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Development of ONCR-177, an armed oncolytic HSV-1 designed for potent and systemic stimulation of antitumor immunity
Christophe Quéva, IO360Feb. 26, 2020
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Oncolytic viruses ignite the tumor microenvironment
3x106 pfu/mL, followed 3 weeks later with injections of up to 4 mL 3E8 pfu/mL T-VEC q2wks. A secondtumor biopsy was performed before administration of the second full dose of T-VEC and beforecommencing combination treatment with pembrolizumab (Ribas, et al., Cell, 2017).
Week 1(prior to therapy)
Week 6(T-VEC only)
Week 30(combination)
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Improved efficacy with unarmed, 1st generation viral immunotherapies
1. Andtbacka, et al., JCO, 2015 and Andtbacka, et al., Ann Surg Oncol, 2016; 2. CALM study,Andtbacka et al., ASCO, 2015; 3. Ribas, et al., Cell, 2017; 4. CAPRA study, Silk et al. SITC, 2017; 5. Chesney, et al., JCO, 2017; 6. MITCI study, Curti, et al., AACR, 2017.
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HSV Platform ONCR-177
• γ34.5 retention for resistance to interferon• gB mutation accelerates entry• UL47 mutation preserves direct antigen presentation
• MicroRNA attenuation for selective replication in tumors• UL37 mutation prevents retrograde transport and latency in
neurons
• IL-12, FLT3LG & CCL4 attract and stimulate APC, T and NK cells• Immune checkpoints counteracted by local expression of PD-1 and
CTLA4 inhibitors
ONCR-177: Intratumorally-Administered Oncolytic Herpes Simplex Virus
Fully Replication Competency & Enhanced Infectivity
Orthogonal Safety Strategies
Largest Number ofImmune Payloads
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Potency improvement is enabled by retention of γ34.5
γ34.5 gene functions to facilitate replication in presence of host antiviral response
• Reverse Host Shutoff of total protein synthesis• Binds TBK-1 to prevent activation of Type I IFN
response• Inhibits autophagy by binding to Beclin-1
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Insertion of microRNA-targets enables conditional replication in tumor cells
0
5 0 0 0
1 0 0 0 0
N o r m a l B r a i n T i s s u e s
M a l i g n a n t T i s s u e
H u m a n m i R - 1 2 4 E x p r e s s i o n
N o r m a l i z e d C o u n t s
P < 0 . 0 0 0 1
P<0.0001
(n=71)
(n=10)
No/low levels of miRs in tumors
Di Leva, et al., Annu Rev Pathol, 2014 and Gurtan & Sharpe, J Mol Biol, 2013
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ONCR-177 is engineered with 10 microRNA targets for broad attenuation
N eg1 2 4 1
1 4 31 2 8
2 1 9 a1 2 2
1 3 72 1 7
1 2 60 .0
0 .5
1 .0
O N C R -1 7 7 m iR N A A tte n u a tio n
m iR N A M im ic
PF
U/N
eg
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ONCR-177 is designed to activate multiple arms of the immune system
ONCR-177 payloads selected among 15 immune stimulatory transgenes for maximally inducing abscopal efficacy
IL-12, FLT3LG & CCL4 designed to expand and activate CD8 and CD4 T cells, NK cells, and Ag cross-presenting classical DCs
Local expression of PD-1 and CTLA-4 antagonists to counteract compensatory upregulation of immune checkpoints
ONCR-177 mouse surrogate, mONCR-177, is used in all non-clinical studies
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mONCR-177 induces systemic anti-tumor responses in mouse syngeneic bilateral tumor models
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mONCR-177 virus and payload primarily remain within the injected tumor
24 h after IT administration of base vector ONCR-159 (3x105 PFU) or mONCR-177
mONCR-177 DNA and payloads detectedprimarily in the injected tumor, modest virusDNA signal in blood at high dose level
PBS
159-3E5
171-3E3
171-3E4
171-3E5
171-3E6
171-3E70.0
0.2
0.4
0.6
0.8
1.0
IL-12
IL-12
, pg/m
l
Plasma
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Robust Recruitment of CD8, NK, cDC and Increase in CD8/Treg by mONCR177 that Translate to Enhanced SurvivalmONCR-177 Transgenes Augment Recruitment of Key Immune Cells to the Injected and Contralateral Tumor Immune Subset Depletion3
I n j e c t e d N o n - I n j e c t e d0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
N K c e l l s
Ce
lls
/ m
g
I n j e c t e d N o n - I n j e c t e d0
2 5
5 0
7 5
1 0 0
1 2 5
1 5 0
C D 8 : T r e g
Ra
tio
**
A. Ex-vivo Flow Cytometry1:
B. Nanostring2:
In je c t e d N o n - In je c t e d
0
5 0
1 0 0
1 5 0
2 0 0
2 5 0
C D 1 0 3 D C s
Ce
lls
/ m
g
*
*
mONCR-177
********** ***** ****
B.
ContralateralInjected ContralateralInjected ContralateralInjected ContralateralInjected
1MC38, 3e6 PFU, Q3Dx3; 24h post last injection; 2A20, 3e6 PFU, Q3Dx3; takedown Day 8; 3A20, 3e6 PFU, Q3Dx3
0 20 40 60 80 1000
20
40
60
80
100
Day of Study
% S
urvi
val
PBS, no depletion
mONCR-177, Serum controlfor NK antibody (no depletion)
mONCR-177, NK depleted
mONCR-177, Isotype controlfor CD8α antibody (no depletion)
mONCR-177, CD8 depleted
Dose
p<0.0001
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mONCR-177 elicits durable and protective responses in mouse syngeneic tumor models
CT26 bilateral tumor model6x106 PFU, Q3Dx3
A20 tumor model1x106 PFU, Q3Dx3
A20 challenge in naïve mice
A20 rechallenge in mice previously cured of A20 tumors
EMT6 challenge in naïve mice
EMT6 challenge in mice previously cured of A20 tumors
A20 challenge in naïve mice
A20 rechallenge in mice previously cured of A20 tumors
EMT6 challenge in naïve mice
EMT6 challenge in mice previously cured of A20 tumors
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mONCR-177 Efficacy is Enhanced by Systemic PD-1 Blockade
MC38 tumor model mONCR-177, IT, 3x106 PFU, Q3Dx3; anti-PD-1 or isotype: IP, 200 µg, Q3Dx3.
PBS
IgG2a Is
otype
anti-PD-1
mONCR-177
mONCR-177 + anti-PD-1 PBS
IgG2a Is
otype
anti-PD-1
mONCR-177
mONCR-177 + anti-PD-1
0
2
4
6
8
10
Cyto
toxi
c Sco
re-lo
g2
**** ***
* *******
* ****
******* ****
***
ContralateralInjected
0 3 6 9 12 15 18
0
400
800
1200
1600
Days on study
PBS
IgG2a Isotype mAb
Anti-PD-1 mAb
mONCR-177 + anti-PD-1 mAb
mONCR-177
Injected Tumor
PBS
IgG2a Is
otype
anti-PD-1
mONCR-177
mONCR-177 + anti-PD-1 PBS
IgG2a Is
otype
anti-PD-1
mONCR-177
mONCR-177 + anti-PD-1
0
2
4
6
8
10
T Ce
ll Sc
ore-
log2
**** ***
* *******
* ****
****
**** ***
* ******
* *** *
ContralateralInjected
0 3 6 9 12 15 18
0
400
800
1200
1600
Days on study
Contralateral Tumor
Nanostring Profiling
0 20 40 60 800
25
50
75
100
Day of Study
Surv
ival
, %
PBS
anti-mPD-1 mAbmONCR-177 +anti-mPD-1 mAb
mONCR-177
p=0.004HR:0.156
Dose
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Part B: Combination w/ anti-PD1
ONCR-177 Clinical Development Plan - Start Phase I 1H2020
Part B: Combination w/ anti-PD1
Part A: Monotherapy
RP2D Confirmation(1)
Phase 1 Trials
Dose Escalation
Dose Escalation & Confirmation
Patient expansions in select indications(2)
Part A: Monotherapy
Dose Escalation
(1) Starting at RP2D(2) Potential for one or more histology expansions in each part of trial; subset
of indications will align with chosen partner approvals
Dose Expansions Histologies #1, #2…
Indications: Surface lesions :• SCCHN, • melanoma, • breast cancer
Dose ExpansionsHistologies #1, #2…
Dose Expansions Histologies #1, 2...
Surf
ace
Lesi
ons
Visc
eral
Lesi
ons
Dose ExpansionsHistologies #1, 2…
Dose Confirmation(1)
RP2D=Recommended Phase 2 Dose; DLT=Dose Limiting Toxicity
Visceral lesions: • Liver mets (uveal melanoma)• Liver mets (CRC) • HCC
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Conclusion
Oncolytic viruses through a dual mechanism of action (oncolysis and stimulation of antitumor immunity) are coming centre-stage as cancer therapies, particularly in combination with checkpoint inhibitors
Promising non-clinical activity and tolerability data warrant clinical development of ONCR-177
• Orthogonal and innovative safety mechanisms enable native replication in tumors• Potent anti-tumor activity delivered by 5 immune-stimulatory payloads• Curative mONCR-177 treatment elicits protective immunity