Oncolytic Virotherapy: A new class of agents to treat cancer

Oncolytic Virotherapy:
A new class of agents to treat cancer
Daniel Sze, MD PhD
Stanford University
Daniel Sze, M.D., Ph.D.
• Stock: SureFire Medical, Inc., NDC, Inc
• Consultant/Advisory Board: EmboIX, Inc.,
Koli Medical, Inc., Boston Scientific, Inc., BTG,
Inc., Codman, Inc., Covidien/Medtronic, Inc.,
W.L. Gore, Inc., Viralytics, Inc.
• Research Grants: Amgen, inc., Merit
Medical, Inc., W.L. Gore, Inc.
Daniel Sze, M.D., Ph.D.
• Reference Unlabeled/Unapproved uses of
drugs or products: Histoacryl, B.Braun Trufill
n-BCS, Codman Lipiodol, Guerbet, Onyx,
Covidien/Medtronic, TheraSphere, BTG, SIRSpheres, Sirtex
History: Viruses fighting cancer
 1904: Dock published a
report on a woman who
experienced remission from
myelogenous leukemia after
an URI, presumed influenza.
Influenza proven to be a
virus 37 years later
History: Viruses fighting cancer
• 1912: De Pace reported
 1923: Levaditi and Nicolau
cervical cancer patient after
“Tumors are more susceptible
being bitten by a rabid dog
to viruses than normal cells,
and receiving rabies vaccine
and tumors act as a sponge
“il tumore non esisteva piú.”
attracting viral replication.”
 1940s: wild type murine
viruses given intravenously to
mice – suppressed tumors,
killed mice
 1950s: HeLa xenografts in rats
cured with adenoviruses,
enteroviruses, vaccinia,
vesicular stomatitis virus, polio
History: Viruses fighting cancer
 1950s: WT hepatitis B, West
Nile, adenovirus used in
human trials
 Given IV, IT, IA, IM, inhaled
 Severe toxicity
 1960s: Search for naturally
oncolytic viruses
 Human: adenovirus,
poliovirus, coxsackie
 Animal: VSV, Newcastle
History: Viruses fighting cancer
• 1970s: viruses tested along
with BCG, bacteria, and
other immunostimulants
• 1974: Mumps virus showed
efficacy in humans – 37/90
CR/PR
In the news…
It must be true…
Mechanisms of genetic therapies
 Genetic therapy for cancer
 Use vectors to introduce
lethal or normalizing genetic
material into malignant cells
OR
 Use genetically specific
viruses to infect and attack
malignant cells
 ONCOLYTIC
VIROTHERAPY
Human clinical trials
Rationale: oncolytic virotherapy
Sze et al., JVIR 2013; 24:1115
Engineered oncolytic viruses
 Attenuated viruses (vaccine
technology, engineering)
 1996: human clinical trials
 2005: Sunway Biotech
received Chinese FDA
approval for Oncorine
(based on ONYX-015 and
Genzyme H101, for
head/neck)
 Small market for Oncorine –
not covered by Chinese
national health insurance
 2014: More trials on
oncolytic viruses than on
gene insertion cancer gene
therapy
 70 studies on ClinicalTrials.gov
 2015: First engineered
oncolytic virus approved by
FDA in USA
Concepts: specificity






Natural oncotropism: Newcastle,
Sindbis, reovirus, parvovirus,
varicella
Tumor
environment/stroma/vascularity
targeting: herpes, measles,
Newcastle, reovirus
Surface receptors: adeno,
coxsackie
Species (bovine, avian)
Cell type (epithelial, neural)
Promoters (AFP, PSA)
High therapeutic index
Concepts: safety, risks, regulation
 Natural immunity, vaccination
 Pattern of transmission
 Rate of mutation, reversion,
integration
 Susceptibility to antivirals
 Replication competence,
selectivity
 FDA, RAC (Recombinant DNA
Advisory Committee), Office of
Biotechnology Activities, NIH
Why use live viruses?
Bystander activity
Thorne; Stanford Bio-Imaging Center
RFA
Y90
TACE
Why use live viruses?
Systemic (abscopal) effect
NOT INJECTED
INJECTED
You can sell it to your dogmatic medical oncologists!
Direct oncolysis vs. immunotherapy
 “Abscopal” effect could
be from either viremia or
immunomodulation
 Viremia cleared in hours,
may cycle at ~3 days
 Immunosuppression
blocks efficacy in mice
 Main mechanism probably
immunomodulation
 Induce circulating
cytokines
 Unmask stealth tumor
antigens
 Stimulate dendritic cells,
NK, T cells
Prototype: Onyx-015 Adenovirus
Onyx-015 in trials
 Intravenous
 Lung (didn’t work)
 Intraperitoneal instillation
 Ovarian (didn’t work)
 Topical
 Barrett esophagus
(didn’t work)
 Leukoplakia (didn’t
work)
 Direct, interstitial injection
into tumors
 Pancreas (didn’t work)

Direct, interstitial injection
into tumors
 Head and neck (Phase III
trial, worked OK)
 Intraarterial
 Hepatic for mCRC – aha!
Radiographic response (CT)
At level of left portal vein (Pt 3013)
pre-treatment
Sze et al., JVIR 2003; 14:279
Day 399
Onyx-015 mCRC results
 Safe – only flu-like syndrome
 Effective even in
chemorefractory patients
 Surprisingly good response
and survival results
 Phase I/II historical controls
only




Reid et al., Gene Ther 2001;8:1618
Reid et al., Cancer Res 2002;62:6070
Sze et al., JVIR 2003; 14:279
Reid et al., Cancer Gene Ther
2005;12:673
 Onyx company flirted with
big pharma
 Bayer partnered with Onyx
to develop Nexavar;
divested virus program
 Eventually acquired and
approved in China for
head/neck injection
Medigene NV1020
 HSV1 with HSV2
glycoprotein gG insertion to
attenuate pathogenicity
 Expresses exogenous HSV1
TK, keeping it sensitive to
acyclovir
 Tumor selectivity from
deletion of ICP0, ICP4,
134.5, UL23, UL24, UL56
 Also given intraarterially
into liver
Proinflammatory cytokines:
IFN-α
IL-6
CRP
TNF
Mean change/infusion/cohort
Medigene NV1020 Response
Pre
5 mo
Salvage, with systemic chemoRx
PET vs CT vs CEA
PET cannot distinguish infection from inflammation from progression
Sze et al., Hum Gene Ther 2012;23:91
MediGene NV1020
 MediGene failed to
attract deep pocketed
partner to perform
Phase III
Jennerex JX-594 (Pexa-Vec)
 Next generation
engineered viruses:
 Attenuated
 Selectively
replication
competent
 Enhanced
immunogenity by
arming with
exogenous
functional gene
 JX-594: Vaccinia vaccine (Wyeth
strain) armed with hGM-CSF
JX-594 pilot:
Monotherapy!
Phase II results JX-594
Phase IIb TRAVERSE
 BSC vs BSC + JX-594 in
Nexavar failures
 Failed to reach endpoint
 Jennerex bought by Korean
partner SillaJen
 Tumors persisted, but my
stock options underwent
complete response
Pexastimogene devacirepvec
(Pexa-Vec)
 Phase III PHOCUS trial
sponsored by SillaJen
 FDA Special Protocol
Assessment (SPA)
 HCC patients who have
failed locoregional
therapies
 Nexavar ± PexaVec
 600 patients
 140 sites internationally
 First patient enrolled Jan
2016
Oncovex (T-VEC, Imlygic)
 HSV-1, ICP34.5 and ICP47 deleted, US11 promoted,
armed with hGM-CSF
 Successful Phase II study on metastatic melanoma, using
direct injection
 Amgen bought BioVex for $1B (2011), renamed product
“talimogene laherparepvec” T-VEC





“imo” immunomodulating
“gene” genetic therapy
“herpa” HSV
“rep” replicating
“vec” vector
T-VEC
Finally – deeper pockets!
www.oncolyticimmunotherapy.com
T-VEC
Phase III OPTiM trial vs SQ hGM-CSF, n = 436
T-VEC
 26% ORR, 11% CR – FDA approved Oct 2015
T-VEC
 Miracle drug?
 Little benefit
for M1
 Little benefit
for refractory
 Skin tumors
are easy to
inject
IR’s role
Sze et al., JVIR 2013; 24:1115
The virus whisperers
 Whoa! RGA!
Oncolytic virotherapy hepatic trials
• T-VEC Phase I
– HCC
– Metastases
– IT injection by
US, CT
• SillaJen Phase
III
– HCC
– IT injection by
CT
• Viralytics
Phase I
– Coxsackie
– Metastases
– IA injection
Oncolytic virotherapy needs Interventional Radiology
It even needs Diagnostic Radiology
Radiographic response evaluation
 Early results very disappointing - high rate of
tumor enlargement even within 1 month.
However, inconsistent with CEA levels, clinical
health
 Now increasingly accepted that WHO, RECIST
criteria are not representative of response for
biologic agents, RFA, TACE, Y90, etc.
 EASL modification, mRECIST, PERCIST, etc.
Radiographic response (CT)
At level of left portal vein (Pt 3006)
Pre-treatment
Day 17, 45, 142
Radiographic response (CT)
At level of left portal vein (Pt 3013)
pre-treatment
Day 26, 51, 78, 138, 399
Tumor burden, responders
 Responders:
defined as ≥10%
decrease in
tumor burden
from maximum;
n=14.
 Tumors get
bigger before
they get smaller
 “Pseudoprogression”
Imaging criteria: irRC
Up to 5 lesions/organ, 10 total
Wolchok JD, Hoos A, O’Day S et al. Guidelines for the evaluation of
immune therapy activity in solid tumors: immune-related response
criteria. Clin Cancer Res 2009; 15: 7412–7420.
irRECIST
Conclusions: Oncolytic virotherapy
immunotherapy
 Biological warfare against cancer
 Exploit existing pathogens, engineer/tailor them
 Mechanism of action profoundly different from other




options (oncolysis, immunomodulation)
Science, regulation extremely complex (1 FDA approved)
New standards of radiographic response
Safety and efficacy depend on mode of administration –
IR is uniquely qualified
Immunotherapy/virotherapy is not a threat to IO - it is a
huge and urgent opportunity!