development of oncr-177, an armed oncolytic hsv-1 designed … · 2020/2/26 · 1 oncorus...

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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


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)


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.


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


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


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


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


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


mONCR-177 induces systemic anti-tumor responses in mouse syngeneic bilateral tumor models


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


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

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N K c e l l s

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/ m

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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


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


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

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**** ***

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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


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


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

development of oncr-177, an armed oncolytic hsv-1 designed … · 2020/2/26 · 1 oncorus...

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