Download Oncolytic Viruses: converting an old enemy in our ally

Oncolytic Viruses: converting an old enemy in our ally
Manel Cascalló PhD.
CEO, VCN Biosciences
Societat Catalana de Biotecnologia Mèdica
March 30th, 2017
Our old enemy : viruses
- Viral infection as causal for many diseases
- Viral infection demonstrated to be causal for tumorigenesis in several cancer
types (infectious ethiology of cancer)
1911, Peyton Rous (Rockefeller Institute)
© American Association for Cancer Research
Our old enemy : viruses
© American Association for Cancer Research
The other part of the history: an ally?
(28/10/2015)
Liu et al., 2007 Nature Reviews Clinical Oncology
Larson et al. Oncotarget. 2015 Aug 21; 6(24): 19976–19989.)
Oncolytic Viruses: where we are
“Infectious Enthusiasm” - BioCentury. 2016 : Feb29th
Oncolytic Viruses: the Identity Crisis
Stimulators of innate immune
response and heating up
immunologically cold tumors
3
Loco-Regional Adjuvants
De novo neo-antigen
presentation by effect of viral
replication under breakage of
immunotolerance
2
In situ vaccines
Tumor
Inductors of systemic and longlasting clinical responses
4
Systemic vaccines
1 Cancer killers –debulking agents
Oncolytic Viruses: the Identity Crisis
Oncolytic Viruses: the Identity Crisis
(Melanoma)
MASTERKEY-265
Trial
ORR: 56%
ORR: 57%
Reduced toxicity profile compared to a-PD1 / a-CTLA-4 combo treatments described to date
Oncolytic Viruses: Adenovirus
Will loco-regional therapy with oncolytic viruses be
sufficient to meet their therapeutic potential?
Oncolytic adenovirus as a well-suited option
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Highly cytopathic
Easy to be genetically-modifyed
Expertise in clinics & industrial manufacturing
Highly Inmunogenic
Able to broad neoantigen-directed T-cell responses
Woller N et al. Mol Ther 2015; 1630-1640
Neoepitope-specific CD8 T-cell responses
(CMT-64 immunocompetent model in mice)
Oncolytic Viruses: Adenovirus
Will loco-regional therapy with oncolytic viruses be
sufficient to meet their therapeutic potential?
Oncolytic adenovirus as a well-suited option
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

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Highly cytopathic
Easy to be genetically-modifyed
Expertise in clinics & industrial manufacturing
Highly Inmunogenic
Able to broad neoantigen-directed T-cell responses
Able to reach the tumors systemically ?
Alemany R. Biomedicines 2014; 2:36-49
Oncolytic Adenovirus: VCN-01
VCN-01 is and tumor-targeted oncolytic adenovirus armed with hyaluronidase
HAd5
(wild-type)
Clinical candidate
VCN-01
E2F boxes
selectivity of replication
in tumour cells
biodistribution selectivity Tumour potency
(tumour targeting)
(diffusion)
HA staining
Biodistribution after iv delivery
Intratumor Virus spreading
-E1A / H&E staining in LIVER after iv injection of 5E10 vp in mice
Rojas et al. Mol Ther 2010; 18(11): 1960-1971
Bayó-Puxan et al. Human Gene Ther 2009; 20:1214-1221
Martínez-Quintanilla et al. Mol Ther 2015; 23(1):108-118
Clinical trial of VCN-01 by Intratumor administration
in Pancreatic Cancer
Incidence:
•
45.000/USA
•
Orphan Indication  Obtained by VCN (2012)
Characteristics:
•
Highly desmoplastic tumor
•
Tumor Matrix as therapeutic target
Current SoC Treatment:
•
Abraxane/Gemcitabine (1st line)
Problems:
(Extracted from Whatcott et al. (2011) Cancer Discov. Sep;1(4):291-6
•
Late detection
•
Progression free survival 5.5 months; overall
survival 8.5 months
Clinical trial of VCN-01 by Intratumor administration
in Pancreatic Cancer
Clinical Trial P-VCNA-002 (NCT02045589)
A Phase I Dose Escalation Study of three Intratumoral VCN-01 Injections with Gemcitabine and Abraxane® in Patients with advanced pancreatic cancer.
US-guided intratumor
administration of VCN-01 (x3)
in combination with nab-paclitaxel
/ gemcitabine)
I-1
3 doses at I-1/dose
+ GE
I-1b
3 doses at I-1b/dose
+ GE / Abrx.
Endpoints:
a) Primary
-
Safety
&
Tolerability
Definition of RP2D
b) Secondary:
- Ability of VCN-01 to
replicate in tumors
Patient
Population:
Patients
with
pancreatic
adenocarcinoma to be treated with nab-paclitaxel /
gemcitabine
Elastogram
Tumor biopsy
Elastogram
Elastogram
Clinical trial of VCN-01 by Intratumor administration
in Pancreatic Cancer
Clinical Trial P-VCNA-002 (NCT02045589)
Positivity for VCN-01 genome in tumor biopsies
Patient ID
Dose Level
Cycle 1 Day 1
FNA Date
FNA Location
vp
VCN-01/sample
002-001002
002-002001
002-001004
002-003001
002-003002
002-002003
002-002004
002-003003
I-1
I-1
I-1b
I-1b
I-1b
I-1b
I-1b
I-1b
25-Jun-14
06-May-14
22-Dec-15
16-Sep-15
30-Dec-15
08-Mar-16
11-Mar-16
08-Mar-16
15-Jul-14
27-May-14
23-Feb-16
27-Oct-15
09-Feb-16
27-May-14
11-Apr-16
18-Apr-16
Pancreas
Pancreas
Pancreas
Pancreas
Pancreas
Pancreas
Pancreas
Pancreas
1,32E+03
1,37E+05
negative
3,58E+04
1,69E+03
1,49E+03
8,43E+03
-
Positivity was observed in 85,7% of the tumor biopsies collected at day 21 or 28 post-intratumoral
administration of VCN-01 in the pancreas, strongly suggesting that VCN-01 is replicating in pancreatic tumors
Clinical trial of VCN-01 by Systemic administration
in Pancreatic Cancer
Clinical Trial P-VCNA-001 (NCT02045602)
A Phase I, multi-center, open-label dose escalation study of intravenous administration of VCN-01 oncolytic adenovirus with or without intravenous
gemcitabine and Abraxane® in advanced solid tumors.
Clinical trial of VCN-01 by Systemic administration
in Pancreatic Cancer
Clinical Trial P-VCNA-001 (NCT02045602)
VCN-01 levels in blood
Dose administration correlated with VCN-01 levels in blood. Most of the patients administered at the highest dose
levels showed secondary viremia peaks and maintained VCN-01 genomes in blood for over 3 weeks after
administration.
Clinical trial of VCN-01 by Systemic administration
in Pancreatic Cancer
Clinical Trial P-VCNA-001 (NCT02045602)
Positivity for VCN-01 genome in tumor biopsies
Patient ID
Pretreatment
Dose Level
AntiAd
Nabs
Cycle 1
Day 1
Biopsy
Collection
Timepoint
Biopsy
Location
vp
VCN-01/sample
001-003001
1/10
II-1
19-Aug-15
D8
Pancreas
1,42E+04
001-002012
1/40
II-1
16-Sep-15
D8
Liver
1,50E+05
001-001013
1/80
II-1
10-Nov-15
D8
Liver
1,95E+04
001-003003
1/80
II-1
02-Jun-16
D28
Pancreas
negative
001-003004
1/80
II-1
08-Jun-16
D28
Pancreas
negative
001-003005
1/80
II-1
14-Jun-16
D28
Pancreas
negative
001-001015
1/20
II-2
05-Jan-16
-
-
-
001-002013
1/10
II-2
09-Feb-16
D28
Liver
negative
001-002014
1/320
II-2
21-Mar-16
D8
Liver
8,24E+02
001-003002
1/20
II-2
22-Mar-16
D28
Pancreas
negative
001-001016
1/320
II-2
06-Sep-16
D28
Pancreas
pending
001-003006
1/10
II-2
14-Sep-16
-
-
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All samples obtained at day 8 after VCN-01 administration were positive for virus presence (both primary or metastatic
biopsies), indicating that VCN-01 reaches the tumor at both II-1 & II-2 doses.
Clinical trial of VCN-01 by Systemic administration
in Pancreatic Cancer
Clinical Trial P-VCNA-001 (NCT02045602)
VCN-01 Antitumor Activity (Part II in combination with GE/Abrx)
a)
RECIST v 1.1 criteria (periodically each 8 weeks) (on-going data)
10 patients with evaluable data; 4 of them still on treatment
Confirmed Response Rate in 4 out of 10 evaluable patients (40%)
5/9 patients beyond stablished Progression Free Survival, 2 of them beyond Overall Survival
1 Patient showed disease restratification to be surgically amenable (9 months after
treatment initiation)
 1 Patient showed Complete Response (15 months after treatment initiation)
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Von Hoff et al. Phase III Increased survival in pancreatic
cancer with nab-paclitaxel plus gemcitabine.
N.Engl J. Med (2013)
Clinical trial of VCN-01 by Systemic administration
in Pancreatic Cancer
Clinical Trial P-VCNA-001 (NCT02045602)
Intratumor staining of Immunological markers
Thank you!!
CLINICAL PARTNERS
Dr. Ramon Salazar
Dr. Marta Gil
Dr. Berta Laquente
Dr. Manuel Hidalgo
Dr. Rafael Álvarez
Dr. Rocío García-Carbonero
Dr. Asunción Díaz-Serrano
VCN Biosciences
Dr. Marta Giménez
Dr. Sara Morgado
Dr. Ana Mato
Dr. Miriam Bazán-Peregrino
Dr. Gabriel Capellà
Dr. Ramon Alemany
Dr. Manel Cascalló
Chief Executive Officer
[email protected]
www.vcnbiosciences.com
Funding:
- PANCATHER Project –CDTI PyD
- Cure4RB Project – RETOS 2015 (MiNECo)
Dr. Jaume Català
Dr. Guillermo Chantada
SCIENTIFIC PARTNERS
Dr. Ramon Alemany
Dr. Sonia Guedan
Dr. Alba Rodríguez-García
Dr. Luis Rojas
Dr. Mireia Morell
Dr. Gabriel Capellà
Dr. Rafael Moreno
Dr. Alba de Martino
Dr. Ángel Montero Carcaboso
Guillem Pascual-Pasto
Dr. Jordi Martínez-Quintanilla