elevator pitch: engineering car t cells on the...
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Elevator Pitch: Engineering Car T cells on the CliniMACsProdigy
Lindsey Clarke, PhD
Clinical Business Manager, Cell Therapy & Therapeutic
Apheresis,Miltenyi Biotec Ltd.
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October 5, 2016 CliniMACS Prodigy CAR-T Cells
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October 5, 2016 CliniMACS Prodigy CAR-T Cells
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Conventional genetic modification of T cells requires...
Donor /
patient
+ + ++ ++
Blood
LeukapheresisStorage
Application
Cell
selection
Cell
transduction
Cell
formulation
Cell
activation
Cell
expansion
CliniMACS Prodigy CAR-T Cells October 5, 2016
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Scalable
Automated
Standardised
Easy Tech Transfer
Cost Efficient
What Miltenyi Provides
October 5, 2016
GMP Raw Materials
LentiviralVectors
QC Instruments
and reagents
Prodigy
Cell processor
Training
CliniMACS Prodigy CAR-T Cells
The complete
CAR- T
package
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Magnet Unit
Liquid Sensor
Pinch valves
Peristaltic pump
Bag hangers
Bag
Compartment
CentriCult Unit
Touch screen
Gas Mix Unit Tube Sealer
Bar code reader
CliniMACS Prodigy
October 5, 2016October 5, 2016 CliniMACS Prodigy CAR-T Cells
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Prodigy: Fully automated clinical transduction
1. Guided installation of TS520 sterile tubing set
2. Sterile docking to CliniMACS® Prodigy:
• Reagents
• Patient sample
• Sterile connection for vector
3. Pre-transduction Cell processing
• Cell washing
• CliniMACS cell separation
4. Addition of TransAct activation reagent
5. Transduction with Lentiviral Vector
6. Cell cultivation
• Media addition and removal
• Supplement addition
7. Final product formulation
• Change buffer
• Concentration
8. Harvest ready to give to patient/cryopreserve
October 5, 2016October 5, 2016 CliniMACS Prodigy CAR-T Cells
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TCT Process Software – In Built Flexibility
Guided User interface (GUI) for culture: “Activity matrix”
• Possibility to start a run at various steps
(e.g. Include/skip enrichment, culture
only, resume culture)“
• Flexibility of the manufacturing run
attained through user defined “activities”
• Transduction
• Shaking conditions
• Feeding (Feed or Media exchange)
• “culture wash”
• In-between samples for in-process
control (+ pictures) can be taken (at any
time-point of culture)
Minimal User Interaction• Attach starting product, media,
TransAct.
• Connection fresh virus (day 1)
• New medium bag (2L for 5-7 days)
• Connect solution for harvest (day 10-
14)
October 5, 2016October 5, 2016 CliniMACS Prodigy CAR-T Cells
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T cell transduction and expansion process
Results
Cell
expansion
Cell
formulation
Cell
transduction
Cell
activation
Cell
selection
Final packaged
Cell product
CliniMACS
Reagents
MACS GMP
TransAct Kit
Transduction
with LV
MACS GMP
IL-2/7/15
TexMACS
Rebuffering
CliniMACS Prodigy
TS 520
Enrichment
• CD4/CD8 or CD62L
Activation
• 1x10E8 T cells
Transduction
Expansion
• Volume: 250 mL
• >2.0x10E9 T cells 1
Functional CAR T cells
• Cytotoxicity/ cytokine secretion
Cryopreserved
or fresh
apharesis
October 5, 2016
1) 3x106 CD19 CAR T cells/kg body weight (Davila et al. (2014) Sci Trans Med)CliniMACS Prodigy CAR-T Cells
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T cell cultivation – High cell densities and high viability
Cell
expansion
Cell
formulation
Cell
transduction
Cell
activation
Cell
selection
Final packaged
Cell product
Cryopreserved
or fresh
apharesis
0 2 4 6 8 10 12 14 16
0
5
10
15
0
100
200
300
time (in days)
Glu
cose (g/L
) pH
valu
e
volume
via
bility
(in %
) tota
l volu
me (in
mL) s
hakin
g s
peed (in
rpm
)
type 3
0 2 4 6 8 10 12 14
0
10
20
30
40
50
60
0
50
100
150
200
250
300
time (in days)
ce
ll d
en
sity ( x
10E
6 )
tota
l cell c
ou
nt ( x10E
8 )
T c
ell e
xp
an
sio
n (x fo
ld)
volume
sh
akin
g s
peed
(in rp
m)
tota
l cu
lture
Vo
lum
e (in
mL
)
typ
e 3
October 5, 2016October 5, 2016 CliniMACS Prodigy CAR-T Cells
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T cell cultivation- robust and reproducible
Cell
expansion
Cell
formulation
Cell
transduction
Cell
activation
Cell
selection
Final packaged
Cell product
Cryopreserved
or fresh
apharesis
count
(day 10-14)
T cells CAR+ T cells
non-transduced 3.11E9 (±1.3) -
transduced 3.13E9 (±0.9) 1.3E9 (±0.3)0 2 4 6 8 10 12 140
10
20
30
40
50
time [days]
cell
count [x10
8]
lentiviral transduced
non-transduced
0 2 4 6 8 10 12 140
25
50
75
100
time [days]
via
bili
ty [%
]
lentiviral transduced
non-transduced
Robust expansion during non-
transduced (n=6) and lentiviral
transduced (n=10) runs
Good viability of each
manufactured cellular product
E.g. dose: 106 CAR+ T cells / kg
(130kg patient)
October 5, 2016October 5, 2016 CliniMACS Prodigy CAR-T Cells
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October 5, 2016 CliniMACS Prodigy CAR-T Cells
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New processes being added in…..
October 5, 2016 CliniMACS Prodigy CAR-T Cells
1. Retroviral transduction (2016/17)
2. Electroporation (2016/2017)
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Everything you need to make CAR-T cells from one
supplier
October 5, 2016 CliniMACS Prodigy CAR-T Cells
One Supplier
One Stop For Quality Paperwork
One Audit
One Purchase/Supply Agreement
One Partner
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Donor /
patient
Blood
LeukapheresisPatient
Cell
selection
Cell
transduction
Cell
formulation
Cell
activation
Cell
expansion
• End-to-End Solution
• Standardised, reproducible, transferable
• Easy commissioning, servicing and QA.
• No connection/transfer complications between
different manufacturers
• Automated
• Manufacture and QC
• Standardised, Reproducible, Transferable.
• Minimised personnel and training considerations.
• Closed-system
• Instantly scalable.
October 5, 2016 CliniMACS Prodigy CAR-T Cells
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Applicable to Centralised Manufacturing…
October 5, 2016 CliniMACS Prodigy CAR-T Cells
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…Or Localised/Point of Care Manufacturing
October 5, 2016 CliniMACS Prodigy CAR-T Cells
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October 5, 2016
1 Prodigy
How many products a month?
How many staff does that require?
How many clean rooms?
How many pieces of equipment?
CliniMACS Prodigy CAR-T Cells
• 3
• 1 - 2
• 1
• 1
Phase I/II
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October 5, 2016
100 Prodigy’s
How may products a month?
How many staff does that require?
How many clean rooms?
How many pieces of equipment?
CliniMACS Prodigy CAR-T Cells
• 300
• 20
• 1
• 100
Roll Out
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October 5, 2016
100 Prodigy’s
How may products a YEAR?
How many staff does that require?
How many clean rooms?
How many pieces of equipment?
CliniMACS Prodigy CAR-T Cells
• 3,600
• 20
• 1
• 100
Roll Out
PC USERS:
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Thank you!
Dr. Lindsey Clarke
Clinical Business Manager
Miltenyi Biotec Ltd
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