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LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

Posted in Autoimmune Inflammatory DIseases, CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, Immuno-Oncology & Genomics, Immunodiagnostics, Immunotherapy, Inflammasome, Innovation in Immunology Diagnostics, Monoclonal Immunotherapy on September 21, 2016| Leave a Comment »

LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14^th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

#BostonDOT16

@BostonDOT

3:20 Chairperson’s Opening Remarks

Guido J.R. Zaman, Ph.D., Managing Director & Head of Biology, Netherlands Translational Research Center B.V. (NTRC)

3:25 FEATURED PRESENTATION: Inhibition of PI3K and Tubulin

Doriano Fabbro, Ph.D., CSO, PIQUR Therapeutics

The PI3K signaling pathway is frequently activated in tumors. PQR309 is a selective dual inhibitor of PI3K and mTOR (currently in Phase I) in cancer patients. The preclinical pharmacology and toxicology of PQR309 is presented, including its activity in lymphoma preclinical models. In addition, we elucidate structural factors defining the PI3K inhibitory activity and tubulin-binding of PQR309 derivatives.

PQR309 & GDC0941 arrest cells i G1/S (typical for PI3K/mTOR Inhibitor)
What drives Antiproliferative Activity of BKM120: PI3K or MT or both?
BKM120 Binds to beta-Tubulin/alpha -Tubulin Interfere
T2R-TTL complex
Orientation of BKM120 in PI3K
PQR309 – is a brain penetrating, PK and BAV by PO, good metabolic stability
PQR309 ANti-proliferative in Lymphoma
Clinical efficacy – Now in Phase II

4:05 Design and Development of a Novel PI3K-p110β/δ Inhibitor, KA2237 with Combined Tumor Immunotherapeutic, Growth Inhibition and Anti-Metastatic Activity

Stephen Shuttleworth, Ph.D., FRSC, CChem, CSO, Karus Therapeutics Ltd.

The design and development of KA2237, a novel and selective inhibitor of PI3K-p110β/δ, will be described. This molecule has clinical potential in the treatment of solid and hematological malignancies, through its direct inhibition of tumor growth and metastatic spread, and through immunotherapeutic mechanisms. Phase I studies for KA2237 are scheduled to commence in Q2 2016 at the MD Anderson Cancer Center.

Design & Development of Novel, Oral, selective PI3K enzyme family: CLass I,II, III, IV based upon:
Class I IA IB
KA2237: DUal PI3K – p110beta/delta-selective inhibitor: CTL, Treg, p1 106 T sell response
Molecular signature in the tumor
WT p110delta, WT 1 10beta+, Mutant p1 10Beta+, PTEN-null, Ibrutinib-resistance, Growth inhibition; suppression of metastesis (p110beta
small molecule combination agents: potential aided by selectivity over p110
KA2237: clinical Pi3K-p110beta/delta Inhibitor- ATP -comtetitive
Doxorubicin -cytotoxic control
KA2237 superior activity to Idelasib
KA2237 – suppression of micro-metastasis in 4T1 synergenic model
Tumor Growth inhibition Pre-Surgery
Tumor Re-Growth Inhibition Post-Surgery
metastasis post surgery
Tumor-free mice post-surgery
CHemistry: IHC -pAKT; IHC – FOxp3+
KA2237 inhibits HGF-stimulated 4T1 tumor
2004 – Preclinical develpemnt PI3K is reported
2006 First PI#K is enter Clinical Trials
Targeting p1110Beta (PIKeCB) mutations in cancer with KA2237
DIscovery of the mutations lead drug discovery
KA@@#&: Potential in treatment of B-Cell Lymphom AS IN TARGETING IBRUTINIB RESISTENCE
GROWTH INHIBITION IN HEMATOLOGICAL CANCERS TUMOE CELL LINE PANEL
KA2237 – differentiated from competing Pi3K is Superior efficacy cf. p110delta
Combination: Not histone deacetylase but a tubulin deacetylase – Hsp90 ans Hsp70
T cell exhausion: Tumor growth inhibition vs Suppression of lung metastasis
Tumor BiologyRationale vs Clinical Agents
Oncogenic mutants, solid tumor supression magrophage, combination PD-1, CTLA$
FDA -approved kinase inhibitors

Summary

phase I clinical study commenced in pathients with B cell Lymphoma
Potential for treatment of solid and hematological malignancies

4:35 InCELL Pulse: A Novel Cellular Target Engagement Assay Platform for Drug Discovery

Daniel Treiber, Ph.D., Vice President, KINOMEscan, DiscoverX Corporation

InCELL Pulse is a quantitative and rapid method for measuring cellular target engagement potencies for small molecule inhibitors. InCELL Pulse capitalizes on two novel DiscoverX technologies, Enzyme Fragment Complementation (EFC) and Pulse Denaturation, which overcome the limitations of related target engagement methods. Examples across multiple target classes will be described.

InCELL Pulse – cellular Target ENgagement Assays
cellular thermal stabilization-based approach
simple, rapid and generig cellular alternative to CETSa
Thermal melting Curves vs Isothermal Inhibitor EC50 curves
Pulse Denaturation compound binding, or not binding
ABL1 Tyrosine Kinase – dose response curve – allosteric Inhibitor
MTH1 Hydrolase: InCELL Pulseassay validated for multiple substrate-competitive inhibitors
Validated InCELL Pulse Assays for Diverse Kinases
Kinase targets; BRAF, MEC1

Summary

validation across proteins

4:50 Potential Application of Fluorescence Lifetime Assays to Enable Robust, Rapid Protein Binding Assays

Paul Wylie, Ph.D., Head, Applications, TTP Labtech

Current methods to screen protein binding interactions often have limitations due to the reliance on antibodies, but also interference from fluorescent molecules. Fluorescence lifetime has the potential to overcome these problems through directly labelled proteins and lifetime measurements that are independent of total fluorescence intensity.

Protein binding as a target class
protein-protein interactions (PPIs)

FRET/HTRF
FP
AlphaScreen

What new in FLT?

long lifetime fluorophores, economical reagent platform
directly labelled reagents – no antibodies
independent of total intensity – reduced interference
robustness screen vs nuisance screen – caspase-3
productive; reduction false positives: FRET
protein-binding assays & FLT formats:

protein – small molecule binding – CECR2
protein – peptide binding: long and sholt lifetime
Site-specific labelling vs Non-selective labelling
Toolbox for PoC
Detection reagents
Further develop technology

5:05 Refreshment Break in the Exhibit Hall with Poster Viewing

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Milestones in Physiology & Discoveries in Medicine and Genomics: Request for Book Review Writing on Amazon.com

Posted in Autoimmune Inflammatory DIseases, Biological Networks, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cancer Informatics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Clinical Diagnostics, Clinical Genomics, Computational Biology/Systems and Bioinformatics, Developmental biology, Diagnostic Immunology, Diagnostics and Lab Tests, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, DNA repair, Drug Delivery Platform Technology, Drug Development Process, Enzyme Induction, Epigenetics and Environmental Factors, Gene Regulation and Evolution, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Human Sensation and Cellular Transduction: Physiology and Therapeutics, Immuno-Oncology & Genomics, Immunodiagnostics, Immunotherapy, Innovation in Immunology Diagnostics, International Global Work in Pharmaceutical, Investment in Technological Breakthrough, Medical and Population Genetics, Microbiologial genetics, Microbiology, Molecular Genetics & Pharmaceutical, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmacogenomics, Population genetics, RNA Biology, RNA Biology, Cancer and Therapeutics, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, Technology Transfer: Biotech and Pharmaceutical on September 11, 2016| Leave a Comment »

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective

http://www.amazon.com/dp/B019VH97LU

2015

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

Preface

Introduction

Chapter 1: Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

1.1 Outline of Medical Discoveries between 1880 and 1980

1.2 The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

1.3 The Classification of Microbiota

1.4 Selected Contributions to Chemistry from 1880 to 1980

1.5 The Evolution of Clinical Chemistry in the 20th Century

1.6 Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

Chapter 2. The search for the evolution of function of proteins, enzymes and metal catalysts in life processes

2.1 The life and work of Allan Wilson
2.2 The evolution of myoglobin and hemoglobin
2.3 More complexity in proteins evolution
2.4 Life on earth is traced to oxygen binding
2.5 The colors of life function
2.6 The colors of respiration and electron transport
2.7 Highlights of a green evolution

Chapter 3. Evolution of New Relationships in Neuroendocrine States
3.1 Pituitary endocrine axis
3.2 Thyroid function
3.3 Sex hormones
3.4 Adrenal Cortex
3.5 Pancreatic Islets
3.6 Parathyroids
3.7 Gastointestinal hormones
3.8 Endocrine action on midbrain
3.9 Neural activity regulating endocrine response

3.10 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Chapter 4. Problems of the Circulation, Altitude, and Immunity

4.1 Innervation of Heart and Heart Rate
4.2 Action of hormones on the circulation
4.3 Allogeneic Transfusion Reactions
4.4 Graft-versus Host reaction
4.5 Unique problems of perinatal period
4.6. High altitude sickness
4.7 Deep water adaptation
4.8 Heart-Lung-and Kidney
4.9 Acute Lung Injury

4.10 Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

Chapter 5. Problems of Diets and Lifestyle Changes

5.1 Anorexia nervosa
5.2 Voluntary and Involuntary S-insufficiency
5.3 Diarrheas – bacterial and nonbacterial
5.4 Gluten-free diets
5.5 Diet and cholesterol
5.6 Diet and Type 2 diabetes mellitus
5.7 Diet and exercise
5.8 Anxiety and quality of Life
5.9 Nutritional Supplements

Chapter 6. Advances in Genomics, Therapeutics and Pharmacogenomics

6.1 Natural Products Chemistry

6.2 The Challenge of Antimicrobial Resistance

6.3 Viruses, Vaccines and immunotherapy

6.4 Genomics and Metabolomics Advances in Cancer

6.5 Proteomics – Protein Interaction

6.6 Pharmacogenomics

6.7 Biomarker Guided Therapy

6.8 The Emergence of a Pharmaceutical Industry in the 20th Century: Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

6.09 The Union of Biomarkers and Drug Development

6.10 Proteomics and Biomarker Discovery

6.11 Epigenomics and Companion Diagnostics

Chapter 7

Integration of Physiology, Genomics and Pharmacotherapy

7.1 Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

7.2 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

7.3 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

7.4 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

7.5 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

7.6 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

7.7 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

7.8 Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

7.9 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

7.10 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by

7.11 Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

Chapter 7. Biopharma Today

8.1 A Great University engaged in Drug Discovery: University of Pittsburgh

8.2 Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

8.3 Predicting Tumor Response, Progression, and Time to Recurrence

8.4 Targeting Untargetable Proto-Oncogenes

8.5 Innovation: Drug Discovery, Medical Devices and Digital Health

8.6 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

8.7 Nanotechnology and Ocular Drug Delivery: Part I

8.8 Transdermal drug delivery (TDD) system and nanotechnology: Part II

8.9 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

8.10 Natural Drug Target Discovery and Translational Medicine in Human Microbiome

8.11 From Genomics of Microorganisms to Translational Medicine

8.12 Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

Chapter 9. BioPharma – Future Trends

9.1 Artificial Intelligence Versus the Scientist: Who Will Win?

9.2 The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

9.3 The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

9.4 Heroes in Medical Research: The Postdoctoral Fellow

9.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

9.6 1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

9.7 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

9.8 Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

9.9 Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

9.10 The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

Epilogue

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On its way for an IPO: mRNA platform Immune-Oncology, Moderna, is recruiting 100 new Life Scientists in Cambridge, MA

Posted in BioTechnology - Venture Creation, BioTechnology - Venture Creation, Venture Capital, Computational Biology/Systems and Bioinformatics, Diagnostic Immunology, Drug Delivery Platform Technology, Drug Development Process, Drug Discovery Chemistry, Genetics & Innovations in Treatment, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Immuno-Oncology & Genomics, Immunodiagnostics, Immunotherapy, Infectious Disease Immunodiagnostics, mRNA platform in Drug DIscovery, RNA Biology, RNA Biology, Cancer and Therapeutics, tagged mRNA-based therapy, vascular endothelial growth factor-A (VEGF-A) on September 7, 2016| Leave a Comment »

On its way for an IPO: mRNA platform, Moderna, Immune Oncology is recruiting 100 new Life Scientists in Cambridge, MA

Curator: Aviva Lev-Ari, PhD, RN

Deals:

Moderna has now raised $1.9 billion from investors like AstraZeneca – 9% stack [AstraZeneca’s Pascal Soriot helped get that all started with a whopping $240 million upfront in its 2013 deal, which was tied to $180 million in milestones.], with another $230 million on the table from grants. In addition to the financing announcement this morning, Moderna is also unveiling a pact to develop a new Zika vaccine, with BARDA putting up $8 million to get the program started while offering an option on $117 million more to get through a successful development program.

Novel Strategy in Biotech:

in biotech. Instead of grabbing one or two new drugs and setting out to gather proof-of-concept data to help establish its scientific credibility, the company has harvested a huge windfall of cash and built a large organization before even entering the clinic. And it did that without turning to an IPO.

Pipeline include:

The deal with AstraZeneca covers new drugs for cardiovascular, metabolic and renal diseases as well as cancer.
partners filed a European application to start a Phase I study of AZD8601, an investigational mRNA-based therapy that encodes for vascular endothelial growth factor-A (VEGF-A)
Moderna CEO spelled out plans to get the first 6 new drugs in the clinic by the end of 2016.
The first human study was arranged for the infectious disease drug mRNA 1440, which began an early stage study in 2015.
Moderna built up a range of big preclinical partnerships.
CEO Bancel says the number of drugs in development has swelled to 11, with the first set of data slated to be released in 2017.
Moderna also plans to add about 10 drugs to the clinic by next summer,

SOURCES

UPDATED: Booming Moderna is raising $600M while ramping up manufacturing and clinical studies

by john carroll – August 29, 2016

http://endpts.com/booming-moderna-is-adding-600m-while-ramping-up-manufacturing-and-clinical-studies/

$1.9B in: Moderna blueprints $100M facility, plans to double the pipeline after a $474M megaround

by john carroll – September 7, 2016

http://endpts.com/moderna-blueprints-100m-facility-plans-to-double-the-pipeline-after-a-474m-megaround/?utm_source=Sailthru&utm_medium=email&utm_campaign=Issue:%202016-09-07%20BioPharma%20Dive%20%5Bissue:7155%5D&utm_term=BioPharma%20Dive

Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?

Curator & Reporter: Stephen J. Williams, PhD – August 11, 2016

https://pharmaceuticalintelligence.com/2016/08/11/moderna-therapeutics-deal-with-merck-are-personalized-vaccines-here/

at #JPM16 – Moderna Therapeutics turns away an extra $200 million: with AstraZeneca (collaboration) & with Merck ($100 million investment)

Reporter: Aviva Lev-Ari, PhD, RN – January 13, 2016

https://pharmaceuticalintelligence.com/2016/01/13/at-jpm16-moderna-therapeutics-turns-away-an-extra-200-million-with-astrazeneca-collaboration-with-merck-100-million-investment/

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Plenary Keynotes TUESDAY 4:00PM – 5:30PM| AUGUST 30 @CHI’s IMMUNO-ONCOLOGY SUMMIT, Marriott Long Wharf Hotel in Boston

Posted in Conference Coverage with Social Media, Immuno-Oncology & Genomics, Oncolytic virus & OncoViro-Therapy on August 30, 2016| Leave a Comment »

Plenary Keynotes TUESDAY | AUGUST 30 4:00PM – 5:30PM @CHI’s IMMUNO-ONCOLOGY SUMMIT, Marriott Long Wharf Hotel in Boston

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

Leaders in Pharmaceutical Business intelligence (LPBI) Group

covers in Real Time the IMMUNO-ONCOLOGY SUMMIT using Social Media

Aviva Lev-Ari, PhD, RN,

Founder, LPBI Group & Editor-in-Chief

http://pharmaceuticalintelligence.com

Streaming LIVE @ Marriott Long Wharf Hotel in Boston

Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

Plenary Keynotes TUESDAY | AUGUST 30

4:00 Personalized, NeoantigenBased Immunotherapy

Edward Fritsch, Ph.D., Chief Technology Officer, Neon Therapeutics, Inc.

Multiple lines of evidence have demonstrated the critical role that Neoantigens have in the immune response to cancer and the availability of next-generation sequencing to identify personal, neoantigen-creating mutations has opened the door to directly enhance the power and breadth of host immunity to overcome this deadly disease.

Yervoy approved for melanoma ipilimumab
ipilimumab and Nivolumab combination
Cancer Vaccine for infections disease – PREVENTIVE NOT TREATMENT HPV
CLASSES OF TUMOR ANTIGENS CT many tumors: Methylation pattern
Selectively expressed: Melanomas
Over expressed antigens – some tumor

Personalized

Scientific Advance I:

Tumor DNA sequences: Kras, PIK3CA, FBXW7
Somatic mutations potential to generate neoantigens
Neoantigents: Native antigens (mage) vs NEOANTIGENS 0 tumor specific Antigens

Scientific Advance II:

Ipilimumab
anti PL-1
single neoantigen reactive CD4+ T cell clone mediates tumor rejection in adoptive therapy

A Neoantigen Vaccine – The Opportunity

T -cell capable of tumor infiltration

DFCI/Broad Institute: Tumor procurement, Target selection Personal caccine manufacturing Vaccine administration

Identify targets: accuracy, epitope features multipla epitopes
Personalised GMP manufacturing – 20 long peptide regulatory acceptance, time and cost

FDA approval:

High risk Melanoma (IIIB/C; IVM1a)
cancer with documented immune responsiveness
12 patients enrolled – Vaccine prepared for 8, 6 dosed
Immunological Responses: DeNovo – detectable directly ex-vivo: ICS Primarily CD4+ Poly-functional
CD8+ Responses – 1 Pre-stim: Pre vs 16 weeks after
Immunizing peptide (IMP)

NEON Therapeutics, Inc.:

Personalized Neoantigens vs Shared Neoantigens
Vaccines vs T-Cells
Moving into Advanced Metastatic disease — COmbination Checkpoint blockade

immediate response
synergies by combination therapy
Neoantigets

4:30 Merck Sasso

Emerging Innate Immune Targets for enhancing

Additional component of the Immune system

Combination of Checkpoint inhibitors – Targeting functionality of T-Cells
Standard of care moving to Goal State by Check point blocade
Monoclonal antibodies blocking PD-1 and CTLA4
Immunogenic cell death
Effectors that promote cross presentation of antigens
recruitment of T cells
reversing the pathways driving a repressing tumor environment

MERCK – Keytruda

Study with Dinociclib – Immunogenic Cell Death – induced by Radiation, combined with CTLA4 – median response overall survival – 20 month

MORE OPTIONS:

OV therapies – enhance tumor Combination:

TVEC +Keytruda – disease control 68%
CAVATAK +Keytruda
CAVATAK + pembrolizumab

TLR agonism

Two Phase I in melanoma
TC-1 Anti-IL-10 MK-1966 induced by SD-101
Innate Immune Triggers against Pathogens and Damaged selt

STING agonism

DNA Sensing cGAS/STING – another approach to viral mechanism for Cancer
Non-nuclear dsDNA is a ‘danger
DMXAA – can’t stimulate HUman only moth STING pathway

RNA – RIG like receptors –

leveraging anti-viral Mechanisms to eliminate Tumors
Activation of RIG-like receptor

SHARED MECHANISMS: INFgamma, TNF alpha

TLR9
RIG-I
STING
Oncolytic viruses

Summary

Merck – Keytruda – will be combined with different strategies to leverage innate immunity in combination with traditional T cell approaches
expend beyond T cell
limitation of checkpoint blockade therapies can be due to aberrant T cell localization and the suppressive microenvironment of the tumor

5:00 Reading Tea Leaves: The Dilemma of Prediction and Prognosis in Immunotherapy

Morganna Freeman, D.O., Associate Director, Melanoma & Cutaneous Oncology Program, The Angeles Clinic and Research Institute

With the rapid expansion of immunotherapeutics in oncology, scientifically significant advances have been made with both the depth and duration of antitumor responses. However, not all patients benefit, or quickly relapse, thus much scientific inquiry has been devoted to appropriate patient selection and how such obstacles might be overcome. While more is known about potential biomarkers, accurate prognostication persists as a knowledge gap, and efforts to bridge it will be discussed here.

CD8+ T cell – Tumor — Imune Priming — CHeckpoint Inhibition CD8+
execution is complex
predict who will benefit from what treatment
Patient and Tumor Profiling

Tcell Prining: TILs, PDL1, IDO, Tcell anergy Treg- Ovarian cancer: CD8+ TILs
microenvironment – immuno-scoring
Immune competence -flow, biomarkers CyTOF – Mass Flow Cytometry
mutation burden – chemo + Vaccine – longer time to progression
mictoenvironment – Tumor Profiling
tumor adaptation – serum ULBP2 NKligand – independent predictor of prognosis in Stage I-III
Predictive Genomic Analysis – Immune SIgnature of Response to CHeckPoint Blockage – liquid biopsy
Neoantigens: Allows analysis of T cell
Multispectral imaging – Immune cell phenotypes visualized and quantified simultaneously – improve TME immune suppression, TIL harvest potential, location of the T celle impact prognosis
Immune monitoring: Pre intervation vs Post Intervention
Tumor heterogeneity: Cancer progression and metastasis, clinical resistance
Intervention Assessments: Tissue marker of Blood which one is the best to use
Cloonal Tracking: Quantifying Tumor
ImmunoPET – anti CD8 immune-PET sensitive of tumor infiltrating
Transcriptomic Signature: IPRES (innate PD-1 resistence) can be induced by MAPKi, furthe account for poor response – due to immune depletion
Tests and immuno-toxicity, Translation to POC
Data assimilation
Ideal BioMarkers related to Mechanism of Action – multivariant scoring systems
Gender differences, BMI differences, Age difference — IN RESPONDING TO IMMUNOTHERAPY IN IMMUNO ONCOLOGY

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1:50 – 5:00 8/30 CONSIDERATIONS IN DESIGNING IMMUNOTHERAPY COMBINATIONS @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

Posted in Conference Coverage with Social Media, Immuno-Oncology & Genomics on August 30, 2016| Leave a Comment »

1:50 – 5:00 8/30 CONSIDERATIONS IN DESIGNING IMMUNOTHERAPY COMBINATIONS @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

Leaders in Pharmaceutical Business intelligence (LPBI) Group covers in Real Time the IMMUNO-ONCOLOGY SUMMIT using Social Media

Aviva Lev-Ari, PhD, RN,

Founder, LPBI Group & Editor-in-Chief

http://pharmaceuticalintelligence.com

I attended a parallel session @ Marriott Long Wharf Hotel in Boston

Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

1:50 – 5:00 8/30 CONSIDERATIONS IN DESIGNING IMMUNOTHERAPY COMBINATIONS

1:50 Rational Combination Immunotherapy Development Stratified by the Presence or Absence of the T Cell-Inflamed Tumor Microenvironment

Jason J. Luke, M.D., FACP, Assistant Professor, Medicine, Melanoma and Developmental Therapeutics Clinics, University of Chicago Medical Center Tumors can be categorized by gene expression based on the presence or absence of a T cell-inflamed tumor microenvironment, and this correlates with either response or lack of response to immune-checkpoint blockade. Categorization of these biologically distinct subsets suggests rational immunotherapy combinations directed toward either a T cell-inflamed or non-T cell-inflamed tumor microenvironment. This approach also facilitates a framework for interrogating molecular mechanism of immune exclusion mediating non-inflamed tumors.

2:20 Programming DCs in situ for Cancer Vaccination

Omar Ali, Ph.D., Staff Scientist, Wyss Institute for Biologically Inspired Engineering, Harvard University The innate components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. We utilize three-dimensional and macroporous, polymeric cancer vaccines incorporating different classes of TLR adjuvants to induce tumor regression and protection in order to identify dendritic cell subsets and cytokines critical to this efficacy. Vaccine-induced tumor regression correlated to local CD8(+) DC and pDC numbers, IL-12, and G-CSF concentrations regardless of the incorporated adjuvant.

2:50 Sponsored Presentations (Opportunities Available)

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 PLENARY KEYNOTE SESSION See Keynotes for details.

4:00 A New Era of Personalized Therapy: Using Tumor Neoantigens to Unlock the Immune System

Matthew J. Goldstein, M.D., Ph.D., Director, Translational Medicine, Neon Therapeutics, Inc. Neon Therapeutics, Inc. launched in 2015 to focus on advancing neoantigen biology to improve cancer patient care. A neoantigen-based product engine will allow Neon to develop further treatment modalities including next-generation vaccines and T cell therapies targeting both personalized as well as shared neoantigens. The company’s first trial will launch later this year investigating the combination of a personalized, vaccine with nivolumab in advanced Melanoma, NSCLC, and Bladder Cancer.

4:30 Emerging Innate Immune Targets for Enhancing Adaptive Anti-Tumor Responses

Michael Rosenzweig, Ph.D., Executive Director, Biology-Discovery, IMR Early Discovery, Merck Research Laboratories Novel cancer immunotherapies targeting T cell checkpoint proteins have emerged as powerful tools to induce profound, durable regression and remission of many types of cancer. Despite these advances, multiple studies have demonstrated that not all patients respond to these therapies, and the ability to predict which patients may respond is limited. Harnessing the innate immune system to augment the adaptive anti-tumor response represents an attractive target for therapy, which has the potential to enhance both the percentage and rate of response to checkpoint blockade.

5:00 Reading Tea Leaves: The Dilemma of Prediction and Prognosis in Immunotherapy

Morganna Freeman, D.O., Associate Director, Melanoma & Cutaneous Oncology Program, The Angeles Clinic and Research Institute With the rapid expansion of immunotherapeutics in oncology, scientifically significant advances have been made with both the depth and duration of antitumor responses. However, not all patients benefit, or quickly relapse, thus much scientific inquiry has been devoted to appropriate patient selection and how such obstacles might be overcome. While more is known about potential biomarkers, accurate prognostication persists as a knowledge gap, and efforts to bridge it will be discussed here.

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1:15 -2:00 8/30 SELECTING PD-L1/PD-1 IMMUNOTHERAPY COMBINATIONS: Rational Combination Cancer Immunotherapy @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

Posted in Conference Coverage with Social Media, Immuno-Oncology & Genomics on August 30, 2016| Leave a Comment »

1:15 -2:00 8/30 SELECTING PD-L1/PD-1 IMMUNOTHERAPY COMBINATIONS: Rational Combination Cancer Immunotherapy @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

Leaders in Pharmaceutical Business intelligence (LPBI) Group covers in Real Time the IMMUNO-ONCOLOGY SUMMIT using Social Media

Aviva Lev-Ari, PhD, RN,

Founder, LPBI Group & Editor-in-Chief

http://pharmaceuticalintelligence.com

I attended a parallel session @ Marriott Long Wharf Hotel in Boston

Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

1:15 -2:00 8/30 SELECTING PD-L1/PD-1 IMMUNOTHERAPY COMBINATIONS: Rational Combination Cancer Immunotherapy

1:15 Chairperson’s Opening Remarks

Arthur M. Krieg, M.D. CEO, Checkmate Pharmaceuticals

1:20 KEYNOTE PRESENTATION: SELECTING PD-L1/PD-1 IMMUNOTHERAPY COMBINATIONS

Edward Cha, M.D., Ph.D., Associate Medical Director, Cancer Immunotherapy Franchise, Genentech Although targeted inhibition of the PD-L1 pathway enhances anti-tumor immunity, not all patients achieve benefit from single-agent immunotherapies. Determining and prioritizing effective combinations will rely on further understanding of the mechanisms that drive immune resistance across indications and individual patients.

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1:15 – 3:15 8/30 TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

Posted in Conference Coverage with Social Media, Immuno-Oncology & Genomics, Personalized and Precision Medicine & Genomic Research on August 30, 2016| Leave a Comment »

1:15 – 3:15 8/30 TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

Leaders in Pharmaceutical Business intelligence (LPBI) Group covers in Real Time the IMMUNO-ONCOLOGY SUMMIT using Social Media

Aviva Lev-Ari, PhD, RN,

Founder, LPBI Group & Editor-in-Chief

http://pharmaceuticalintelligence.com

Streaming LIVE @ Marriott Long Wharf Hotel in Boston

Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

1:15 – 5:00 8/30 TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY

1:15 Chairperson’s Opening Remarks

Pramod K. Srivastava, M.D., Ph.D., Professor, Immunology and Medicine, Director, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine

Increased cancer incidence in immunosuppred transplant patients 25 times more risk for cancer

Tumor immunity – if you immunize a mouth, tumor will not occur or regress or not progress
Tumor are antigenically distinct
errors in replication cand tumor sell divide
identical normal cells sameness to individuality Normal >> Tumor >> Neoepitopes few Neoepitope becomes mutant
199502006Reponse to Mage correlate with better prognosis — all clinical trials FAILED
Immune response to Neoepitopes – not clear cut

1:20 Basics of Personalized Immunotherapy: What Is a Good Antigen?

Pramod K. Srivastava, M.D., Ph.D., Professor, Immunology and Medicine, Director, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine The definition of host-protective immunogenic antigen(s) of any human cancer of non-viral origin is still an enigma. New approaches in cancer genomics and bioinformatics are now offering a plethora of candidate antigens, whose role in cancer immunity, and specifically in host-protective cancer immunity, is under extensive testing. Outlines of some broad rules are emerging and some of these shall be discussed.

Likelihood of being proteasomally processed MHC I binding affinity
1994 affinity threshold 50nM
equivalent : Affinity -. difference self .. checkpoint blockade
Testing the tumor-protective immunogenicity of neo-epitopes: Tumor
Score of binding of mutant Is there tolerance to these – difference from self is a predictor of affinity – DAI score of difference
CD8- dependence of neo-epitope-elicited cancer immunity
Differential of Testing the tumor-protective immunogecity of neo-epitopes
Other tumor models: tumor rejection and low affinity
Immunological microenvironment
strong affinity in combination with CTLA4 – Tumore rejection by some epitopes not by others
CTLA4 blockade – CHeckpoint or T re inhibition
Strong influence of T regs on the neoepitope repertoire of a tumor
Immune response to neoepitope may: MHC I – peptide affinity, minor player in definition of effectiveness of neoepitopes
Epithelial ovarian cancer Stage III/IV and T cell response – Phase I

Questions

mutated epitope in melanoma – MHC 1 is important
CD4 affinity

1:50 Novel Antibodies against Immunogenic Neoantigens

Philip M. Arlen, M.D., President & CEO, Precision Biologics, Inc.

Two novel antibodies, NEO-102 (ensituximab) and NEO- 201, were developed from an allogeneic colorectal cancer vaccine that had previously shown activity in patients with metastatic colorectal cancer This vaccine was derived from an immunogenic component of the cell membrane from pooled surgical specimens from both primary and metastatic colon cancer. Patients who benefited from the vaccine in the prior clinical trial produced and sustained high levels of serum IgG against the vaccine. Several thousand candidate antibodies were screened against this vaccine and NEO- 102 and NEO-201 were candidates that demonstrated the ability to bind to colon cancer vs. normal tissue.

solid tumor studies: tumor specific monoclonal
Only Human Derived & Human Tested Pltform to Create Novel Therapeutics

patient-derived tumor samples –>> prepararion of cancer vaccince –> anti-cancer vaccine – molecular weight – are these components immunogenic –.. Production of anti-cancer-specific monoclonal antibodies –.. testing and development of mAbs –.. Hollinshead’s clinical testing of anti-cancer vaccines
Human screening to select active vaccine
Mount IgG response to the Vaccine — colorectal cancer
immune response – 10,00 – 3 sensicitivy
NEO -102 – Pancreatic cancer – novel monoclonal antibody MUCSAC – no Ensituximab binding –>> Novel mucin trget
anti tumor activity of a novel mAb NEO-102 optimize for regorgnition of antigens
antibody dependent cell cytotoxicity –
Tumor-specific ANtigen (TSA)
Phase I and Phase II – monotherapy completed
Phase 3 Regorafanib doses: 1.5 mg/Kg
3 mg/Kg – hyperbilirubinemia – Liver mestastasis Patients, hemolysis, anemia, N&V
Affinity correlates with immune activity
30% of Panceratic Cancer pt receive FOLFIRINX as front line therapy, and Gemcitabine/Abraxane as 2nd line.
New Trial: Gemcitabine/ .. NabPaxital –.. NEO-102
NEO-201 (h16C3) mAb – CEACAM-5, CEACAM-6

Biological way as Novel Immunotherapy

2:20 PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Luis Alberto Diaz, M.D., Associate Professor, Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Somatic mutations have the potential to encode “non-self” immunogenic antigens. Tumors with a large number of somatic mutations due to mismatch-repair defects appear to be highly susceptible to immune checkpoint blockade. This presentation will summarize the clinical and genomic data of using mutations as neoantigens.

Mismatch repair tumor – colon cancer – genetic and Epigenetic defects in mismatch repair 15% carcinomas across all stages
mutagen associated tumor
sporadic solid tumors (colon cancer)
pediatric tumors
liquid tumors

Background

Tx of tumor
Colorectal cancers vs Non-Colorectal Cancers
Cohort: A, B, C Autoimmune events

Biochemical Response (CEA): Merck Kyrdura,, single agent

MMR-proficient CRC – low tumor burden – 12 patients
MMR-deficient CRC – HIGH Tumor burden – 12 patients
% change from baseline

Summary

% change from Baseline = Mismatch in genomic vs Histology independence

Mutation Burden va Response to PD-1 Blockade

Mutations per Genome vs % Objective Response Rate

Future direction

Markers in genomics not tissue origin
Molecular etiology of primary and secondary resistance in MRD tumors with PD-1 blockade
kidney cancer non-Hodgkis Lynphona – low tumor burden: mismatch mutation burden, virus
Melanoma & Lunf Cancers: Mutagen Associated tumors

2:50 In situ Vaccination for Lymphoma

Joshua Brody, M.D., Director, Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai

Prior ex vivo combinations of dendritic cells (DC) with tumor antigens have yielded immunologic and clinical responses. Intratumoral immunomodulation may bypass the need for ex vivo production of vaccine. In situ vaccination combines: intratumoral Flt3L to recruit DC, low dose radiotherapy to load DC with tumor antigens, and intratumoral TLR agonist to activate tumor-antigen-loaded DC. Preliminary results demonstrate DC recruitment and activation, systemic tumor regressions, and induction of neoantigen specific CD8 T cell responses after vaccination.

TLR9a-based insitu vaccine – convert tumor into vaccine-manufacturing facility
B cell lymphona – Keppa expression treated by CpG – rediation
induction antitumor immunity by anti-tumor T-cells
CD8 vs IFNgamma
CD137 vs CD 45RO – memory cells: pre and post
Flt3L-primed in situ vaccine on dendritic cells + poly-IC – vaccine activate T-cells
60 patients

Pre-rx, Pre-vaccine
post Flt3L Post- Vaccine
post-poly-ICLC (agonist)

Flt3L immune repertoire effects with CyTOF – pre-Flt3L

In site vaccine: cellular and molecular Mechanism
T cells, Macrophages, Ly6chi, mono, Dendritic Cells
pIC +antiPD1

Is there a Better AIXS than PD/PD-L1?

YES – Just EGFP Dealth Inducing CD8 T cells = JEDI
YES – Targeted (CRISPR) approach – 600 genes on Receptor “3”
CRISPR discovers PD-L1 spiked in with preferential – Edit and induce genes: Library of 600 genes – PD1 is in the library
GFP vs MHC-1 vs Jedi T cells
Kill-able lymphoma vs resistant lymphoma
more Dendritic cella with intratumoral than systemic Flt3L <<– has highest % of living cells

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 PLENARY KEYNOTE SESSION See Keynotes for details.

4:00 A New Era of Personalized Therapy: Using Tumor Neoantigens to Unlock the Immune System

4:30 Emerging Innate Immune Targets for Enhancing Adaptive Anti-Tumor Responses

5:00 Reading Tea Leaves: The Dilemma of Prediction and Prognosis in Immunotherapy

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LIVE 9:55 – 12:00 8/29 UNDERSTANDING MECHANISMS OF ACTION @IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

Posted in Conference Coverage with Social Media, Immuno-Oncology & Genomics, Oncolytic virus & OncoViro-Therapy on August 29, 2016| Leave a Comment »

LIVE 9:55 – 12:00 8/29 UNDERSTANDING MECHANISMS OF ACTION @IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

Leaders in Pharmaceutical Business intelligence (LPBI) Group covers in Real Time the

IMMUNO-ONCOLOGY SUMMIT using Social Media

Aviva Lev-Ari, PhD, RN,

Founder, LPBI Group & Editor-in-Chief

http://pharmaceuticalintelligence.com

Streaming LIVE @ Marriott Long Wharf Hotel in Boston

Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

9:55 – 12:00 UNDERSTANDING MECHANISMS OF ACTION

9:55 Chairperson’s Remarks

Fares Nigim, M.D., Massachusetts General Hospital and Harvard Medical School

First phase:

OV infection/replication

Second phase

Immune response

Clinical considerations: viral delivery, Patient’s selection, Biomarkers, combination with Immunomodulators

10:00 Designing Clinical Trials to Elucidate Oncolytic Virus Mechanisms-of-Action

Caroline Breitbach, Ph.D., Vice President, Translational Development, TurnstoneBiologics

Oncolytic viruses have been shown to target tumors by multiple complementary mechanisms-of-action, including direct oncolysis, tumor vascular targeting and induction of anti-tumor immunity. Phase I/II clinical trials can be designed to validate these mechanisms. Development experience of an oncolytic vaccinia virus and a novel rhabdovirus oncolytic vaccine will be summarized.

Mechanism of Action:
Clinical trial design and choosing population
Pex-Vec: Oncolytic Vaccinia – Infection and SPread within tumors follwoing IV AdministrationCCRC vd Ovarian cancer
dose threshold for IV delivery Defined
Tumor-specific Trnsgene
dose-dependent induction of antibodies to beta-galactosidase
Delayed Virema and evidence of GM-CSF Expression – day 4 nad Day 6
Oncolytic Viral Immunotherapy: Oncolytic Virus and T-cell Vaccine
Maraba MG1 Oncolytic Virus – Rhabdovirus Structure – from insects not a human pathogen.
MG1 boosts immunity- engage memory T cells,
Unique Biology of T Cell Boosting:

virus infects follicular B cells: Lung metastesis DCT Prima, DCT Boost
COmparison MG1 to other Vaccine Platforms
Immunecheck Inhibitors – combined to augment Immune activity in preclinical models
T- cells recruited to tumors post Ad-GM!
MAGE-A3: in Human in CLinical studies – fresh peripheral blood underwent in vitro stimulation with MAGE-A3 peptide pools for 6 hours follwoed by staining and flow
First Human CLinical Trial – Status: Enrolling – 70 patients

Arm A, B, C and Pahse II: Prescreen MA3, Screening CT/biopsy ADvirus Biopsy CT
MOA – Amplification in tumor
transgene expresion systemic delivery induction of anti-viral antibodies/immunity
Efficacy ENdpoints:
Radiographic endpoints
Cancers with tumor markers
must ensure suggogate endpoints are approvable
Acute reduction of Perfusion after Pexa-Vec Treatment
unmasking of existing lesions
response in non-injected tumors: baseline, week 8,20
Lymphocytic inflitrate
Selection of Patient Population: Injectable Unresectable Stage IIIB -IV

Liver Cancer: HCC – First-lineLow and High dose

Phase 2b – Second-line: Single agent NOT approriate for advanced disease

Pharmacokinetics – unique Replication-dependent PK

GM-CSF – cytokine autoimmunity

10:30 T- Stealth Technology Mitigates ANtagonism between Oncolytic Viruses and the Immune System through Viral Evasion of ANti-Viral T-Cells

Matthew Mulvey, PhD, CEO, BeneVir

Virus evading immune response – resist interferon

T-Vec vs T-Stealth = viral spread continues enhanced efficacy

T-Stealth – unique ability to evade clearance by T-cells in order to permit stimultaneous co-administration of OV and immune checkpoint inhibitors

evades of T-cells
induction and systemic anti tumor T-cells
synergy with checkpoint
Efficacy of repeat dose
Inhibitor of innate immunity, T-cell
Bladder cancer MBT-2 injection bi-lateral : T-Stealath + AntiPD1 + CTLA4
improved T-Cell receptor diversity in untreated tumors suggestin that t-Stealth induces immune response system to target a wider range of tumor neo-antigens

DRUG PROFILE

Replicate,spread
mitigate antagonism with checkpoint inhibitorscan be armed with 3 additional transgenes to promote anti-tumor
One stop shopping
systemic OV dosing:
more efficacious because virus spreads

11:00 Improving Oncolysis and Therapy with Pharmacologic Modulation – Glioblastoma

Antonio Chiocca, Professor & Chairman, Department of Neurosurgery , Brigham & Women’s Hospital/ Harvard Medical School

Glioblastoma (GBM) – survival 15 month – heterogenous, target therapies – FAILED, subclones – mutation burden – OV – injection into tumor

if inject into the Brain – bad effect – tolerated, efficacy NOT established
Current therapies aimed at ICP6 – Herpes+ Nestin
HSV strain attenuated ICP4 mutation
UL39
Mice models: Animal survival is 80% when OV is injected 7 days
Animal survival is 50% when OV is injected 14 days after tumor implant
GBM Clinical Trial
VPA – Valporic Acid – FDA approved – antitumor efficacy of Herpes-based OV – Histone deacetylase
HDAC6 – major deacetylase in cytoplasm – improves shuttling of post-entry oHSV into nuclei vs lysosomes
2015 – Histone deacetylase 6 Inhinbition enhances OV replication in glioma
The nestin promoter in rQNestin34.5
VPA demethylate oncolytic HSV promoter
barriers to OV therapy and maneuvers to circovent
Transcript profile analyses of Glioma
NK cells are recruited to brain GBM following oncolytic HSV
PD-L1 expression in Glioma Stem cells after oHSV
immunocompetent mouse Glioma cells that replicate oHSV to high levels – testing
Conclusions

11:30 Moving Toward MultiFunctionality in PoxvirusBased Oncolytic Virotherapy

Eric Quemeneur, Ph.D., Pharm.D., Executive VP and CSO, Transgene

Poxviruses are powerful immunotherapeutics and tumor-targeting platforms. We recently expanded Transgene’s portfolio of armed oncolytic Vaccinia Viruses (oVV) by engineering a vector that targets anti-PD1 IgG expression into the tumor. Local concentration of virus-encoded antibody was ~10-50 times higher than the reference mAb, leading to significant improvement of survival in a sarcoma preclinical model. Such results announce the next-generation OVs, combining immunogenic oncolysis with the capacity to deliver complex therapeutic modalities in the tumor micro-environment.

The merit of poxyviruses for UV – envelop Virus – cytosol replocation
suitable for molecular engineering: large genome
Enzyme – Fcu1 VV(TK-RR-)-Fcu1
FCU1 is a chimeric bifunctional enzyme
Activity of TG6002 in human tumors: Growth control: SKOV (ovarian) and U87-MG (control) Ovarian
TG6002 also active on Cancer stem cells, compatible with Chemotherapy: Human Pancreatic Cancer

Activity in immuno-competent models –

TG6002 (WR) in mice synergy study and
Lymphocyte infiltration into the tumor
Complementarity with PD1 blocker
induce abscopal response – effect on survival
Combination OV/ICI in the clinic
Genetic recombination of mAb expression cassettes

IgG
Fab
scFv

T cell depletion experiment – Anti- CD4 and CD8

Pre-Clinical results – in vivo expression and biodistribution of WR-mAb1

Tumor growth inhibition & survival (MCA205 sarcoma model
Overcoming the tumor access barrier
cavitation-enhanced ultrasonic virus delivery

Summary

Poxviruses – safe, potent and versatile
IV route
synergy with other immunotherapies
platform is customizable

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LIVE 8:25 – 9:30 8/29 REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY @IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

Posted in Conference Coverage with Social Media, Immuno-Oncology & Genomics, Oncolytic virus & OncoViro-Therapy on August 29, 2016| Leave a Comment »

LIVE 8:25 – 9:30 8/29 REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY @IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

Leaders in Pharmaceutical Business intelligence (LPBI) Group

covers in Real Time the IMMUNO-ONCOLOGY SUMMIT using Social Media

Aviva Lev-Ari, PhD, RN,

Founder, LPBI Group & Editor-in-Chief

http://pharmaceuticalintelligence.com

Streaming LIVE @ Marriott Long Wharf Hotel in Boston

Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

8:25 – 9:30 REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY

LIVE 8:25 Chairperson’s Opening Remarks

Brian Champion, Ph.D., Senior Vice President, R&D, PsiOxus Therapeutics Ltd

Different viruses
Engineering
Manufacturing: CMC
Systemic vs IT Delivery
Tumor Markers environment: Tumor cell lysis and immune response
Biomarkers Clinical Development
Role of Pre-clinical Models
regulatory affairs

8:30 T-Vec: From Market Approval to Future Plans

Jennifer Gansert, Ph.D., Executive Director, Global Development Lead, IMLYGIC, Amgen, Inc.

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus type -1 designed to selectively replicate in tumors and to promote an anti-tumor immune response. T-VEC is approved for metastatic melanoma based on a randomized phase III trial; T VEC significantly improved durable response rate vs GM-CSF. Data from the pivotal trial and combination studies with checkpoint inhibitors will be presented.

T-VEC – HSV-1

Viral Protein:

ICP47 – Deleltion ,
ICP34.5 – Deletion ,
US11 – Temporal expression,
GM-CSF – Insertion

Engineering Change:

Injected Tumor
Contralateral tumors

Dual MOA
Administration: Largest lesion first, 4 cycles of injections
OpTim – Phase III: N = 436 Stage III-IV Melanoma
T-VEC (N = 295)
GM-CSF (N=141)
Key ENTRY Criteria
END POINT: Primary and Secondary – Survival benefit
2/3 – prior infection with HIV – melanoma not resectable with spread to lymph nodes
Response rate with T-VEC: 30% response 2/3 – control of the disease
Lesion-Level, Lesion-Type Response Analysis
Overal Survival:Over 20% reduction of burdon
Retrospective analysis: If not spread yet to lymph nodes: Best response to treatment
Early disease stage and early therapy are correlated
T-VEC double survival vs GM-CSF
Adverse effects: Cellulitis

Phase I

Phase II

Phase III

Regulatort Interactions for US BLA – Full approval in 10/2015
Rationale for Combination wiht CHeckPoint Inhibitors

Immunologic response:
Control
OncoVEX mGM-CSF
CTLA4
Ipilimumab – 3
Pembrolizumab -4
Neoadjuvant – 2
unserectable safety – 1

Changes in Tumor Burden by DIsease CHange
Progression-Free Survival – 72%
Adverse events: as expected
Phase II design: Pembrolizumab 200mg
Monotherapy vs Combination
Address multiple Tumor type: Menaloma, RCC, mCRC, BrCA, Gastric, NSCLC, HCC
Other: Head & Neck (completed), Pacreatic (completed), Hepatic injection (ongoing), Pediatric study (planned)

9:00 Oncolytic Virotherapies as a Single Shot Cure?

Stephen J. Russell, M.D, Ph.D., Professor, Mayo Clinic

VYRIAD, CEO

Oncolytic virotherapy is increasingly used as a cancer immunotherapy. However, certain oncolytic viruses can also mediate wholesale tumor destruction independently of an antitumor immune response. This is the oncolytic paradigm, where a cytolytic virus with preferential tumor tropism spreads extensively at sites of tumor growth and directly kills the majority of the tumor cells in the body leaving only a few uninfected tumor cells to be controlled by the concomitant antitumor immune response.

Virus – does the heavy lifting – small virus inoculum, local spread, systemic virus spread – via blood stream -VIREMIA – killing of infected cells Immune response help Virus elimination
Engineer virus: Tropism, dose, route
Immune response: Killing Uninfected cells killing tumors cells
Second exposure – preformed antibodies: Viremia – neutrilized + Memory cytotoxic T-Cells CTL
Oncolytic ViroTherapyFirst dose more effecitve then subsequence
VSV- Vesiculat Stomatisis Virus: IFNbeta and NIS
SIngle dose: Intratumorally: complete regression – controlling tumor
Reaching mestastesis: IV delivery
After systemic delivery: Mode of Virus spread in Tumors: tumor distruction: density of tumors: Delivery and SPread
Second and subsequent – Ovarian Cancer: single dose vs six doses: no significant (three doses – NO additional therapeutic benefit
Pet-dog with lynphoma: Multi center – single shot
HUMAN: Clinical Trial in Mayo, Arizona, Redractory/Intolerant HCC: In Patient 12:necrosis of the tumors, markers: HCC – metastasis to ColonRectal Cancer – developed Day 13 Hepatorenal outcome – virus infected non-injected tumors
NGS – error rat 1 in 1000 of virus genome sequence – 164 mutations 103 coding and 61 are noncoding or silent mutations
What determined rapid virus spear in Patient12: 4 gees of thr 84 genes:

antiviral state
antiviral sensing and signaling
IFN signaling
Antigen processing and presenation

NOW Companion Diagnostics is been developed

CASE: Measles Seronegative: – Complete response to IV MV-NIS – patient with melanoma

no systemic response – Oncolytic debulking and lasting immune control

Summary

Single shot cure for cancer – and likely transform Cancer care
Oncolytic and Immune two MOA – killing infected and uninfected tumor cells

Success: monitor viral spread

exploit first dose
develop tests to match with tumor
combine with immuno modulatory drugs
continue create better viruses

VYRIAD: Companion Diagnostic: Lung, Head & Neck, Bladder

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The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

Posted in “Antibody–enzyme conjugates”, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Genome Biology, Immuno-Oncology & Genomics, Immunodiagnostics, Immunology, Immunotherapy, Mutagenesis, tagged Editing the cancer cell glycocalyx with an antibody–enzyme conjugate on August 23, 2016| Leave a Comment »

The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

Reporter: Aviva Lev-Ari, PhD, RN

Significance

Successful tumors are able to evade the immune system, which is otherwise capable of killing transformed cells. Therapies that prevent this evasion have become revolutionary treatments for incurable cancers. One mechanism of evasion is the presentation of sugars, called sialic acids, within the cell surface’s sugar coating, or glycocalyx. Here, we designed biotherapeutic molecules, termed “antibody–enzyme conjugates,” that selectively remove sialic acids from tumor cells. The antibody directs the enzyme to the cancer cells, the enzyme cleaves the sugars, and then the antibody directs immune cells to kill the desialylated cancer cells. The conjugate increased tumor cell killing compared with the antibody alone. Editing the cancer cell glycocalyx with an antibody–enzyme conjugate represents a promising approach to cancer immune therapy.

SOURCE

http://www.pnas.org/content/early/2016/08/16/1608069113.abstract

AUGUST 22, 2016

Stanford chemists develop a new method of cancer immunotherapy

BY AMY ADAMS

A team of Stanford ChEM-H scientists has discovered a novel form of cancer immunotherapy, which works by removing certain sugars from the surface of cancer cells and making those cells visible to the immune system.

“All of the world of immune therapy is now thinking about the immune system as calculating pluses and minuses. If you want to tilt the scale toward immune activation, you can either augment the activator or remove inhibitor, or both,” said Bertozzi, who is also an investigator with the Howard Hughes Medical Institute.

Current immunotherapies on the market work by blocking one of the inhibitory signals that are recognized by the adaptive immune system. Block those and the balance tilts in such a way that the immune system will attack the now recognizable cancer.

Bertozzi’s approach provides a second way of tiling the balance in favor of attack, this time for the innate immune system. She said this study shows just one example of how it could work, but her sugar-removing lawnmower could be used on a wide variety of cell types, not just those expressing HER2, and on different types of sugars.

“It’s almost always the case that you need a component of both the adaptive and innate immunity to get a robust reaction against infectious pathogens, such as during vaccination,” said Bertozzi. “The smart money suggests that the same will be true with tumors.”

Bertozzi said the approach also highlights the importance of paying attention to the much ignored glycocalyx.

SOURCE

Stanford chemists develop a new method of cancer immunotherapy

http://news.stanford.edu/2016/08/22/new-method-cancer-immunotherapy/

A symbolic representation of a glycocalyx chain attached to a cytoskeleton.

IMAGE SOURCE: google images

image glycocalyx

IMAGE SOURCE: google images

Glycocalyx – www.futura-sciences.us576 × 284Search by image

The carbohydrates, glycoproteins and proteoglycans making up the glycocalyx

IMAGE SOURCE: google images

PNAS – Original Article

Precision glycocalyx editing as a strategy for cancer immunotherapy

Author Affiliations

Edited by Laura L. Kiessling, University of Wisconsin-Madison, Madison, WI, and approved July 11, 2016 (received for review May 24, 2016)

Abstract

Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody–sialidase conjugates that enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag. The antibody–sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by natural killer (NK) cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and enhanced binding to the NK-activating receptor natural killer group 2D (NKG2D). Sialidase conjugation to trastuzumab enhanced ADCC against tumor cells expressing moderate levels of HER2, suggesting a therapeutic strategy for cancer patients with lower HER2 levels or inherent trastuzumab resistance. Precision glycocalyx editing with antibody–enzyme conjugates is therefore a promising avenue for cancer immune therapy.

SOURCE

http://www.pnas.org/content/early/2016/08/16/1608069113.abstract

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Archive for the ‘Immuno-Oncology & Genomics’ Category

Milestones in Physiology & Discoveries in Medicine and Genomics: Request for Book Review Writing on Amazon.com

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective

http://www.amazon.com/dp/B019VH97LU

2015

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

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On its way for an IPO: mRNA platform Immune-Oncology, Moderna, is recruiting 100 new Life Scientists in Cambridge, MA

On its way for an IPO: mRNA platform, Moderna, Immune Oncology is recruiting 100 new Life Scientists in Cambridge, MA

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The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

Significance

Stanford chemists develop a new method of cancer immunotherapy

PNAS – Original Article

Precision glycocalyx editing as a strategy for cancer immunotherapy

Abstract

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LIVE 9/21 3:20PM to 6:40PM KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS & KINASE INHIBITORS FOR AUTOIMMUNE AND INFLAMMATORY DISEASES at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

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Media Partner of CHI for CHI’s 14th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

#BostonDOT16

@BostonDOT

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Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective

2015

Author, Curator and Editor

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On its way for an IPO: mRNA platform, Moderna, Immune Oncology is recruiting 100 new Life Scientists in Cambridge, MA

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Plenary Keynotes TUESDAY | AUGUST 30 4:00PM – 5:30PM @CHI’s IMMUNO-ONCOLOGY SUMMIT, Marriott Long Wharf Hotel in Boston

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1:15 -2:00 8/30 SELECTING PD-L1/PD-1 IMMUNOTHERAPY COMBINATIONS: Rational Combination Cancer Immunotherapy @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

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LIVE 8:25 – 9:30 8/29 REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY @IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

Leaders in Pharmaceutical Business intelligence (LPBI) Group

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The Strategy of Precision Editing the Cancer Cell Glycocalyx using an “antibody–enzyme conjugate” for Cancer Immunotherapy: Research Beyond “augment the activator or remove inhibitor, or both”

Significance

Stanford chemists develop a new method of cancer immunotherapy

PNAS – Original Article

Precision glycocalyx editing as a strategy for cancer immunotherapy

Abstract

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Media Partner of CHI for CHI’s 14^th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.