SepLember 2014

Engineered T cell therapies

A new paradigm in oncology
This communication expressly or implicitly contains certain forward-looking
statements concerning Cellectis SA and its business.
Such statements involve certain known and unknown risks, uncertainties and
other factors, which could cause the actual results, financial condition,
performance or achievements of Cellectis SA to be materially different from any
future results, performance or achievements expressed or implied by such
forward-looking statements.
Cellectis SA is providing this communication as of this date and does not
undertake to update any forward-looking statements contained herein as a
result of new information, future events or otherwise.
Cellectis proprietary information.
Not to be copied, distributed or used without Cellectiss prior written consent.
FORWARD LOOKING STATEMENT
SepLember 2014 2
Brief introduction to Cellectis
SepLember 2014
Cellectis in brief
Discovery and development in engineered T cell therapy for oncology Paris France
NYSE Alternext Paris (ALCLS)
27.9 M shares outstanding (32.5 fully diluted) - !319 M market cap
1

73 employees
Corporate
Technologies
Products 12 programs one preclinical proof of concept
Lead product: UCART19 allogeneic T cell for ALL and CLL
Phase I planed for Q3 - 2015
Partnerships Series of agreements since inception with recurrent revenues
An alliance with Servier on UCART19 and 5 targets in solid tumors
An alliance with Pfizer on 15 targets in oncology
Engineered T cell CAR 5
th
generation immunotherapy
Nuclease based genome engineering TALEN, meganucleases
Proprietary electroporation technologies PulseAgile
>120 patents granted and over 355 patent applications
4
Subsidiary 1 fully owned subsidiary: Cellectis plant sciences in New Brighton, MN (14 FTE)
1
August 29, 15 2014
Core technology
SepLember 2014
DNA genome engineering
Cellectis competitive advantage: rational genome engineering
The innovation: NUCLEASES or DNA scissors!
14 years of experience in quality, throughput & innovation
TALEN
MNs
6
4 criteria for genome editing technologies:
1. Precision: How close a nucleotide could be targeted in the genome?
2. Efficacy: What will be the percentage of cells with a gene editing?
3. Safety: How little does it cut elsewhere (off target effect)?
4. Vectorization: How well could it be vectorized?
SepLember 2014
GENE SPECIFIC
AT A SAFE HARBOR LOCUS
FOR GENE
COMPLEMENTATION
AT THE GENE LOCUS
TALEN cut DNA at a unique target site
(30 base pairs recognition site)
Induce an opening in DNA to allow
sequence insertion, deletion and/or repair
Pioneer and leader in genome engineering: core technology
7
A new paradigm in the treatment of cancer
SepLember 2014
CAR T cells the 4
th
generation of mAb technology
Anti-
CD3
Anti-
tumor
Ag
TCR/CD3
Naked Ab
Ab-Drug
Conjugate
Bi-specific CAR T cell
9
SepLember 2014
Expending the space of targeted therapies
Anti-
CD3
Anti-
Tumor Ag
TCR/
CD3
Naked Ab
Ab-Drug
Conjugate
Bi-specific CAR T cell
10
Density of surface antigens / tumor cell
Number of accessible targets
~100,000 >10,000 <5,000 <1,500
SepLember 2014
11
Immunotherapy breakthrough with CAR T cells
Diseases Patients
treated
CR
2
N (%)
PR
3
N (%)
Patients
responding
4
N (%)
CLL 32 7 (22%) 8 (25%) 15 (47%)
ALL 22 19 (86%) NC NC
Results from pilot trials testing CTL019 for CD19+ malignancies
(UPenn/Novartis)
1
presented at ASH 2013
1
Results communicated at ASH, December 2013
2
CR: complete remission
3
PR: partial remission
4
CR+PR
CARs in the clinics: the numbers
! 33 ongoing clinical trials with CARs (all autologous)
! Over 300 patients recruited
! Impressive results on liquid tumors are changing the paradigm of cancer
treatment
SepLember 2014
Cellectis platform the 5
th
generation of mAb technology
Anti-
CD3
Anti-
Tumor Ag
TCR/
CD3
Naked Ab
Ab-Drug
Conjugate
Bi-specific CAR T cell
12
Cellectis
Engineered
CAR T cell
First focus on:
" Allogeneic cells: by removing capacity for alloreactivity
" Enhance cell engraftment (resistance to chemotherapy)
" Enhance T cell potency (checkpoint inactivation)
SepLember 2014
Cellectis revolutionizing T cell CAR adoptive immunotherapy
13
1. Best in class gene editing technology: TALEN
2. Proprietary CAR platform technology
3. A cGMP manufacturing process
4. Broad preclinical and clinical portfolio with proprietary innovative features
5. Reduced time to market
6. Contained costs of goods
The 6 key features of Cellectis T cell adoptive immunotherapy platform
SepLember 2014
14
Cellectis engineered T cells for improved clinical outcomes
1 Allogeneic, non alloreactive Off the shelf product
2 Resistant to chemotherapy Compatible with SoC
Use in combination therapies
3 Resistant to lymphodepleting agents Enhanced engraftment
4 Resistant to tumor inhibition Enhanced efficacy
5 Suppressed cross T cell reaction Better suited for specific tumors
6 Bispecific Ab enabled T cells For a combinatorial use
Enhancing the potential of T cells through genome engineering
The future of T cell therapies is in genome engineering
SepLember 2014
Cellectis best in class technology
Current CAR T cell therapies : autologous
Good efficacy with no GvHD and no rejection
Significant patient to patient variability
High cost of goods and complex logistics
Major limitations in market access
Allogeneic treatment: off-the-shelf frozen pharmaceutical product
Fixed dose and superior efficacy
Cost effective GMP manufacturing process (70-80% gross profit range)
Broad market access
Risk mitigation through suicide receptor
Strong IP position on process and TALEN
Cellectis allogeneic CAR T cell platform
15
SepLember 2014
scFvs targeting different epitopes
scFvs with variable affinities
Multiple hinge/transmembrane structures
Co-stimulatory domain (CD28 vs 41BB)
Key considerations for the optimal CAR
Tuning up CAR development
12
SepLember 2014
CD123 CAR: reaching the target
Impact of the hinge domain length on CAR activity
long hinge medium hinge short hinge Negative Control
!
"
!
$
"
%
&
'
(

)* +,-./0 +12!
long hinge
medium hinge
short hinge
14
SepLember 2014
Plasma
membrane
1
st
generation
CAR
2
nd
generation
CAR
3
rd
generation
CAR
Cellectis proprietary
multichain CAR
18
The next generation CARs: multichains multiply potentials
SepLember 2014
0
10
20
30
40
30
60
w/o CA8 mc CA8 4 g rsL sc CA8 ll
3
4
5
6
4
7
8
9
:
4

,
;

6
4
<
<

<
=
.
>
.

mc CAR-CD19 sc CAR-CD19
Multichain CAR matches antitumor activity of scCAR with lower
surface expression
31% 76%
19
VH
scF
V
VL
scF
V
mcCAR 4
mcCAR architecture provides
" Added flexibility
" Possibility for additional activation/co-stimulatory domains
" Compatibility with multiple ligands targeting
" Engineering compatibility with mAb and bispecific Ab
Based on the high affinity IgE receptor
mc CAR-CD19 sc CAR-CD19 w/o CAR
SepLember 2014
0,00
2000,00
4000,00
6000,00
8000,00
10000,00
12000,00
14000,00
16000,00
n1 CA8ll mcCA84-o
%?&-:
1 cells
MA
uaudl
k362
Multichain CAR confers a sharp cytotoxic target specificity
Multichain CAR shows Improved specificity compared to scCAR (safety)
20
mc CAR-CD19 sc CAR-CD19 w/o CAR
SepLember 2014
Glucocorticoid resistant T cells by genome editing
100
200
GR TALEN CTL
ND D ND D
50
76%
indels
500
2 Gy irradiated
NSG mice
Human
T cells
GR TALEN
electroporation
T cell injection
Analysis of GR gene
cleavage effciency
10 days
2 weeks
daily
dexamethasone
treatment
Mice sacrificed
GR
GAPDH
TALEN
- + +
Dex
- - +
Purification of
human T cells from
spleen
Analysis of GR
expression by
Western blot:
In vivo, GR TALEN-treated T cells resist to glucocorticoid treatment
Only GR-negative cells survive in vivo
dexamethasone treatment
Engraftment
analysis
5 days
21
SepLember 2014
22
Resistance to standard of care: fludarabine resistant T cells
Inactivation of deoxycytidine kinase enables CD19 CAR T cells to resist to Fludarabine and
Clofarabine
Cmax
oral i.v.
Cmax
)@$(& A+B C
- + -
D A9=. ED A9=.
+<,;959F>74 GE H*I
J8
A9=. 3,.8 (K
mutated
alleles
wt alleles
SepLember 2014
Overcoming checkpoint inhibition:
PD-1 inactivation overcome suppressive impact of PDL-1
23
Cytotoxicity assay
T
a
r
g
e
t

c
e
l
l

l
y
s
i
s

(
%
)

T
a
r
g
e
t

c
e
l
l

l
y
s
i
s

(
%
)

CAR/PD1-KO T Cell have improved cytotoxic capacity
against PDL-1 expressing cells
PD-1 KO in T cells in a local solution to a local problem
SepLember 2014
A solid IP foundation
24
Patents on the process
! TALEN
! Electroporation (Cytopulse)
! Methods on engineering of allogeneic T cells
Patent applications protecting first product (UCART19)
Patent applications protecting the platform and further products
! Specific CARs
! Multisubunit CARs
! Bispecific/multispec CARs
! Engineering methods for allogeneic T cells
! Modular allogeneic T cells to be used with bispecific antibodies
Cellectis proprietary or in licensed IP on Process/Products
GMP-compatible manufacturing process
SepLember 2014
Our platform: towards a universal adoptive T cell immunotherapy
Off-the-shelf (TCR disruption
1
)
Avoiding GvHD
CAR expression to redirect T cells to
tumor antigens
Suicide gene for safety
Other gene editing
Engineered
1
Knock-out by using TALEN
2
Allogeneic CAR T cell targeting CD19+ malignancies
" For UCART19
2
- CD52 disruption
1
to
prevent destruction by high risk CLL mAb
Alemtuzumab therapy
" Other gene disruptions/mutations in further
programs
SG
SG
Enhance killer T cells by genome engineering
26
SepLember 2014
Healthy
Donor
Apheresis
Frozen PBMC
Patients
10
9
T cells 10
9
T cells
Efficiency >70%
2 x 10
9
T cells
100X
2x 10
11
T cells
Double KO Efficiency >50%
1 x 10
10
CAR
+
TCR
-
T cells
>40% CD52
KO
Off the shelf
cell therapy product
27
Qualifying
testing
Activation
T cells
D0
Transduction
D3
Electroporation
TALEN mRNA
D5
Cell Separation
D17
An established cost effective manufacturing process platform
! A robust process designed for cGMP compatibility
! A short manufacturing cycle (< 20 days)
SepLember 2014
UCART19 - Consistency of manufactured product
28
Cell surface phenotype
Expansion /transduction intra and inter process robustness
Cell expansion
Transduction efficiency
C
D
4
5
R
A

CD62L
SepLember 2014
Cellectis proprietary technology for TALEN
TM
electroporation
29
Proprietary large volume
electroporation chamber
Electroporation system
Proprietary cGMP
Electroporation buffer
Proprietary PulseAgile electroporation waveform
A series of high voltage, short duration pulses followed
by lower voltage, longer duration pulses
" High transfection efficacy
" High cell viability
V
time
SepLember 2014
Simultaneous inactivation: TCR# and CD52
C
D
5
2

TCR/CD3
Simultaneous inactivation rates of TCR and CD52 over 50% of triple KO
+1LC 97A )+M
TALEN mRNA electroporation
" development and optimization of TALEN targeting TCR# and CD52
" optimization of proprietary electroporation process for T cell transfection
30
SepLember 2014
C. June trial (UPenn)
41BB-! CAR in CLL, ALL
" CR with 1.1x10
9
CAR T cells
" PR* with 5.8x10
8
CAR T cells
" CR with 1.4x10
7
CAR T cells
M. Sadelain trial (Memorial Sloan Kettering)
CD28-! CAR in adult ALL
" Patients received approximately 1-3x10
8
cells
High productivity foreseen for Cellectis' process
One donor
10
9
cells
10
10
UCART19 cells
Treatment of
1000 patients with
10
7
cells per treatment
31
Cellectis process
! Contained manufacturing COGs (<10k$ / treatment dose expected)
! Economies of scale anticipated for critical raw materials
SepLember 2014
Fast track from target choice to lead selection: 6 - 7 months
32
CHOICE OF TUMOR ASSOCIATED ANTIGEN(S)
(TAA)
CAR DESIGN
Design and construction
of candidate CARs
CAR T CELL ENGINEERING
First tests on CAR T cell
GO/
NO GO
In Vitro
Assay
development
/ Target cell
engineering
5-6 months
1 month
TIMELINES
UCART PROGRAM
CHOICE OF
ATTRIBUTES AND
NUCLEASE DESIGN
1
IN VITRO ASSAYS
Functional in vitro tests on target cell
Selection of lead CAR
IDENTIFICATION OF TAA-SPECIFIC MAB(S) OR
OTHER LIGANDS
Lead product UCART19
SepLember 2014
# UCART19 first product for CLL and ALL
" Preclinical development ongoing with in vivo POC established
" Manufacturing process established, fully cGMP compatible Q4 2014
" Alliance with UCL in place for first in man studies
# Phase I Q3 2015
" Clinical Development plan in place
UCART19 development status: where we stand
34
SepLember 2014
Cellectis UCART19 cells induce CD19+ cell destruction in vitro
NT
CAR
C
D
1
9

C
D
1
9

C
D
1
9

C
D
1
9

CD3 CD3
CD3
CD3
SupT1-
CD19 cells
SupT1-
CD19 cells
SupT1 cells SupT1 cells
T cells transduced with vector
encoding Cellectis CD19 CAR
35
Efficient CAR-induced destruction
of CD19+ target cells
SepLember 2014
UCART19 CAR: superior in vitro cytolytic capability
36
Target cell lysis by Cr
51
release
Benchmarked against
FMC63-41bb-zeta CAR (used by UPENN)
-10
0
10
20
30
40
30
60
70
80
30:1 13:1 8:1 3:1
n1
supe
M13622
supe
M13624
%

c
e
l
l

l
y
s
i
s

Benchmark CAR
Ctx CAR final version
Effector:Target
-3
0
3
10
13
20
23
30
30:1 13:1 8:1 3:1
n1
supe
M13622
supe
M13624
%

c
e
l
l

l
y
s
i
s

Effector:Target
Benchmark CAR
Ctx CAR final version
-10
0
10
20
30
40
30
60
70
80
30:1 13:1 8:1 3:1
n1
supe
M13622
supe
M13624
%

c
e
l
l

l
y
s
i
s

Effector:Target
Benchmark CAR
Ctx CAR final version
RAJI (CD19 positive Burkitts lymphoma cells) SUPT1-CD19
SUPT1
CD19 negative cells
CD19 expressing cells
UCART19 CAR exhibits comparable/
higher cytolytic capability than benchmark
CAR on target cells
SepLember 2014
PMA/Iono
TCR!+
CD52+
K562
(CD19-)
Stim.:
C
D
1
0
7
A

+ + -
-
Daudi
(CD19+)
- +
"CD19-CAR:
NT CAR
TCR#+
CD52+
NT CAR
TCR#
KO
CD52
KO

TCR" & CD52 double KO does not impact in vitro activity of the CAR
In vitro antitumor reactivity is comparable in wt or CD52/TCR KO cells
TCR!
KO
CD52
KO
FSC
Daudi
(CD19+)
37
SepLember 2014
wt cells
TCR- cells
Activation marker: CD25
wt cells
TCR- cells
no
stimulation
+ TCR
stimulation
No functional T cell receptor for GvHD
Activation marker: CD69
TCR-deficient cells cannot
be activated via TCR
38
SepLember 2014
Anti-tumor potency UCART19 / benchmark CAR
1.44 Gy
Daudi
Non modified
1.44 Gy
Daudi
UCART19
Day 0
Day 1
Day 2
Day 3
Day 4
1.44 Gy
Daudi
Benchm. CAR
Day 4
Before
T cells
treatment
Day 7
Day 21
1.44 Gy
Daudi
UCART19
1.44 Gy
Daudi
CAR
1.44 Gy
Daudi
Benchm. CAR
5/5
tumor progression
5/5 3/3 5/5 5/5 5/5
Tumor model: 1x10
6
Daudi-Luc cells injected in NOG mice
mice treated with 4x10
6
CAR T cells
Tumor cells elimination
39
SepLember 2014
UCART19 cells eradicate lymphoma in vivo in
presence of lymphodepleting mAb
In collaboration with Dr. Martin Pule, University College London
40
Raji
18 h
3
days
13
days
alemtuzumab
Raji
UCART19
alemtuzumab
Raji
Day -1
Day 0
Day +1
6/6
tumor
progression
6/6
tumor
progression
6/6 CR
5/7 CR
2/7 PR
Raji
UCART19
SepLember 2014
TCR-deficient T cells do not induce GvHD in vivo
Mean body weight
G2, fresh non modified T cells
G4, mock transfected T cells
G3, non modified T cells, cultured 15 days
G5, TCR#
-/-
T cells
G1, No T cells
! GvHD development, associated with body weight loss, in all mice injected with non modified T cells
! With TCR-deficient T cells: no clinical symptoms of GvHD observed
NOG mice irradiated (2.5 Gy) 1 day before T cell injection (i.v., 30x10
6
cells)
41
SepLember 2014
Exploratory Phase I/II
adult refractory ALL
Phase I/IIa
Rescue therapy
in adult relapsed
ALL
Phase IIb
Rescue therapy
in adult relapsed
ALL
Paediatric Investigational Plan
ALL : 2
nd

& 1
st
complete
remission
consolidation
therapy
42
UCART19 clinical development overview
Market. Auth
Exploratory Phase I/II
rescue therapy high
risk CLL
Phase I/IIa
consolidation
therapy in
relapsed CLL
CLL Rescue therapy in
Refractory relapsed
CLL in second line
MRD+ consolidation
Therapy
UCART19 Clinical Development: CLL
UCART19 Clinical Development: ALL
Phase IIB
(confirmatory)
consolidation
therapy in
relapsed CLL
Extension to any B-lymphomas
SepLember 2014
43
Phase I early results providing solid rationale for GO/ NO GO decision
" Tumor burden lysis at day 8-15
" Safety profile (cytokine release syndrome)
Low capital investment versus protein manufacturing
" cGMP manufacturing for Cellectis products in 200-300sqm facility
sufficient for initial clinical phases
Short manufacturing cycle < 20 days (w/o release testing)
Cost effective
" Contained manufacturing COGs (<10k$ / treatment dose expected)
" Economies of scale anticipated for critical raw materials
Cellectis platform is versatile, and the technology is leveragable for future
liquid and solid tumor products
UCART19 - contained investment and costs of goods
Roll out in liquid and solid tumor indications
SepLember 2014
" A candidate product is a cell population with:
- one given set of endogenous modifications (knock outs, other): attributes
- one given set of antigen-specific recognition features: ligand(s)
Broad CAR T cell pipeline product / antigen oriented
45
SepLember 2014
Broad CAR T cell pipeline
(1)
46
(*) Subject to an exclusive worldwide option agreement with Servier (S2-S6, targets undisclosed)
(**) Target under Pfizer-Cellectis joint research effort
UCART19 (*)
UCART123
UCARTCS1
UCART38 (**)
S-2 (*)
S-3 (*)
S-4 (*)
S-6 (*)
S-5 (*)
Q3 2015
Q3 2014
Q2 2015
Q1 2015
Q1 2015
Q2 2015
Q3 2015
Q3 2015
! CD19+ B cell malignancies
! Acute myeloid leukemia (AML)
! Multiple myeloma (MM)
! Multiple myeloma (MM)
Discovery Preclinical Phase I
(1) Not including 15 targets in Pfizer alliance
Q2 2015
SepLember 2014
On March the 7
th
, Cellectis has entered into an alliance with Servier
" Scope: development of
UCART19 in B-cell malignancies
5 other candidates in solid tumors
" Responsibilities:
Cellectis will be responsible for the R&D of certain candidates through the end of clinical
phase I.
Servier may exercise an exclusive worldwide option for each candidate developed under
the agreement.
Upon exercising each option, Servier will be responsible for taking over clinical
development, registration and commercialization of each product.
" Financials:
Upfront payment of $10 million
Up to $140 million for each of the six candidates potentially developed, spread over
various milestones in the development and commercialization phases.
In addition, Cellectis will receive royalties on the sales of commercialized products.
Alliance with Servier
47
SepLember 2014
On June the 18
th
, Cellectis has entered into an alliance with Pfizer
" Scope: development of CAR-T cell therapies in oncology
15 Pfizer targets
12 Cellectis targets
" Exclusivity:
For 4 years, Cellectis will not enter into another preclinical CAR-T alliance in oncology
No exclusivity on each Cellectis product once IND filed
" Responsibilities:
Both companies work together on preclinical research for 15 Pfizer targets and 4 Cellectis targets (the
other 8 Cellectis targets are developed outside the alliance).
Each company is responsible and has all worldwide rights for clinical development and commercialization
of any product directed at its own targets.
Pfizer has right of first refusal on the products directed at the 4 Cellectis targets developed in the alliance.
" Financials:
Upfront payment of $80 million
Up to $185 million for each product targeting a Pfizer target potentially developed, spread over
various milestones in the development and commercialization phases.
In addition, Cellectis will receive royalties on the sales of commercialized products.
" Equity:
Pfizer purchased about 10% of Cellectis capital through newly issued shares at a price of !9.25 per
share.
Alliance with Pfizer
48
Financials & Conclusion
SepLember 2014
Ad hoc world class scientific & medical Advisory Board of key opinion leaders in oncology
and cell therapy:
Professor Ton Schumacher
Professor Alain Fischer
Professor Vronique Leblond
Professor David Linch
Professor Herv Dombret
Consultants:
Christopher A. Bravery, PhD (for Pharm. Assesor MHRA)
Paul Chamberlain, PhD (former Reg. Specialist Amgen, former Director Drug Dev.
Prog. MDS)
Mickael Kamarck (former President Merck Biologicals and vaccines)
Dr. Bruce Burlington, M.D. (former president Wyeth regulatory affairs)
Best-in-class expertise for development
50
SepLember 2014
51
Shareholding structure built to foster growth
Breakdown of capital as of August 29, 2014
(27,9 million shares*)
# !319 M market capitalization (August 29, 2014)
# Significant increase in liquidity
! 220,000 shares traded / day in 2014 YTD
! 105,000 shares traded / day in 2013
! 20,000 shares traded / day in 2012
! 16,000 shares traded / day in 2011
Founders: 7,2%
International float: 42,3%
BPI: 11,3%
Family offices: 15,1%
*32.5 million on a fully diluted basis
Pfizer: 10,0%
# Shareholding structure in line with the growth
strategy
# Float of ~ 56 %
French float: 14.1%
SepLember 2014
52
Management team & board of directors
MANAGEMENT
# Andr Choulika, Chairman and CEO
# David Sourdive, Executive Vice President
Corporate Development
# Mathieu Simon, Executive Vice President
# Thierry Moulin, Chief Financial Officer
# Philippe Duchateau, Chief Scientific Officer
# Philippe Valachs, Company Secretary
BOARD OF DIRECTORS
# Andr Choulika Ph.D.
# David Sourdive Ph.D.
# Mathieu Simon M.D.
# Laurent Arthaud
# Annick Schwebig M.D.
# Pierre Bastid
# Alain Godard
# Roger J. Hajjar M.D.
SepLember 2014
1hank you
Cellectis
8 rue de la Croix Jarry
75013 Paris
France
www.cellectis.com
Tel. : +33 (0) 1 81 69 16 00