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Cellular based therapy programs at Radiumhospitalet
Oslo University Hospital
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Department of Cellular Therapy
Head of Department and Production
Site, Qualified Person
Prof. Gunnar Kvalheim
Substituted by: Dag Josefsen
Head of Staff:
Merete Djupedal Head of Quality Management
Merete Djupedal
Cleanroom
Facility
Analysis
Laboratory
Leukapheresis DC Production T-cell
Production
RNA
Production
Immune
Monitoring
Research and
Development
Facility
Manager:
Bente
Woldseth
Responsible
Biomedical
Scientists:
Sissel Nygren
Marianne Dyr-
Haug
Production
Leader:
Grete
Andreassen
Production
Leader:
Hege
Haakenstad
Production
Leader:
Marianne
Lundby
Production
Leader:
Stein Sæbøe-
Larssen
Head:
Else Marit I.
Suso
Head:
Gunnar
Kvalheim
Biomedical
Scientists Biomedical
Scientists
Biomedical
Scientists
Biomedical
Scientists
Biomedical
Scientists
Research
Scientists
Biomedical
Scientists
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Department of Cellular Therapy - for GMP production of cell products –
in size one of the largest in Europe
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BIOBANK
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Department of Cellular Therapy
INSPECTED AND ACCREDITATED BY:
Norwegian Health and Social Department
EU cell directive (2004/23/EC)
JACIE
National Marrow Donor Program(NMDP)
Statens Legemiddelverk
GMP production of cell products
(EU directive 2003/94EC/91/412/EC)
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Translational research and clinical activites at
Department of Cellular Therapy
Cellular based Personalized Immunotherapy
• DC vaccination with autologous mRNA from tumor in Glioblastoma
Multiforme, Prostate, Melanoma, Ovarian;
• Adotive T-cell Therapy.
Clinical use of Somatic Stem Cells:
• Hematopoietic stem cells – auto/allo stem cell program;
• Pancreatic Islets treatment in diabetes – preclinical …clinical 2013;
• Adipose Derived Stem Cells;
• Vascular Stromal Fraction cells. Clinical program on non-healing
chronic wounds following curative radiotherapy and in breast
reconstruction after radiotherapy… clinical 2013.
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Oslo University Hospital
Dept. of Immunology
Gustav Gaudernack
Dept. of Neurosurgery
Iver Langmoen
Einar Wiik-Moe
Dept. of Surgery-Radiumhospitalet
Karol Axcrona
Bjørn Brennhovd
Dept. of Hematology
Geir E. Tjønnfjord
Ingunn Dybedal
Dept. of Cellular Therapy
Gunnar Kvalheim
Kirsti Hønnåshagen
Anne-Merete Tryggestad
Stein Sæbøe-Larssen
Jon Amund Kyte
Dag Josefsen
Iris Bigalke Hilde Almåsbak Else Marit Indreberg Suso Marit Renee Myhre Kari Lislerud Kristina Anderson
Dept. of Clinical Cancer Research
Steinar Aamdal
Svein Dueland
Paal Brunsvig
Study coordinators/nurses
Dept. of Cancer Therapy
Wolfgang Lilleby
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Cancer Facts & Figures 2012. American Cancer Society
Estimated Cancer Deaths in USA 2012
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9
Acute Lymfatisk Leukemi (ALL)
• Mest vanlige type leukemia hos barn
• 15% av akutte leukemier hos voksne
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Allotransplant
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Acute Lymphoblastic Leukemia Overall Survival Unrelated Transplantation with Bone Marrow for Pediatric Patients, by Disease
Status at Transplant (2000-2009)
The NATIONAL MARROW DONOR PROGRAM® operates
the Be The Match Registry®.
SOURCE: Data and analysis on NMDP-facilitated transplants
through CIBMTR®, the research arm of the NMDP.
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Acute Lymphoblastic Leukemia Overall Survival Unrelated Transplantation with PBSC for Adult Patients,
by Disease Status at Transplant (2000-2009)
The NATIONAL MARROW DONOR PROGRAM® operates
the Be The Match Registry®. SOURCE: Data and analysis on NMDP-facilitated transplants
through CIBMTR®, the research arm of the NMDP.
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Department of Cellular Therapy
11.04.2013
Critical issues that affect outcome after allo-SCT
-3 -2 -1 -4 -6 -5 +14 +21 +100 >180 0
Graft
Stem Cell
Source Conditioning
regimen
Supportive care
GVHD prophylaxis
Disease-related
features (lym. vs. myl., stage,
kinetics…)
Patient-related
features (age, gender,
serostatus, comorbidities…)
1
2
3 5
6
4
Prior therapy
(type of chemo,
high dose chemo…)
2
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Impact of a graft-versus-host disease (GVHD)
on post-hematopoietic cell transplantation outcomes
Baron F et al. JCO 2005;23:1993-2003 ©2005 by American Society of Clinical Oncology
Acute GVHD Chronic GVHD R
ela
pse
(%
)
Re
lap
se
(%
)
No
nre
lap
se
mo
rta
lity
(%
)
No
nre
lap
se
mo
rta
lity
(%
)
Pro
gre
ss
ion
fre
e s
urv
iva
l (%
)
Pro
gre
ss
ion
fre
e s
urv
iva
l (%
)
Months from onset Months from onset
Grad 0
Grad 1
Grad 2
Grad 3
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Genmodifiserte
T celler i behandling
av leukemi og lymfom
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Adoptiv T-celleterapi
Tilbakeføre store mengder modifiserte T celler for å eliminere leukemi/lymfomceller
PBMC
Isolere immunceller
Reaktivere disse
Ekspandere antallet
Genmodifisere for å dirigere spesifisitet mot leukemi/lymfom
Hilde Almåsbak [email protected]
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Hilde Almåsbak [email protected]
Adapted from Chekmasove et al. Discovery Medicine 2010
T-celler med kimær antigen reseptor (CAR)
T-celle reseptor
Antistoff som
binder tumor
CAR
tumordrap
leukemicelle
Genmodifisert T celle
(virusvektorer)
CD19 molekyl
Anti-CD19
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Sadelain et al. Cancer Discovery 2013
CAR i prekliniske studier rundt i verden
Kreftform:
Leukemi
Lymfom
Ovaria cancer
Melanom
Brystkreft
Myelom
Glioblastom
Prostatakreft
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Kochenderfer & Rosenberg (2013) Treating B-cell cancer with T cells
expressing anti-CD19 chimeric antigen receptors. Nat. Rev. Clin. Oncol.
Publiserte studier med CD19-CAR
for leukemi og lymfom
Alle I USA
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Hilde Almåsbak [email protected]
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Behandling med CD19 CAR T celler på UPENN
Kronisk Lymfatisk Leukemi
9 pasienter behandlet,
Resistente mot annen terapi
4 pasienter CR
2 pasienter PR 3-5 mnd varighet
3 pasienter NR (T-cellene ikke overlevd)
1-2 kg tumorceller eliminert
Akutt Lymfoblastisk leukemi
2 barn behandlet,
7 år gammel jente, 2 tilbakefall, kjemoterapi uten videre virkning, forhindret allo-SCT
10 år gammel jente, 2 tilbakefall etter navlestrangsblodtransplantasjon
Begge pasienter i morfologisk remissjon 1 mnd etter T celler (<0.01% MRD)
7 åringen fremdeles uten påviselig sykdom (>11 mnd)
10 åringen i tilbakefall med CD19-negative blaster
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All patients eligible
No need for HLA matching
Offered to young as well as elderly patients
”Engineered T cell therapies likely to replace allogeneic transplantation”
Hilde Almåsbak [email protected]
Dr Carl June, University of Pennsylvania
”The benefits of
allogeneic bone
marrow
transplantation
may be achieved
without the risk
of GVHD with
autologous CAR
T cells”
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Hilde Almåsbak [email protected]
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Adoptive T-celle terapi i Norge
• Internasjonalt forskningssamarbeide etablert (CAR 19 - EU-grant CHILDEHOPE)
• Preklinisk studier
• Translasjon pågynt
• Klinisk i bruk Høst 2013/2014
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Gene transfer
• Transient expression (7-9 days)
• Less risky safety profile
• Regulatory/technol. less demanding
• Less expensive
• No memory
• Constitutive expression
• Safety issues
• Regulatory/technologically demanding
• Expensive
• In vivo expansion and differentiation, memory
mRNA electroporation Integrating virus (gammaretro-, lenti-)
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IVT CAR mRNA
Electroporation
CD3CD28
Dynabeads
activated and
expanded T cells
In vitro assays for
CAR expression and
functionality
Formulation for i.v.
injection in NSG mice
Overview over the process
mRNA
expression
vector
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Low in vivo anti-leukemia activity despite excellent in vitro functionality; modified CAR format significantly better
No treatment Empty
T cells
Pre-ATC
Day 3
Day 8
Day 15
Day 23
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Adoptive T-celle terapi i Norge
• Internasjonalt forskningssamarbeide etablert (CAR 19 - EU-grant CHILDEHOPE)
• Preklinisk studier
• Translasjon pågynt
• Klinisk i bruk Høst 2013/2014
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Adoptive T-celle terapi kostnader
Allo transplant CD19 CARS
Avdeling for blodsykdommer
Avdeling for celleterapi
DRG+ DRG-
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Phase1 Phase3 Phase2
Translational research T1 T2
Pre clinical research Clinical trials
Financing
Health authorities
Universities
Norwegian Research Council
Others: Industry, Cancer Society