications has reached nearly $50bn, according to the company. The Smart Sharps bin system by HealthBeacon has made it easier for patients using injectable medications to stay on track with their treatment. This has resulted in improved patient medication adherence, driving patient care.

In December, HealthBeacon was named eHealth Innovation of the Year by the Irish Medtech Association.

“I’ve been using the HealthBeacon for over two years, and their Smart Sharps bin has had a profound impact on how patients manage their treatment,” said Doug Veale, professor of rheumatology at St Vincent’s Hospital in Dublin.

“I know with confidence as to whether my patients are adhering to their treatment strategy.”

Editor John Kennedy is an award-winning technology journalist.

editorial@siliconrepublic.com

 

SOURCE

https://www.siliconrepublic.com/start-ups/healthbeacon-series-a-investment

Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: #JPM2019 for Jan. 8, 2019; Opening Videos, Novartis expands Cell Therapies, January 7 – 10, 2019, Westin St. Francis Hotel | San Francisco, California

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 8, 2019: Deals and Announcements

 

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The Convergence of Medical Devices & Drugs: Advances in Drug Delivery May 3, 2018 12:00 PM – 5:00 PM, Westin Hotel, Waltham, MA

Westin Waltham Boston 
70 3rd Avenue Waltham MA US 02451

MassBio’s second annual Medical Device Event will focus on opportunities and advances in drug delivery, including the unique developmental and regulatory challenges these products face, the many scientific advances in the space and new opportunities for funding.  Panelists will discuss innovation and commercialization strategies.

Advances in drug delivery technologies are improving the safety and efficacy of new and existing therapies. The success of many new therapies in development is contingent on the development of effective delivery systems.   Traditional drug delivery methods won’t work for some compounds and biologics.   Stability issues create challenges for storage and transport.  There are opportunities for combination drug delivery products to extend the patent life of drugs on the market.  From diffusion based polymer systems to complex delivery devices utilizing diagnostic sensors and sophisticated control systems for precise and timely delivery of life-saving agents, a diverse set of scientific and engineering disciplines are being brought to bear within this space.  However, combination products involve components that would normally be developed under different types of regulations, design criteria, and controls.  This symposium will explore many of the diverse aspects impacting drug delivery products.

This event will feature an active exhibit hall, panel discussions, a keynote speaker and networking sessions. This is an excellent opportunity for companies to reach a diverse audience that represents nearly every aspect of the life sciences industry, including academic researchers, entrepreneurs, device engineers and biopharma executives.

Clinicians will discuss the medical challenges for which drug delivery innovations have provided a unique solution.  Academic researchers will discuss scientific advances which may lead to breakthrough products.   Entrepreneurs will discuss strategies for funding new product ventures, and development issues specific to drug delivery products.  Corporate speakers will discuss the challenges across the value chain of manufacturing and selling combination products globally.  Regulatory speakers will address current thinking and approaches to drug delivery products within government agencies, both US and internationally.

SOURCE

https://www.massbio.org/events/the-convergence-of-medical-devices-and-drugs-advances-in-drug-delivery-2624?utm_campaign=med-device-18&utm_medium=email&utm_source=email-signature&utm_content=&utm_term=

Registration

12:00 pm  12:30 pm

Opening Remarks

12:30 pm  12:45 pm

Keynote Presentation

12:45 pm  1:15 pm

Innovation & Development Panel

1:30 pm  2:45 pm

Networking Break

2:45 pm  3:15 pm

Commercialization Pathways Panel

3:15 pm  4:30 pm

Networking Reception

4:30 pm  5:30 pm

Speakers

  • Bob Coughlin, President & CEO, MassBio

Keynote Speaker: Michael J. Cima, Ph.D., Associate Dean of Innovation, MIT

  1. Intraperiotneal Chemotherapy needed to remove the few cells left after surgery _ delivery of drugs to a single compartment
  2. Hyperthermic Intraperiotneal Chemotherapy
  3. Tumor burden – stage 3 women ovarian cancer
  4. Extended IP drug exposure
  5. device for drug delivery to the bladder (cancer): Inflammatory bladder disease, overactive Bladder, bladder (cancer); bladder removal (radical cystectomy – residual tumor size 3 cm tumor)
  6. Local Drug delivery for stone disease in ureter
  7. Change the pharmacology and change the lesion in the bladder – lesion disappeared in a single compartment
  8. Mutation burden in Brain Cancer and in Ovarian Cancer much smaller than in Lung cancer
  9. local drug delivery to one location in the brain and the drug will be carried to the entire body – pathology of the brain leads to different disease related to the Human Brain. Treatment of hemorrhage
  10. Cervical cancer under MRI deliver drug to the tumor hypoxy of the tumor, guide the drug dosage using imaging MRI is Radiation therapy not drug therapy

PANEL 1: Product Development: Drug-Device Technology moderated by Kristina Bieker-Brady, Ph.D., Partner, McDermott Will & Emery LLP

  1. Basic research to clinical development: Drug delivery System
  • Benjamin S. Bleier, MD, FACS, FARS, Associate Professor, Director of Endoscopic Skull Base Surgery, Co-Director Center for Thyroid Eye Disease and Orbital Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School
  1. BBB – Invasive, Non-invasive, Drug modification
  2. Platform technology , Enabling technology to pass BBB Scalable technology: SAfe
  3. Nasal bleed
  4. Nasal Cavity – ENTRY point to the brain use vascularized tissue
  5. nasal mucosa more permeable that any other tissue – diffuse drugs into the brain
  6. Autologous tissue – Nasal Mucosa: Proteins Oligonucleotides,
  • Maria Palasis, President and CEO, 480 Biomedical, Inc.
  • Maria Berkman, MD, MBA, Director and Head of MedTech practice, Broadview Ventures
  • Evan Sherr
  1. Brent Buchine, Ph.D., Co-Founder and CTO, Windgap Medical, Inc.

 PANEL 2: Commercialization Challenges

Moderator: Harry Glorikian, General Partner, New Ventures Funds

  • Paul Just, PharmD, Senior Principal, Medical Device Health Economics, ICON plc
  1. VALUE (outcome achieved per $) is the currency for market ACCESS knock down barriers Care COST
  2. Physician choose product that they wish to use while providing therapy as the lowest cost
  3. Assessing Differentiating Value and Reimbursement
  4. No guidance for combination products: New method of treating patients: Drug-Device
  5. Value: Who benefits from the Value – Target stakeholders: 90 days vs 18-24 month, long term value
  • Pamela J. Weagraff, Director, MedTech Regulatory, IQVIA [Quantile merged IMS]
  1. MedTech meet BioPharma
  2. Clinical data requirements for medical devices on the increase but not not necessarily in many cases
  3. Combination Products: Microfluidics, micronization – not chemistry but features of the drug delivery device
  4. Option 1,2,3 for Combination Product Pathways: Draft Guidance –>> FINAL immediately in effect
  • Jessica Ballinger, Chief Operating Officer, Lyndra
  1. Lyndra’s Ultra-long drug release – Extended Release Oral Capsule: 7 days
  2. Dosage Form – Safety
  3. Drug delivery – material manufacturing for long term resident inside the human body
  4. Candidates: AD, Diabetes
  5. Encapsulation automated – 3 partners assembly in several int’l locations in the supply chain: complications in making tablets – three years before the launch, freeze design 1st generation, 2nd generation
  • Steven Rosenberg, Otsuka Pharmaceutical

 

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FDA Approval of Anti-Depression Digital Pill Tracks Use When Swallowed and transmits to MDs Smartphone – A Breakthrough in Medication Remote Compliance Monitoring

 

Reporter: Aviva Lev-Ari, PhD, RN

 

The so-called digital pill is a version of Otsuka Pharmaceutical Co.’s Abilify, which treats depression, bipolar disorder and schizophrenia. The sensor, developed by Proteus Digital Health, is activated by stomach fluids, sending a signal to a patch worn on the patient’s torso and transmitting the information to a smartphone app.

  • Sensor in depression pill transmits data to a smartphone app
  • Lets doctors track patient’s use, prevent missing medicines

SOURCE

https://www.bloomberg.com/news/articles/2017-11-14/fda-approves-a-digital-pill-that-can-track-when-you-swallowed-it

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Image Source:Koch Institute

 

LIVE – OCTOBER 16 – DAY 1- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium

Koch Institute Immune Engineering Symposium 2017

http://kochinstituteevents.cvent.com/events/koch-institute-immune-engineering-symposium-2017/agenda-64e5d3f55b964ff2a0643bd320b8e60d.aspx

 

#IESYMPOSIUM

 

Image Source: Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Aviva Lev-Ari, PhD, RN will be in attendance covering the event in REAL TIME

@pharma_BI

@AVIVA1950

#IESYMPOSIUM

@KOCHINSTITUTE

  • The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The Immune System and Therapeutics (Series D: BioMedicine & Immunology) Kindle Edition – on Amazon.com since September 4, 2017

https://www.amazon.com/dp/B075CXHY1B

SYMPOSIUM SCHEDULE

OCTOBER 16 – DAY 1

7:00 – 8:15 Registration

8:15 – 8:30Introductory Remarks
Darrell Irvine | MIT, Koch Institute; HHMI

  • Stimulating the Immune system not only sustaining it for therapies

K. Dane Wittrup | MIT, Koch Institute

8:30 – 9:45Session I
Moderator: Douglas Lauffenburger | MIT, Biological Engineering and Koch Institute

Garry P. Nolan – Stanford University School of Medicine
Pathology from the Molecular Scale on Up

  • Intracellular molecules,
  • how molecules are organized to create tissue
  • Meaning from data Heterogeneity is an illusion: Order in Data ?? Cancer is heterogeneous, Cells in suspension – number of molecules
  • System-wide changes during Immune Response (IR)
  • Untreated, Ineffective therapy, effective therapy
  • Days 3-8 Tumor, Lymph node…
  • Variation is a Feature – not a bug: Effective therapy vs Ineffective – intercellular modules – virtual neighborhoods
  • ordered by connectivity: very high – CD4 T-cells, CD8 T-cels, moderate, not connected
  • Landmark nodes, Increase in responders
  • CODEX: Multiples epitome detection
  • Adaptable to proteins & mRNA
  • Rendering antibody staining via removal to neighborhood mapping
  • Human tonsil – 42 parameters: CD7, CD45, CD86,
  • Automated Annotations of tissues: F, P, V,
  • Normal BALBs
  • Marker expression defined by the niche: B220 vs CD79
  • Marker expression defines the niche
  • Learn neighborhoods and Trees
  • Improving Tissue Classification and staining – Ce3D – Tissue and Immune Cells in 3D
  • Molecular level cancer imaging
  • Proteomic Profiles: multi slice combine
  • Theory is formed to explain 3D nuclear images of cells – Composite Ion Image, DNA replication
  • Replication loci visualization on DNA backbone – nascent transcriptome – bar code of isotopes – 3D  600 slices
  • use CRISPR Cas9 for Epigenetics

Susan Napier Thomas – Georgia Institute of Technology
Transport Barriers in the Tumor Microenvironment: Drug Carrier Design for Therapeutic Delivery to Sentinel Lymph Nodes

  • Lymph Nodes important therapeutics target tissue
  • Lymphatic flow support passive and active antigen transport to lymph nodes
  • clearance of biomolecules and drug formulations: Interstitial transport barriers influence clearance: Arteriole to Venule –
  • Molecular tracers to analyze in vivo clearance mechanisms and vascular transport function
  • quantifying molecular clearance and biodistribution
  • Lymphatic transport increases tracer concentrations within dLN by orders of magnitude
  • Melanoma growth results in remodeled tumor vasculature
  • passive transport via lymphatic to dLN sustained in advanced tumors despite abrogated cell trafficking
  • Engineered biomaterial drug carriers to enhance sentinel lymph node-drug delivery: facilitated by exploiting lymphatic transport
  • TLR9 ligand therapeutic tumor in situ vaccination – Lymphatic-draining CpG-NP enhanced
  • Sturcutral and Cellular barriers: transport of particles is restriced by
  • Current drug delivery technology: lymph-node are undrugable
  • Multistage delivery platform to overcome barriers to lymphatic uptake and LN targeting
  • nano particles – OND – Oxanorbornade OND Time sensitive Linker synthesized large cargo – NP improve payload
  • OND release rate from nanoparticles changes retention in lymph nodes – Axilliary-Brachial delivery
  • Two-stage OND-NP delivery and release system dramatically – OND acumulate in lymphocyte
  •  delivers payload to previously undraggable lymphe tissue
  • improved drug bioactivity  – OND-NP eliminate LN LYMPHOMAS
  • Engineered Biomaterials

Douglas Lauffenburger – MIT, Biological Engineering and Koch Institute
Integrative Multi-Omic Analysis of Tissue Microenvironment in Inflammatory Pathophysiology

  • How to intervene, in predictive manner, in immunesystem-associated complex diseases
  • Understand cell communication beteen immune cells and other cells, i.e., tumor cells
  • Multi-Variate in Vivo – System Approach: Integrative Experiment & COmputational Analysis
  • Cell COmmunication & Signaling in CHronic inflammation – T-cell transfer model for colitis
  • COmparison of diffrential Regulation (Tcell transfer-elicited vs control) anong data types – relying solely on mRNA can be misleading
  • Diparities in differential responses to T cell transfer across data types yield insights concerning broader multi-organ interactions
  • T cell transfer can be ascertained and validated by successful experimental test
  • Cell COmmunication in Tumor MIcro-Environment — integration of single-cell transcriptomic data and protein interaction
  • Standard Cluster Elucidation – Classification of cell population on Full gene expression Profiles using Training sets: Decision Tree for Cell Classification
  • Wuantification of Pairwise Cell-Cell Receptor/Ligand Interactions: Cell type Pairs vs Receptor/Ligand Interaction
  • Pairwise Cell-Cell Receptor/Ligand Interactions
  • Calculate strength of interaction and its statistical significance
  • How the interaction is related to Phenotypic Behaviors – tumor growth rate, MDSC levels,
  • Correlated the Interactions translated to Phynotypic behavior for Therapeutic interventions (AXL via macrophage and fibroblasts)
  • Mouth model translation to Humans – New machine learning approach
  • Pathways, false negative, tumor negative expression
  • Molecular vs Phynotypical expression
  • Categories of inter-species translation
  • Semi-supervised Learning ALgorithms on Transcriptomic Data can ascertain Key Pathways/Processes in Human IBD from mapping mouse IBD

9:45 – 10:15 Break

10:15 – 11:30Session II
Moderator: Tyler Jacks | MIT, Koch Institute; HHMI

Tyler Jacks – MIT, Koch Institute; HHMI
Using Genetically Engineered Mouse Models to Probe Cancer-Immune Interactions

  • Utility of genetically-engineered mouse models of Cancer:
  1. Immune Response (IR),
  2. Tumor0immune microenvironment
  • Lung adenocarcinoma – KRAS mutation: Genetically-engineered model, applications: CRISPR, genetic interactions
  • Minimal Immune response to KP lung tumors: H&E, T cells (CD3), Bcells (B220) for Lenti-x 8 weeks
  • Exosome sequencing : Modeling loss-and gain-of-function mutations in Lung Cancer by CRISPR-Cas9 – germline – tolerance in mice, In vivo CRISPR-induced knockout of Msh2
  • Signatures of MMR deficient
  • Mutation burden and response to Immunotherapy (IT)
  • Programmed neoantigen expression – robust infiltration of T cells (evidence of IR)
  • Immunosuppression – T cell rendered ineffective
  • Lymphoid infiltration: Acute Treg depletion results in T cell infiltration — this depletion causes autoimmune response
  • Lung Treg from KP tumor-bearing mice have a distinct transcriptional heterogeneity through single cell mRNA sequencing
  • KP, FOXP3+, CD4
  • Treg from no existent to existance, Treg cells increase 20 fold =>>>  Treg activation and effectiveness
  • Single cells cluster by tissue and cell type: Treg, CD4+, CD8+, Tetramer-CD4+
  • ILrl1/II-33r unregulated in Treg at late time point
  • Treg-specific deletion of IL-33r results in fewer effector Tregs in Tumor-bearing lungs
  • CD8+ T cell infiltration
  • Tetramer-positive T cells cluster according to time point: All Lung CD8+ T cells
  • IR is not uniform functional differences – Clones show distinct transcriptional profiles
  • Different phynotypes Exhaustive signature
  • CRISPR-mediated modulation of CD8 T cell regulatory genes
  • Genetic dissection of the tumor-immune microenvironment
  • Single cell analysis, CRISPR – CRISPRa,i, – Drug development

Wendell Lim – University of California, San Francisco

Synthetic Immunology: Hacking Immune Cells

  • Precision Cell therapies – engineered by synthetic biology
  • Anti CD19 – drug approved
  • CAR-T cells still face major problems
  1. success limited to B cells cancers = blood vs solid tumors
  2. adverse effects
  3. OFF-TUMOR effects
  • Cell engineering for Cancer Therapy: User remote control (drug) – user control safety
  • Cell Engineering for TX
  1. new sensors – decision making for
  2. tumor recognition – safety,
  3. Cancer is a recognition issue
  • How do we avoid cross-reaction with bystader tissue (OFF TISSUE effect)
  • Tumor recognition: More receptors & integration
  • User Control
  • synthetic NOTCH receptors (different flavors of synNotch) – New Universal platform for cell-to -cell recognition: Target molecule: Extracellular antigen –>> transciptional instruction to cell
  • nextgen T cell: Engineer T cell recognition circuit that integrates multiple inputs: Two receptors – two antigen priming circuit
  • UNARMED: If antigen A THEN receptor A activates CAR
  • “Bystander” cell single antigen vs “tumor” drug antigen
  • Selective clearance of combinatorial tumor – Boulian formulation, canonical response
  • Cell response: Priming –>> Killing: Spatial & Temporal choreographed cell
  • CAR expression while removed from primed cells deminished
  • Solid Tumor: suppress cell microenvironment: Selected response vs non-natural response
  • Immune stimulator IR IL2, IL12, flagellin in the payload — Ourcome: Immune enhancement “vaccination”
  • Immune suppression –  block
  • Envision ideal situation: Unarmed cells
  • FUTURE: identify disease signatures and vulnerabilities – Precision Medicine using Synthetic Biology

Darrell Irvine – MIT, Koch Institute; HHMI
Engineering Enhanced Cancer Vaccines to Drive Combination Immunotherapies

  • Vaccine to drive IT
  • Intervening in the cancer-immunity cycle – Peptide Vaccines
  • poor physiology  of solute transport to tissue
  • endogenous albumin affinity – Lymphe Node dying
  • Designing Albumin-hitchhiking vaccines
  • Amphiphile-vaccine enhance uptake in lymph nodes in small and large animal models
  • soluble vaccine vs Amphiphile-vaccine
  • DIRECTING Vaccines to the Lymph nodes
  • amph-peptide antigen: Prime, booster, tetramer
  • albimin-mediated LN-targeting of both antigen and adjuvant maximizes IR
  • Immuno-supressed microenvironment will not be overcome by vaccines
  • Replacing adoptive T cell transfer with potent vaccine
  • exploiting albumin biology for mucosal vaccine delivery by amph-vaccines
  • Amph-peptides and -adjuvants show enhanced uptake/retention in lung tissue
  •  Enhancing adoptive T cell therapy: loss of T cell functionality, expand in vivo
  • boost in vivo enhanced adoptive T cell therapy
  • CAR-T cells: Enable T cells to target any cell surface protein
  • “Adaptor”-targeting CAR-T cells to deal with tumor cell heterogeneity
  • Lymph node-targeting Amph as CAR T booster vaccine: prining, production of cytokines
  • Boosting CAR T with amph-caccines: anti FITC CAR-T by DSPE=PEG-FITC coated
  • Targeting FITC to lymph node antigen presenting cells
  • Modulatory Macrophages
  • Amph-FITC expands FITC-CAR T cells in vivo – Adjuvant is needed
  • Hijacking albumin’s natural trafficking pathway

11:30 – 1:00  Lunch Break

1:00 – 2:15Session III
Moderator: Darrell Irvine | MIT, Koch Institute; HHMI

Nicholas P. Restifo – National Cancer Institute
Extracellular Potassium Regulates Epigenetics and Efficacy of Anti-Tumor T Cells

Why T cell do not kill Cancer cells?

  • co-inhibition
  • hostile tumor microenvironment

CAR T – does not treat solid tumors

Somatic mutation

  1. resistence of T cell based IT due to loss of function mutations
  2. Can other genes be lost?

CRISPR Cas9 – used to identify agents – GeCKOv2 Human library

Two cell-type (2CT) CRISPR assay system for genome-wide mutagenesis

  • work flow for genome-scale SRISPR mutagenesis profiling of genes essential for T cell mediate cytosis
  • sgRNA enrichment at the individual gene level by multiple methods:
  1. subunits of the MHC Class I complex
  2. CRISPR mutagenesis cut germline
  • Measutring the generalizability of resistance mechanism and mice in vivo validation
  • Validation of top gene candidates using libraries: MART-1
  • Checkpoint blockade: cells LOF causes tumor growth and immune escape
  • Weird genesL Large Ribisomal Subunit Proteins are nor all essential for cell survival
  • Bias in enrichment of 60S vs 40S
  • Novel elements of MHC class I antigen processing and presentation
  • Association of top CRISPR hits with response rates to IT – antiCTLA-4
  • CRISPR help identify novel regulators of T cells
  • Analyzed sgRNA – second rarest sgRNA for gene BIRC2 – encoded the Baculoviral Inhibitor
  • Drugs that inhibit BIRC2
  • How T cells can kill tumor cells more efficiently
  • p38kiaseas target for adoptive immunotherapy
  • FACS-based – Mapk14
  • Potent targets p38 – Blockade PD-1 or p38 ??
  • p38 signaling: Inhibition augments expansion and memory-marked human PBMC and TIL cells, N. P. Restifo
  • Tumor killing capacity of human CD19-specific, gene engineered T cells

Jennifer Elisseeff – Johns Hopkins University
The Adaptive Immune Response to Biomaterials and Tissue Repair

  • design scafolds, tissue-specific microenvironment
  • clinical translation of biosynthetic implants for soft tissue reconstruction
  • Local environment affects biomaterials: Epidermis, dermis
  • CD4+ T cells
  • Immune system – first reponders to materials: Natural or Synthetic
  • Biological (ECM) scaffolds to repair muscle injury
  • Which immune cells enter the WOUND?
  • ECM alters Macrophages: CD86, CD206
  • Adaptive system impact on Macrophages: CD86
  • mTOR signaling pathway M2 depend on Th2 Cells in regeneration of cell healing of surgical wounds
  • Systemic Immunological changes
  • Is the response antigen specific? – IL-4 expression in ILN,
  • Tissue reconstruction Clinical Trial: FDA ask to look at what cells infiltrate the scaffold
  • Trauma/biomaterial response – Injury induction of Senescence, anti apoptosis
  • Injury to skin or muscle
  • Is pro-regenerative environment (Th2/M2) pro-tumorigenic?
  • SYNTHETIC Materials for scafolds
  • Biomaterials and Immunology
  1. Immune response to bioscafolds
  2. environment modulate the immune system
  • Regenerative Immunetherapy

Marcela Maus – Massachusetts General Hospital

Engineering Better T Cells

  • Comparing CD19 CARs for Leukemia – anti-CD19- directed CAR T cells with r/r B-cell ALL – age 3-25 – FDA approved Novartis tisagenlecleucel – for pediatric r/r/ ALL
  • Phase II in diffuse large B cell lymphoma. Using T cells – increases prospects for cure
  • Vector retroviral – 30 day expression
  • measuring cytokines release syndrome: Common toxicity with CAR 19
  • neurological toxicity, B-cell aplagia
  • CART issues with heme malignancies
  1. decrease cytokine release
  2. avoid neurological toxicity – homing
  3. new targets address antigene escape variants – Resistance, CD19 is shaded, another target needed
  4. B Cell Maturation Antigen (BCMA) Target
  5. Bluebird Bio: Response duratio up to 54 weeks – Active dose cohort
  6. natural ligand CAR based on April
  7. activated in response to TACI+ target cells – APRIL-based CARs but not BCMA-CAR is able to kill TACI+ target cells
  • Hurdles for Solid Tumors
  1. Specific antigen targets
  2. tumor heterogeneity
  3. inhibitory microenvironment
  • CART in Glioblastoma
  1. rationale for EGFRvIII as therapeutic target
  2. Preclinical Studies & Phase 1: CAR t engraft, not as highly as CD19
  3. Upregulation of immunosuppression and Treg infiltrate in CART EGFRvIII as therapeutic target, Marcela Maus
  • What to do differently?

 

2:15 – 2:45 Break

2:45 – 4:00 Session IV
Moderator: Arup K. Chakraborty | MIT, IMES

Laura Walker – Adimab, LLC
Molecular Dissection of the Human Antibody Response to Respiratory Syncytial Virus

  • prophylactic antibody is available
  • Barriers for development of Vaccine
  • Prefusion and Postfusion RSV structures
  • Six major antigenic sites on RSV F
  • Blood samples Infants less 6 month of age and over 6 month: High abundance RSV F -specific memory B Cells are group  less 6 month

Arup K. Chakraborty – MIT, Institute for Medical Engineering & Science
How to Hit HIV Where it Hurts

  • antibody  – Model IN SILICO
  • Check affinity of each Ab for the Seaman panel of strain
  • Breadth of coverage
  • immmunize with cocktail of variant antigens
  • Mutations on Affinity Maturation: Molecular dynamics
  • bnAb eveolution: Hypothesis – mutations evolution make the antigen binding region more flexible,
  • Tested hypothesisi: carrying out affinity maturation – LOW GERMLINE AFFINITY TO CONSERVE RESIDUES IN 10,000 trials, acquire the mutation (generation 300)

William Schief – The Scripps Research Institute
HIV Vaccine Design Targeting the Human Naive B Cell Repertoire

  • HIV Envelope Trimer Glycan): the Target of neutralizing Antibodies (bnAbs)
  • Proof of principle for germline-targeting: VRC)!-class bnAbs
  • design of a nanoparticle
  • can germline -targeting innumogens prime low frequency precursors?
  • Day 14 day 42 vaccinate
  • Precursor frequency and affinity are limiting for germline center (GC) entry at day 8
  • Germline-targeting immunogens can elicit robust, high quality SHM under physiological conditions of precursor frequency and affinity at day 8, 16, 36
  • Germline-targeting immunogens can lead to production of memory B cells

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