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Archive for the ‘Innovation in Immunology Diagnostics’ Category


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

During pregnancy, the baby is mostly protected from harmful microorganisms by the amniotic sac, but recent research suggests the baby could be exposed to small quantities of microbes from the placenta, amniotic fluid, umbilical cord blood and fetal membranes. One theory is that any possible prenatal exposure could ‘pre-seed’ the infant microbiome. In other words, to set the right conditions for the ‘main seeding event’ for founding the infant microbiome.

When a mother gives birth vaginally and if she breastfeeds, she passes on colonies of essential microbes to her baby. This continues a chain of maternal heritage that stretches through female ancestry for thousands of generations, if all have been vaginally born and breastfed. This means a child’s microbiome, that is the trillions of microorganisms that live on and in him or her, will resemble the microbiome of his/her mother, the grandmother, the great-grandmother and so on, if all have been vaginally born and breastfed.

As soon as the mother’s waters break, suddenly the baby is exposed to a wave of the mother’s vaginal microbes that wash over the baby in the birth canal. They coat the baby’s skin, and enter the baby’s eyes, ears, nose and some are swallowed to be sent down into the gut. More microbes form of the mother’s gut microbes join the colonization through contact with the mother’s faecal matter. Many more microbes come from every breath, from every touch including skin-to-skin contact with the mother and of course, from breastfeeding.

With formula feeding, the baby won’t receive the 700 species of microbes found in breast milk. Inside breast milk, there are special sugars called human milk oligosaccharides (HMO’s) that are indigestible by the baby. These sugars are designed to feed the mother’s microbes newly arrived in the baby’s gut. By multiplying quickly, the ‘good’ bacteria crowd out any potentially harmful pathogens. These ‘good’ bacteria help train the baby’s naive immune system, teaching it to identify what is to be tolerated and what is pathogen to be attacked. This leads to the optimal training of the infant immune system resulting in a child’s best possible lifelong health.

With C-section birth and formula feeding, the baby is not likely to acquire the full complement of the mother’s vaginal, gut and breast milk microbes. Therefore, the baby’s microbiome is not likely to closely resemble the mother’s microbiome. A baby born by C-section is likely to have a different microbiome from its mother, its grandmother, its great-grandmother and so on. C-section breaks the chain of maternal heritage and this break can never be restored.

The long term effect of an altered microbiome for a child’s lifelong health is still to be proven, but many studies link C-section with a significantly increased risk for developing asthma, Type 1 diabetes, celiac disease and obesity. Scientists might not yet have all the answers, but the picture that is forming is that C-section and formula feeding could be significantly impacting the health of the next generation. Through the transgenerational aspect to birth, it could even be impacting the health of future generations.

References:

https://blogs.scientificamerican.com/guest-blog/shortchanging-a-babys-microbiome/

https://www.ncbi.nlm.nih.gov/pubmed/23926244

https://www.ncbi.nlm.nih.gov/pubmed/26412384

https://www.ncbi.nlm.nih.gov/pubmed/25290507

https://www.ncbi.nlm.nih.gov/pubmed/25974306

https://www.ncbi.nlm.nih.gov/pubmed/24637604

https://www.ncbi.nlm.nih.gov/pubmed/22911969

https://www.ncbi.nlm.nih.gov/pubmed/25650398

https://www.ncbi.nlm.nih.gov/pubmed/27362264

https://www.ncbi.nlm.nih.gov/pubmed/27306663

http://www.mdpi.com/1099-4300/14/11/2036

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464665/

https://www.ncbi.nlm.nih.gov/pubmed/24848255

https://www.ncbi.nlm.nih.gov/pubmed/26412384

https://www.ncbi.nlm.nih.gov/pubmed/28112736

http://ndnr.com/gastrointestinal/the-infant-microbiome-how-environmental-maternal-factors-influence-its-development/

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FDA cleared Clever Culture Systems’ artificial intelligence tech for automated imaging, analysis and interpretation of microbiology culture plates speeding up Diagnostics

Reporter: Aviva Lev-Ari, PhD, RN

 

 

FDA clears automated imaging AI that speeds up infectious disease Dx

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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

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 14th 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

 

KINASE INHIBITORS FOR CANCER IMMUNOTHERAPY COMBINATIONS

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

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

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

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

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

Treiber_Daniel

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

  1. validation across proteins

TTP Labtech4:50 Potential Application of Fluorescence Lifetime Assays to Enable Robust, Rapid Protein Binding Assays

Wylie_Paul

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)
  1. FRET/HTRF
  2. FP
  3. 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:
  1. protein – small molecule binding – CECR2
  2. protein – peptide binding: long and sholt lifetime
  3. Site-specific labelling vs Non-selective labelling
  4. Toolbox for PoC
  5. Detection reagents
  6. Further develop technology

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

 

6:40 End of Day

 

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


physiology-cover-seriese-vol-3individualsaddlebrown-page2

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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Pioneers of Cancer Cell Therapy:  Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

Curator: Aviva Lev-Ari, PhD, RN

Chimeric Antigen Receptor T-Cell Therapy: Players in Basic & Translational Research and Biotech/Pharma

The companies are teamed with academic pioneers:

  • Novartis with University of Pennsylvania;
  • Kite Pharma with the National Cancer Institute; 
  • Juno Therapeutics with Sloan Kettering,
  • the Fred Hutchinson Cancer Research Center in Seattle and Seattle Children’s Hospital.

cancer33

IMAGE SOURCE: National Cancer Institute

 

 “CAR-T cell immunotherapy” –  genetically modified T cells that are engineered to target specific tumor antigens and/or genes that are involved in survival, proliferation, and the enhancement of effector functions have been under intense research.

 

CAR technology was originally reported by Zelig Eshhar in 1993.

https://www.weizmann.ac.il/immunology/sci/EshharPage.html

Prof. Zelig Eshhar, Ph.D., served as Chairman of the Department of Immunology at the Weizmann Institute. Prof. Eshhar has been Chair of Scientific Advisory Board at TxCell S.A. since April 2016. Prof. Eshhar has been a Member of Scientific Advisory Board at Kite Pharma, Inc. since August 8, 2013. Prof. Eshhar served as a Member of Scientific Advisory Board at Intellect Neurosciences, Inc. since April 2006.

Prof. Eshhar pioneered the CAR approach (or T-Body as he termed it) to redirect T cells to recognize, engage and kill patient’s tumor cells by engineering them with a construct that combines the anti-target specificity of an antibody with T cell activation domains. Prof. Eshhar serves on several editorial boards, including Cancer Gene Therapy, Human Gene Therapy, Gene Therapy, Expert Opinion on Therapeutics, European Journal of Immunology and the Journal of Gene Medicine. He was a Research Fellow in the Department of Pathology at Harvard Medical School and in the Department of Chemical Immunology at the Weizmann Institute in Israel. His achievements were recognized by several international awards, most recently the CAR Pioneering award by the ATTACK European Consortium. Prof. Eshhar obtained his B.Sc. in Biochemistry and Microbiology and his M.Sc. in Biochemistry from the Hebrew University, and his Ph.D. in the Department of Immunology from the Weizmann Institute of Science.

http://www.bloomberg.com/research/stocks/people/person.asp?personId=32720993&privcapId=32390485

 

Zelig Eshhar and Carl H. June honored for research on T cell engineering for cancer immunotherapy

New Rochelle, NY, November 11, 2014–Zelig Eshhar, PhD, The Weizmann Institute of Science and Sourasky Medical Center, and Carl H. June, MD, PhD, Perelman School of Medicine, University of Pennsylvania, are co-recipients of the Pioneer Award, recognized for lentiviral gene therapy clinical trials and for their leadership and contributions in engineering T-cells capable of targeting tumors with antibody-like specificity through the development of chimeric antigen receptors (CARs). Human Gene Therapy, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers, is commemorating its 25th anniversary by bestowing this honor on the leading Pioneers in the field of cell and gene therapy selected by a blue ribbon panel* and publishing a Pioneer Perspective by the award recipients. The Perspectives by Dr. Eshhar and Dr. June are available free on the Human Gene Therapy website at http://www.liebertpub.com/hgt until December 11, 2014.

In his Pioneer Perspective entitled “From the Mouse Cage to Human Therapy: A Personal Perspective of the Emergence of T-bodies/Chimeric Antigen Receptor T Cells” Professor Eshhar chronicles his team’s groundbreaking contributions to the development of the CAR T-cell immunotherapeutic approach to treating cancer. He describes the method’s conceptual development including initial proof-of-concept, and the years of experimentation in mouse models of cancer. They first tested the CAR T-cells on tumors transplanted into mice then progressed to spontaneously developing cancers in immune-competent mice, which Dr. Eshhar describes as “a more suitable model that faithfully mimics cancer patients.” He recounts successful antitumor effects in mice with CAR modified T-cells injected directly into tumors, with effects seen at the injection site and at sites of metastasis, and even the potential of the CAR T-cells to prevent tumor development.

Dr. Carl H. June has led one of the clinical groups that has taken the CAR therapeutic strategy from the laboratory to the patients’ bedside, pioneering the use of CD19-specific CAR T-cells to treat patients with leukemia. In his Pioneer Perspective, “Toward Synthetic Biology with Engineered T Cells: A Long Journey Just Begun” Dr. June looks back on his long, multi-faceted career and describes how he combined his knowledge and research on immunology, cancer, and HIV to develop successful T-cell based immunotherapies. Among the lessons Dr. June has embraced throughout his career are to follow one’s passions. He also says that “accidents can be good: embrace the unexpected results and follow up on these as they are often times more scientifically interesting than predictable responses from less imaginative experiments.”

“These two extraordinary scientists made seminal contributions at key steps of the journey from bench to bedside for CAR T-cells,” says James M. Wilson, MD, PhD, Editor-in-Chief of Human Gene Therapy, and Director of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.

SOURCE

http://www.eurekalert.org/pub_releases/2014-11/mali-ze111114.php

The General procedure of CAR-T cell therapy involves the follwoing steps:

1) Separate T cells from patient;

2) Engineer these T cells to express an artificial receptor, which is called “CAR” that usually targets tumor-specific antigen;

3) Expand the CAR T cells to a sufficient amount;

4) Re-introduce the CAR T cells to patient.

There are two major components that are critical to the CAR-T cell immunotherapy:

  • the design of CAR itself and
  • the choice of the targeted tumor specific antigen.

SOURCE

http://www.ochis.org/node/209

 

First publication on Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses

Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19

James N. Kochenderfer, Wyndham H. Wilson, John E. Janik, Mark E. Dudley, Maryalice Stetler-Stevenson, Steven A. Feldman, Irina Maric, Mark Raffeld, Debbie-Ann N. Nathan, Brock J. Lanier, Richard A. Morgan, Steven A. Rosenberg

Abstract

Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses. We treated a patient with advanced follicular lymphoma by administering a preparative chemotherapy regimen followed by autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognized the B-cell antigen CD19. The patient’s lymphoma underwent a dramatic regression, and B-cell precursors were selectively eliminated from the patient’s bone marrow after infusion of anti–CD19-CAR-transduced T cells. Blood B cells were absent for at least 39 weeks after anti–CD19-CAR-transduced T-cell infusion despite prompt recovery of other blood cell counts. Consistent with eradication of B-lineage cells, serum immunoglobulins decreased to very low levels after treatment. The prolonged and selective elimination of B-lineage cells could not be attributed to the chemotherapy that the patient received and indicated antigen-specific eradication of B-lineage cells. Adoptive transfer of anti–CD19-CAR-expressing T cells is a promising new approach for treating B-cell malignancies. This study is registered at www.clinicaltrials.gov as #NCT00924326.

SOURCE

According to Setting the Body’s ‘Serial Killers’ Loose on Cancer

After a long, intense pursuit, researchers are close to bringing to market a daring new treatment: cell therapy that turbocharges the immune system to fight cancer.

By ANDREW POLLACK  AUG. 1, 2016

http://www.nytimes.com/2016/08/02/health/cancer-cell-therapy-immune-system.html?_r=0

Dr. June’s 2011 publications did not cite Dr. Rosenberg’s paper [Blood, 2010] from the previous year, prompting Dr. Rosenberg to write a letter to The New England Journal of Medicine. Dr. June’s publications also did not acknowledge that the genetic construct he had used was the one he had obtained from Dr. Campana of St. Jude.

From the Lab to the bedside to the Out Patient Clinic

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Pathophysiology in Hypertension: Opposing Roles of Human Adaptive Immunity

Reporter: Aviva Lev-Ari, PhD, RN

T regulatory lymphocytes counteract hypertensive effects by suppressing innate and adaptive immune responses and T effector lymphocytes promote differentiation towards pro-inflammatory T helper cells

 

Dual opposing roles of adaptive immunity in hypertension

, , ,

DOI: http://dx.doi.org/10.1093/eurheartj/ehu119 1238-1244 First published online: 30 March 2014

Abstract

Hypertension involves remodelling and inflammation of the arterial wall. Interactions between vascular and inflammatory cells play a critical role in disease initiation and progression. T effector and regulatory lymphocytes, members of the adaptive immune system, play contrasting roles in hypertension. Signals from the central nervous system and the innate immune system antigen-presenting cells activate T effector lymphocytes and promote their differentiation towards pro-inflammatory T helper (Th) 1 and Th17 phenotypes. Th1 and Th17 effector cells, via production of pro-inflammatory mediators, participate in the low-grade inflammation that leads to blood pressure elevation and end-organ damage. T regulatory lymphocytes, on the other hand, counteract hypertensive effects by suppressing innate and adaptive immune responses. The present review summarizes and discusses the adaptive immune mechanisms that participate in the pathophysiology in hypertension.

  • Blood pressure
  • Adaptive immunity
  • Inflammation
  • T effector lymphocytes
  • T regulatory lymphocytes
  • Cytokines

Conclusion

Experimental and clinical evidence discussed in this review strongly suggests that adaptive immunity, represented by T effector and regulatory lymphocyte subsets, plays a dual role in hypertension (Figure 2). Increased sympathetic outflow as a consequence of stimulation of the CNS by hypertensive stimuli may result in mild blood pressure elevation, causing tissue injury and formation of neoantigens2 and/or damage-associated molecular patterns (DAMPs).80 Activation of innate APCs by DAMPs, or by pathogen-associated molecular patterns (PAMPs) generated in response to low-grade infection,80,81 and direct stimulation by CNS, may be the cause of activation of CD4+, and perhaps CD8+, T effector lymphocytes, and differentiation of CD4+ T cells towards pro-inflammatory Th1/Th17 phenotypes.41 Th1/Th17 effector lymphocytes contribute to the progression of hypertension by producing pro-inflammatory mediators, including ROS, IFN-γ, TNF-α, and IL-17, to promote low-grade inflammation.24,41,42,51,52 T regulatory lymphocytes, on the other hand, counteract hypertensive abnormalities by suppressing innate and adaptive immune responses, perhaps by secreting IL-10.6571 As such, circulating levels of Tregs or their immune-suppressive activity may be affected in hypertension.

 SOURCE

http://eurheartj.oxfordjournals.org/content/35/19/1238

Idris-Khodja et al. (2014) Dual opposing roles of adaptive immunity in hypertension. European Heart Journal (doi: 10.1093/eurheartj/ehu119)

 

Adaptive Immunity

Figure 1

Differentiation of naïve T lymphocytes into various subsets in a normal immune response. Antigen-presenting cells (dendritic cells and monocyte/macrophages) present antigens on major histocompatibility complex (MHC)-II to naïve T cells (Th0) in secondary lymphoid tissues, leading to T-cell clonal expansion and differentiation into effector T cells, such as T helper (Th)1, Th2, and Th17 or T regulatory (Treg) cells according to combined stimulation by different cytokines. Th effector lymphocytes and Tregs migrate into tissues such as the vasculature, particularly at the level of the adventitia and perivascular fat. The effector lymphocytes (Th1 and Th17) cells activate other immune cells and participate in inflammation by producing pro-inflammatory cytokines such as interferon-γ, interleukin (IL)-6, and IL-17. T regulatory lymphocytes suppress innate and adaptive responses via production of anti-inflammatory cytokines IL-10 and transforming growth factor-β. CD, cluster of differentiation; DC, dendritic cell; MΦ, macrophage; NK cell, natural killer cell; Tc, cytotoxic T cell; TCR, T-cell receptor.

IMAGE SOURCE

http://eurheartj.oxfordjournals.org/content/35/19/1238

 

Hypertention

 

IMAGE SOURCE

http://eurheartj.oxfordjournals.org/content/35/19/1238

Figure 2

Proposed role of T effector and regulatory lymphocytes in hypertension. Slight elevation in blood pressure (BP) in response to hypertensive stimuli (angiotensin II, aldosterone, endothelin-1, salt and genetic susceptibility) occurs due to increased central signalling, perhaps causing mild tissue injury and formation of damage-associated molecular patterns (DAMPs) and neoantigens. This may lead to activation of innate antigen-presenting cells (APCs) and, subsequently, activation and polarization of naïve CD4+ T effector lymphocytes (Th0) towards pro-inflammatory T helper (Th)1/Th17 phenotypes. Th1/Th17 may contribute to vascular and kidney damage via production of reactive oxygen species (ROS), interferon (IFN)-γ and interleukin (IL)-17 and lead to maintenance of hypertension and progression of end-organ damage. T regulatory lymphocytes counteract hypertension and associated injury by producing IL-10 or by other mechanisms, and suppression of innate and adaptive immune responses. CD, cluster of differentiation; CNS, central nervous system; MHC-II, major histocompatibility complex-II; PAMPs, pathogen-associated molecular patterns; TCR, T-cell receptor.

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CHI’s NK Cell-Based Cancer Immunotherapy Symposium, September 19 in Boston

Reporter: Aviva Lev-Ari, PhD, RN

 

Announcement from LPBI Group: key code LPBI16 for Exclusive Discount to attend Boston’s Discovery on Target (September 2016)

https://pharmaceuticalintelligence.com/2016/05/13/announcement-from-lpbi-group-key-code-lpbi16-for-exclusive-discount-to-attend-bostons-discovery-on-target-september-2016/

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FEATURED SESSION:

Natural killer (NK) cells have been known to have advantages over T cells, yet their therapeutic potential in the clinic has been largely unexplored.

Cambridge Healthtech Institute’s NK Cell-Based Cancer Immunotherapy Symposium, September 19 in Boston, is dedicated to the exploration of utilizing NK cells for new adoptive cell therapies, including updates from ongoing clinical studies.

NK CELL IMMUNO-ONCOLOGY AND CLINICAL STUDIES

Harnessing Adaptive NK Cells in Cancer Therapy

Karl-Johan Malmberg, M.D., Ph.D., Professor, Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital

  • We have recently completed a Phase I/II clinical trial with transfer of haploidentical NK cells to patients with high-risk myelodysplastic syndrome. Six of the 16 treated patients achieved morphological complete remission and five of these underwent allogeneic stem cell transplantation resulting in long-term survival in four patients. The quality and number of infused NK cells as well as their transient engraftment in the recipient correlated with decrease in mutational burden and clinical outcomes. These results suggest that adoptive transfer of allogeneic NK cells may hold utility as a bridge to transplant in patients who are refractory to induction therapy. Current efforts to selectively expand metabolically optimized adaptive NK cells for the next generation NK cell cancer immunotherapy will be discussed.

Update on Systemic and Locoregional Cancer Immunotherapy with IL-21-Expanded NK Cells

Dean Anthony Lee, M.D., Ph.D., Professor, Pediatrics; Director, Cellular Therapy and Cancer Immunotherapy Program, Nationwide Children’s Hospital; James Comprehensive Cancer Center/Solove Research Institute, The Ohio State University

  • The ability to generate clinical-grade NK cell products of sufficient purity, number, and function has enabled broader application of adoptive NK cell therapy in clinical trials. We translated our IL-21-based NK cell expansion platform to clinical grade and scale and initiated 7 clinical trials that administer NK cell immunotherapy with high cell doses or repeated dosing in transplant, adjuvant, or stand-alone settings. These trials have collectively delivered approximately 150 infusions to over 60 patients at doses of up to 10e8/kg. We will discuss the importance of STAT3 signaling in this setting, describe early outcome and correlative data from these studies, and present preclinical data supporting future clinical trials that build on this platform.

REGISTER

BY AUGUST 12 TO

SAVE UP TO $200

VISIT

WEBSITE

DOWNLOAD PDF AGENDA

Suggested Event Package

SYMPOSIUM

NK Cell-Based Cancer Immunotherapy

SEPT. 19

CONFERENCE

Antibodies Against Membrane Protein Targets (Part One)

SEPT. 20-21

CONFERENCE

Antibodies Against Membrane Protein Targets (Part Two)

SEPT. 21-22

The exhibit hall was sold out in 2015, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2016, contact:

Jon Stroup

Sr. Business Development Manager

P: 781-972-5483

E: jstroup@healthtech.com

Sponsorship/Exhibitor Information >>

 

DiscoveryOnTarget.com | Register by August 12 to SAVE up to $200 | Download PDF Agenda

Cambridge Healthtech Institute | 250 First Avenue, Suite 300, Needham, MA 02494 | www.healthtech.com | 781-972-5400

SOURCE

From: NK Cell Symposium <heidio@healthtech.com>

Date: Tuesday, August 9, 2016 at 1:40 PM

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

Subject: NK Cells for Adoptive Therapies: The Future of Cancer Immunotherapy?

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