infectious diseases cancer center for diseases of …...anti-cd40 highly effective in liver, kidney...
TRANSCRIPT
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T R A N S L A T I N G R E S E A R C H I N T O H E A L T H ®
Infectious Diseases
Cancer
Center for Diseases of Aging
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Translating Research into Health®
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Independent, non-profit biomedical research institute
100,000 sq ft facility with active research groups in place
~70% of space dedicated to pure research activities
Awarded nearly $40M in grant funding (NIH, amfAR, corporate, etc.) in last four years
VGTI Florida®: At a Glance
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
25+ years as PI, Professor, Program
Director, Department Chair, Associate
Director for Basic Research, Cancer
Center Deputy Director, Director of
Research Institute
Recently at the Beckman Research
Institute at City of Hope
NIH funded research in areas of:
tumor virology; molecular oncology;
cytokine signaling; targeted
therapeutics; and translational
research
VGTI Florida®: Leadership
Richard Jove, Ph.D.
Institute Director
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
VGTI Florida is conducting discovery
research and developing innovative,
immune-based therapies for the
treatment and prevention of :
Cancers
Infectious Diseases
Diseases Associated with Aging
VGTI Florida®: A Center of Excellence in Immunotherapeutics
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
VGTIFL Core Resources
• Dedicated technical resources available to all research groups
• Centralized leadership and advisory steering committee to meet research needs
• Dedicated highly trained staff using SOP driven workflows
• Standardized technical platforms for data consistency and integration
• Collaborative research centers (assist with study design, grant applications, publications)
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Collaborative Genomics Center
ILLUMINA HiSeq 2500 • Illumina CsPro certified lab
• GCLP certified SOPs and workflows
• Microarray, NGS Genomic DNA, mRNA, miRNA, Exome, epigenetics, SNP analysis
• Fluidigm platform for 96x96 digital QPCR with dedicated staff for gene panel design
• Small scale genomics (200 cells in bulk and single cell applications)
• Fully integrated with Bioinformatics for data analysis
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Bioinformatics Core
• Dedicated staff for data analysis, consultation and pipeline development
• Integrated data analysis and visualization approach
• Dedicated compute cluster 66 cores ~800GB RAM
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Flow Cytometry core
• Multiparametric flow analysis and cell sorting
• BSL-3 level sorting
• Index sorting for single cell “omics” analysis
• Dedicated staff with SOP driven workflows
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Vivarium and BSL-3 labs
• Animal facility for specific pathogen free rodent studies
• Humanized mouse models for immune system study
• Large capacity for ferret biology studies
• Select agent and BSL-3 dedicated spaces (CDC and USDA certified)
• AAALAC certified facility
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Additional Resources
• Clinical trials core (protocol development, IRB, clinical resource alignment)
• In house development of Intellectual property
• Cell Therapy Core (large scale clinical grade production CD34+ stem cells, RPE cells, Cardiac stem cells, T and NK cell expansion)
• Imaging suite for confocal and live cell imaging
• Seahorse XP for kinetic cellular metabolic monitoring
• Immune monitoring suite (ELISpot, Luminex, high throughput ELISA)
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
The Global Impact of Vaccines
In the last century, vaccines have
saved more lives than any other
health intervention. It is
estimated that every year, more
than two million deaths are
prevented worldwide due to
immunization.
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
VGTI Florida® Research Programs: Cancer Vaccines & Immune Therapies
Keith Knutson, Ph.D.
Director, Cancer
Programs
Former Director of Cancer
Immunotherapy at Mayo Clinic
Developing vaccines for primary &
secondary prevention of cancers
- Breast, Ovarian and Brain
Innovative immune-based approaches
to destroy and eliminate progressive
disease
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Taking Aim at Preventing Breast & Ovarian Cancers
Active Immunotherapy vaccines
for the prevention of breast &
ovarian cancers is a reality
Active versus passive
- Triggers durable, long-lasting immunity
VGTI Florida® is accelerating next-
gen cancer vaccines from bench to
patients
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
VGTI Florida® Research Programs: Cancer Vaccines & Immune Therapies
Advancing the use of oncolytic vaccine
vectors
Genetically modified viruses that
specifically target and destroy tumor
cells (HSV, Reo, Vaccinia, Measles, VSV)
Spares healthy cells
Researching this approach in multiple
tumor types including CLL, prostate
cancer and lung cancers
John Hiscott, Ph.D.
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
VGTI Florida® Research Programs: HIV and Immune function
Major Discoveries Leading
to Curative Approaches:
Identification of mechanisms of
immune dysfunction in chronic
viral diseases and cancer
Identification of the role of
negative immune regulators that
suppresses the body’s immune
response to HIV
Lydie Trautmann, Ph.D.
Elias Haddad, Ph.D.
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
VGTI Florida® Research Programs: Vaccines & Viral Immunity
Universal Flu Vaccine Programs:
Next-gen vaccines capable of protecting
against all strains of seasonal flu
VLP Technology
Boosting immunity in the young and
elderly
Emerging Viral Threat Programs:
Dengue, Rift Valley Fever, West Nile
Virus, Ebola, Marburg
State-of-the-Art BSL-3 Labs
Ted Ross, Ph.D.
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
CDA (Ctr. Diseases of Aging)
• State funded collaborative venture with VGTIFL and Karolinska Institutet
• 3 KI laboratories currently operating at VGTIFL
• Collaborative studies integrating immune therapies with regenerative medicine
• Bringing KI scientists and clinical trials to the US market
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Targeting Age-Related Diseases
• Infectious diseases – Flu, HIV, Hantavirus, Dengue, etc
• Cancer – Breast, ovarian, prostate, melanoma, brain, etc
• Neurodegenerative diseases – Parkinson’s, Alzheimer’s, ALS, etc
• Cardiovascular diseases – Heart attack, stroke, birth defects, etc
• Others – Diabetes, macular degeneration, multiple sclerosis, etc
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NK cells and Multiple Myeloma
Evrin Alici
Adil Doganay Duru
Cell and Gene Therapy Group
HERM
Karolinska Institutet
21 January 2015 Adil Duru, HERM SAP Seminar Spring 2014 22
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Natural Killer cells
Ex vivo NK cell expansion
Clinical trial
Developing NK cell culture medium
Optimization
Genetic modification of NK cells
Improving gene delivery
IL-2/IL2ER
Genetic screening
NK cell-derived exosomes
NK cell phenotyping and genotyping
Multiple Myeloma
Impact of chromosomal abnormalities on
disease progression
Effects of Immunomodulatory drugs on
myeloma cells and Lymphocytes
Developing alternative treatments
Immunotherapy
Cell therapy
Tumor stroma
ex vivo in vivo
Tumor stroma
21 January 2015 Adil Duru, HERM SAP Seminar Spring 2014 23
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Natural Killer cells
Ex vivo NK cell expansion
Clinical trial
Developing NK cell culture medium
Optimization
Genetic modification of NK cells
Improving gene delivery
IL-2/IL2ER
Genetic screening
NK cell-derived exosomes
NK cell phenotyping and genotyping
Multiple Myeloma
Impact of chromosomal abnormalities on
disease progression
Effects of Immunomodulatory drugs on
myeloma cells and Lymphocytes
Developing alternative treatments
Immunotherapy
Cell therapy
ex vivo in vivo
Tumor stroma
Viral
vector
21 January 2015 Adil Duru, HERM SAP Seminar Spring 2014 24
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Natural Killer cells
Ex vivo NK cell expansion
Clinical trial
Developing NK cell culture medium
Optimization
Genetic modification of NK cells
Improving gene delivery
IL-2/IL2ER
Genetic screening
NK cell-derived exosomes
NK cell phenotyping and genotyping
Multiple Myeloma
Impact of chromosomal abnormalities on
disease progression
Effects of Immunomodulatory drugs on
myeloma cells and Lymphocytes
Developing alternative treatments
Immunotherapy
Cell therapy
ex vivo in vivo
Tumor stroma
No target Autologous PBMCs Autologous tumor
Degranulation assays
Genetic modification
21 January 2015 Adil Duru, HERM SAP Seminar Spring 2014 25
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Natural Killer cells
Ex vivo NK cell expansion
Clinical trial
Developing NK cell culture medium
Optimization
Genetic modification of NK cells
Improving gene delivery
IL-2/IL2ER
Genetic screening
NK cell-derived exosomes
NK cell phenotyping and genotyping
Multiple Myeloma
Impact of chromosomal abnormalities on
disease progression
Effects of Immunomodulatory drugs on
myeloma cells and Lymphocytes
Developing alternative treatments
Immunotherapy
Cell therapy
21 January 2015 Adil Duru, HERM SAP Seminar Spring 2014 26
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Natural Killer cells
Ex vivo NK cell expansion
Clinical trial
Developing NK cell culture medium
Optimization
Genetic modification of NK cells
Improving gene delivery
IL-2/IL2ER
Genetic screening
NK cell-derived exosomes
NK cell phenotyping and genotyping
Multiple Myeloma
Impact of chromosomal abnormalities on
disease progression
Effects of Immunomodulatory drugs on
myeloma cells and lymphocytes
Developing alternative treatments
Immunotherapy
Cell therapy
21 January 2015 Adil Duru, HERM SAP Seminar Spring 2014 27
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Natural Killer cells
Ex vivo NK cell expansion
Clinical trial
Developing NK cell culture medium
Optimization
Genetic modification of NK cells
Improving gene delivery
IL-2/IL2ER
Genetic screening
NK cell-derived exosomes
NK cell phenotyping and genotyping
Multiple Myeloma
Impact of chromosomal abnormalities on
disease progression
Effects of Immunomodulatory drugs on
myeloma cells and lymphocytes
Developing alternative treatments
Immunotherapy
Cell therapy
21 January 2015 Adil Duru, HERM SAP Seminar Spring 2014 28
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A New Strategy of Immune Modulation
Matthias Corbascio MD PhD
Associate Professor of Cardiothoracic Surgery
Dept of Cardiothoracic Surgery and Anesthesiology
Karolinska University Hospital, Stockholm
Sweden
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Successful transplantation of Stem cells or Islet Cells must overcome immune rejection
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Blocking immune activators to facilitate transplantation
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HLA-G
Modified by Corbascio
Mesynchemal Stem Cells alter immune environment
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The model
• Balb/c islets + C57BL6 Bone Marrow MSCs injected intraportal into MHC-mismatched diabetic C57BL6 mice
• Treated with CTLA4Ig or CTLA4Ig+anti-CD40L for the first ten days.
• Follow blood glucose and harvest grafts at 100 days
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Clinical Implications
3396 clinical trials register in ClinicalTrials.gov with MSC Most have an immunological or inflammatory target CTLA4Ig is FDA approved for kidney transplantation and rheumatoid arthritis Anti-CD40 highly effective in liver, kidney and islet transplantation in non-human primates and in Phase 1 clinical trials MSC + Costimulation blockade = good for transplant, autoimmunity, regenerative medicine
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
NK cell based immunotherapy against solid tumors
Andreas Lundqvist
Dept. of Oncology-Pathology Karolinska Institutet
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
• Expansion of peripheral blood NK cells correlates with clinical outcome in cancer patients receiving IL-2 and IFNa
• Tumor-infiltrating natural killer cells play a crucial role in the generation of anti-tumor T lymphocytes. • Low peripheral blood NK cell activities have been related to the poor prognosis in patients with a number of different cancers • Peripheral blood NK cell count is associated with clinical outcome in patients with diffuse large B-cell lymphoma
NK Cells and Cancer
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Rate limiting factors for succesful clinical outcome of adoptive NK cell therapy
• How to make infused NK cells reach the tumor?
• How to make NK cells kill tumor cells as effectively as possible?
• How to make NK cells survive in the tumor
microenvironment?
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
How to make infused NK cells reach the tumor?
CXCL10+ CXCL10-
0
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tota
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CXCL10 + CXCL10 - 0
1000
2000
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tum
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CD16
CX
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3
100
101
102
103
104
100
101
102
103
104
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CD16
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100
101
102
103
104
100
101
102
103
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Fresh NK
CX
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3
CD16
Expanded NK
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Engineering NK cells to kill tumor cells more effectively
0
10
20
30
40
50
0 2 4%
lysis
E:T ratio
DOX
UNT
0 10 20 30 40
0
200
400
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Wennerberg E. Int. J Cancer 2013 Sarhan D. Eur. J. Immunol. 2013
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Other CDA projects
• Stem cell transplants for repair of macular degeneration and cardiac damage
• Define mechanisms to overcome stem cell transplant rejection
• Integration of VGTIFL cores and technologies with KI projects in the CDA for novel therapies and clinical trials
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Potential interactions with FAU
• VGTIFL Principal Investigators hold adjunct appointments with FAU (training of grad students, committee service)
• Collaborative research efforts (joint grant applications)
• Shared resources available to FAU scientists
• Summer Undergraduate Research Fellowship (SURF) program: http://www.vgtifl.org/internships
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V A C C I N E & G E N E T H E R A P Y I N S T I T U T E
Acknowledgments
• Dr. Jove President and Director VGTIFL
• Dean of KI Hans-Gustaf Ljunggren
• State and local legislators
• CDA scientists – Dr. Alici – Dr. Lundqvist – Dr. Carbascio – Dr. Grinnemo – Dr. Hovatta
• VGTI investigators – Dr. Ross – Dr. Hiscott – Dr. Haddad – Dr. Trautmann – Dr. Knutson
• VGTI core staff