surface-tethered il-12 improves tumor-specific t cell
TRANSCRIPT
Confidential | © 2017 Torque
TITLE:
Surface-tethered IL-12 improves tumor-specific T cell therapy and enhances inflammatory activity in tumors without inducing systemic toxicities
AUTHORS: Douglas Jones1, De-Kuan Chang1, Gulzar Ahmad1, Jonathan Nardozzi1, Kate Sackton1, PengpengCao1, Lars Peterson2, Ditte Jaegher2, Esben Christensen2, Jesse Lyons1, Karsten Sauer1, Thomas Andresen1
1Torque Therapeutics, Cambridge, MA USA 2Technical University of Denmark, Copenhagen, Denmark
PRESENTING AUTHOR: Douglas Jones, PhD IL-12 Scientific Program Lead Torque Therapeutics
March 31, 2019
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Torque platform is designed to overcome key cell therapy limitationsDeep-Priming harnesses natural T cell biology
surface-anchoredimmunomodulators
natural t cell receptors primed for tumor antigens
Torque Deep-PrimedTM T Cell
T cell
Multi-target, antigen-primed T CellsFor efficacy against heterogeneous tumors
Surface-anchored cytokines / ImmunomodulatorsTo overcome immunosuppression in the tumor microenvironment
High margin of safety • Outpatient, without myeloablative chemotherapy• Enables repeat dosing
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
D DM T
Torque platform harnesses natural T cell biology with ex vivo process
Antigen cassettes
Isolate cells
Dendritic cellMonocyte
Multi-Target Deep Primed T Cell
1
T cells trained by dendritic cells
Apheresis
2
Surface anchoring
Cytokines/Immunomodulators
T
T
T cell
• Deep IL-15• Deep IL-12• Deep TLR
“Primed”
18 Days
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Deep IL-12 delivers controlled dose loading on the T cell surface
Controlled, uniform IL-12 loadingDeep IL-12
VH
CC
H1
VLC
Ck
IL-12B
IL-12A
Deep IL-12 Primed T cell
Humanized anti-CD45 Fab
T cell
TRQ12-01
CD45
IL-12p70
(-) control
Deep IL-12
500 nM
100 nM
20 nM
4 nM
0.8 nM
0.16 nM
Anti-IL-12 MFI
0 nM
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Cell-tethered Deep IL-12 delivers superior efficacy Deeper and more durable response than systemic recombinant IL-12
PMEL / B16 melanoma tumor model
In vivo tumor growth inhibition
0 5 10 15 20 25 30 350
500
1000
1500
Days after ACT
Tum
or v
olum
e (m
m3 ) HBSS
PMEL
PMEL / IL12 TF (Preloaded)PMEL + 3.575pmole (250ng) sol rIL12Vehicle
control
PMEL T cells
Deep IL-12 Primed PMEL~150ng IL-12
PMEL + Systemic IL-12250ng IL-12
In vitro cytotoxicity
In vitro B16 melanoma cell killing at 48 hr
Effector:Target ratio
0.1 1 10
% T
um
or
cell
surv
ival
PMEL T cells
Deep IL-12 Primed PMEL
B16-F10
CD8 T cells
Activate
Deep IL-12 tethering
PMEL-1
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Deep IL-12 delivers favorable systemic profile
Systemic IL-12IFNg elevation and systemic toxicities
Deep IL-12 Primed T cellsTransient circulating IFNg
Daily systemic IL-12 C57BL6
Day
1
Day
3
Day
7
24h
afte
r 1s
t dos
e
24h
afte
r 3r
d do
se
24h
afte
r 7t
h do
se
0
5000
10000
15000
20000
Pla
msa
IFNγ
(pg/
mL)
Circulating IFNg from 5ug Daily IL-12
Daily IL-12 - 5ug i.p.
Day
1
Day
3
Day
7 0 4 7
80
85
90
95
100
Time (days post ACT)
Bod
y w
eigh
t (%
)
Transform of Mouse weight change - Day 0,4,7
CD45Fab-IL12: 1 dose
Day
0
Day
4
Day
0
Day
4
Day
7
CD
45Fa
b-IL
12: 1
dos
e
CD
45Fa
b-IL
12: 1
dos
e
0500
1000
5000
10000
15000
20000
Pla
sma
IFNγ
(pg/
ml)
P48 Plasma_Day1,4_IFN - update y-ax - Deep only, noCTX
Day 1 Day 4
C57BL6
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Deep IL-12 induces immune activation in the tumorUpregulates IFNg, co-stimulation, and MHC expression
Vehi
cle
cont
rol -
tum
or
Pm
el -
tum
or
Pm
el +
250
ng
i.v. I
L12
- tum
or
Pm
el /
chM
1Fab
-IL12
- tu
mor
0
5000
10000
15000
pg /
g tu
mor
Tumor IFNg
Dee
p IL
-12
/ PM
EL~
250n
g IL
-12
Syst
. IL-
12 +
PM
EL50
0ng
IL-1
2
PMEL
Vehi
cle
IFNg
(pg/
mL)
Increased IFNgproduction in the tumor
Activating myeloid-derived suppressor cells(Mo-MDSC) in the tumor
Deep IL-12Primed PMEL
CD86
MC
HII
PMEL Syst. IL-12 + PMEL
9%
54%36%
1% 17%
46%34%
3% 37%
13%27%
23%
Day 4 Mo-MDSC: CD11b+/CD11c-/Ly6GLow/Ly6Chi
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Cell-tethered Deep IL-12 drives activity specifically in the tumor
Increased PMEL T cell expansion and activity in tumor No activity in spleen
Day 4 Day 4
HB
SS
5M P
mel
5M P
mel
/125
nM C
D45
Fab-
IL12
0
2000
4000
6000
8000
10000
Pmel
/g tu
mor
p = 0.013
Dee
p IL
-12
/ PM
EL
PMEL
Veh.
con
trol
PMEL
/ g
tum
or
HB
SS
5M P
mel
5M P
mel
/125
nM C
D45
Fab-
IL12
0
5
10
15
% o
f IFN
g+ P
mel
in tu
mor p = 0.002
Dee
p IL
-12
/ PM
EL
PMEL
Veh.
con
trol
%IF
Ng +
of P
MEL
in tu
mor
Dee
p IL
-12
/ PM
EL
PMEL
Veh.
con
trol
%IF
Ng +
of P
MEL
in s
plee
n
HB
SS
5M P
mel
5M P
mel
/125
nM C
D45
Fab-
IL12
0
5
10
15
% o
f IFN
g+ P
mel
in s
plee
n
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Memory cell expansionDay 5 cytotoxicity
Deep IL-12 and Deep IL-15 combination further enhance T cell activityLeveraging complementary biology of Deep IL-15 and Deep IL-12
CD62L
CD
44
Eff Naive
EM CM
Dee
p IL
-15
/ PM
EL
PMEL
Dee
p IL
-12
/ PM
EL
Com
bina
tion
Dee
p IL
-15
/ PM
EL
PMEL
Dee
p IL
-12
/ PM
EL
Com
bina
tion
Pm
el
Pm
el+D
eep
IL15
Pm
el+D
eep
IL12
Pm
el+c
o-lo
ad
Pm
el
Pm
el+D
eep
IL15
Pm
el+D
eep
IL12
Pm
el+c
o-lo
ad
0
50
100
150
200
Rel
ativ
e tu
mor
cel
l sur
viva
l
Transpose of MTT-Day5-5000cells per well - rmv 10:1 grp
E:T 1:1
E:T 1:10
% B
16 c
ell s
urvi
val
0 1 2 3 4 50
2
4
6
8
10
Time (days)
T ce
ll fo
ld e
xpan
sion
Fold-expansion of PMEL
Pmel+Deep IL12
Pmel+co-load
Time (days)
Combination
Deep IL-12/PMEL
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Torque’s Deep Primed T Cell PipelineThree Phase 1 Programs in 2019
PRODUCTIND
FILINGANTIGEN
TARGETING IMMUNOMODULATORCHECKPOINT
INHIBITORLEAD
OPTIMIZATIONIND-
ENABLING PHASE 1UPCOMING
MILESTONES
TRQ-1501 ✓ Antigen Cassette #1
Deep IL-15Phase 1
underwayDeep IL-15 ✓
TRQ-1502 2019 Antigen Cassette #2
Deep IL-15Phase 1:
4Q19Deep IL-15 ✓
TRQ-1201 2019 Antigen Cassette #1
Deep IL-12
Phase 1:4Q19
Deep IL-12Deep IL-15
Deep IL-12Deep IL-15 ✓
TRQ-TLR 2020 TBD Deep TLR Candidate:2019
Solid & hematologic
tumors
Solid &hematologic
tumors
Solidtumors
ANTIGEN & IMMUNOMODULATORCOMBINATIONS
è è
Combo
Combo
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Torque Therapeutics • Gulzar Ahmad, PhD • De-Kuan Chang, PhD• Jonathan Nardozzi, PhD • Kate Sackton, PhD • Pengpeng Cao, PhD • Jesse Lyons, PhD • Karsten Sauer, PhD • Thomas Andresen, PhD
Technical University of DenmarkAPC profiling in TME• Lars Peterson, PhD • Ditte Jaegher• Esben Christensen
AcknowledgementsCONFIDENTIAL
Jonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
Confidential | © 2017 Torque
Surface-tethered IL-12 for T cell cancer immunotherapy
AACR Annual Meeting 2019
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics
CONFIDENTIALJonathan FitzgeraldTorque Therapeutics