Concept of oncolytic virotherapy- clinical implementation

Concept of oncolytic virotherapyclinical implementation
Simona Donina
A. Kirchenstein Institute of Microbiology and Virology,
Riga Stradiņš University
Riga East University Hospital
4.04.2014.
Timeline of the clinical history of oncolytic viruses
Ta-Chiang Liu et al.,Nature Clinical Practice Oncology 2007
A. Complete regression of Burkitt's lymphoma over 2 weeks in a patient
experiencing acute measles infection.
B. Complete hematologic response of chronic lymphocytic leukemia following
patient vaccination with vaccinia and subsequent virus dissemination.
Permission obtained from Elsevier © Bluming AZ and Ziegler JL (1971) Lancet 2 and from American Medical Association © Hansen
RM and Libnoch JA (1978) Arch Intern Med Nature Clinical Practice Oncology 2007
Advantages of oncolytic virotherapy
L Braidwood et al., Oncolytic Virotherapy 2013:2
Feature
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Replicates within tumor cells to
increase viral dose
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Replicates only within tumor cells
Can be used safely with other cancer
treatments and may have synergistic
effect
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Can also be engineered or armed to
carry a wide variety of transgenes to
enhance the therapeutic effect such
as prodrugs or inducers of
immunological response
Some evidence that oHSV are
capable of targeting and eliminating
cancer stem cells
Advantage
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Amplification leads to oncolysis in cells
beyond those initially infected
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Increases therapeutic index
Minimal toxicity to normal tissues
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Dual effect of viral oncolysis and the
added effect of the prodrug or immune
stimulator
Eliminates the population of cells that
are often resistant to chemotherapy
and radiotherapy
Infection and killing of tumor cells
by oncolytic viruses
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Selective targeting to tumor cells
 innate properties of native viral particles
 engineered viruses through deletion of nonessential viral genes
or insertion of tumor targeting sequences to provide the virus with
the property of tumor-selective infection
Ability to induce tumor cell lysis
Induction of local and systemic antitumor immune respons
 expression of viral proteins and release of antigens eventually
also leads to immune-mediated lysis of infected cells by CD8+
cells.
T Hughes et al, Oncolytic Virotherapy 2014
Infection and killing of tumor cells
by oncolytic viruses
L Aurelian et al., Oncolytic Virotherapy 2013
Increased binding to
altered target
Reduced target binding
Replication/intratumoral
spread
Virus does not replicate
Cell lysis/antigen release/immune
response/virus spread
Healthy tissue undamaged
The immune response to oncolytic
virotherapy is an essential factor
determining the success of virus
as an antitumor agent
NK
Mf
B
Tc
Th
Hypothesis...
During the virotherapy
 downregulate early innate immune response in order
to allow the virus longer to enter cells and undergo
initial viral replication
 upregulate later cellular immune response to make
infected tumor cells more likely targeted for
destruction by immune system
L Aurelian et al., Oncolytic Virotherapy 2013
The oncolytic virotherapy paradigm
Barriers to optimal delivery of oncolytic viruses
to tumours in vivo
Kelley A et al., Nature Reviews Cancer 2005
Challenges
Bazan-Peregrino M, et al., J Control Release. 2012
Miller CG et al., Mol Ther. 2003
Benencia F et al., Hum Gene Ther. 2005
J Goldufsky et al, Oncolytic virotherapy 2014
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Increasing the replicative capacity of the virus within cancer cells
Alteration of the microenvironment (inhibition of angiogenesis)
Combination with chemo- and immunotherapy
Avoidance of neutralizing antibodies
April 14, 2010 Biovex
OncoVEX(gm-csf) uses a highly potent oncolytic virus that
replicates selectively in tumors and do not replicate in
normal cells), destroying cancer cells while leaving
surrounding healthy cells unharmed
Talimogene laherparepvec (T-VEC)
The drug was initially developed by BioVex, Inc. under the name
OncoVEXGM-CSFuntil it was acquired by Amgen in 2011.
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. T-VEC was engineered from herpes simplex virus
A number of genetic modifications (deletion in both copies of
ICP34.5 + ICP47 disruption) were made to the virus in order to:
 attenuate the virus ( it can no longer cause herpes)
 increase selectivity for cancer cells ( it destroys cancer cells while
leaving healthy cells unharmed)
 secrete the cytokine GM-CSF
T-VEC
Kaufman HL et al., Ann Surg Oncol. 2010;17(3):718-30.
Núñez MA et al., 2013.
Amgen announced the initial results
of the Phase III OPTiM trial on Mar. 19, 2013.
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The objective response rate (any response) with TVEC was 26%, (11% CR)
The most common side effects with T-VEC were
fatigue, chills, and fever. No serious side effect
occurred in more than 3% of patients in either arm of
the study.
http://www.medscape.com/viewarticle/814740_print
Feb. 5, 2014
Amgen And Merck Announce Collaboration To Evaluate
Investigational Combination Treatment For Advanced Melanoma
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About Talimogene Laherparepvec
Talimogene laherparepvec is an investigational oncolytic immunotherapy designed to selectively
replicate in tumor tissue and to initiate a systemic anti-tumor immune response.
Talimogene laherparepvec is injected directly into tumor tissue and is intended to replicate
preferentially in tumor cells causing lytic cell death and releasing an array of tumor-derived
antigens.
Talimogene laherparepvec is also engineered to express granulocyte-macrophage colonystimulating factor (GM-CSF),which can help to activate the immune system.
The aim of this combination of actions is to initiate a systemic anti-tumor immune response that
targets tumor cells throughout the body.
About MK-3475
Many tumors are able to evade the immune system through a mechanism that exploits the PD-1
inhibitory checkpoint protein.
MK-3475 is an investigational, highly selective anti-PD-1 immunotherapy designed to restore the
natural ability of the immune system to recognize and target cancer cells by selectively achieving
dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein.
By blocking PD-1, MK-3475 enables activation of the immune system's T-cells that target cancer
by essentially releasing a brake on the immune system.
http://www.merck.com/clinical-trials/.
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Viralytics trial shows Cavatak well-tolerated
12 November, 2012
Cavatak is a proprietary formulation of coxsackievirus A21, is a naturally occurring
common cold like virus shown in pre-clinical studies to stimulate in vitro and in vivo
oncolytic activity across a range of cancers.
The virus achieves this by binding to the N-terminal domain of surface expressed ICAM-1 –
which is present on the surface of cancers including melanoma, breast and prostate cancers
– triggering cytosis in the cells.
The results of the phase I trial fulfilled the criteria required for Viralytics to advance to a phase
II trial under its IND application for the treatment with the US FDA.
Viralytics revealed it has so far dosed 13 patients in the phase II melanoma trial, with three
of these demonstrating immune-related progression free survival at six months.
The primary objective of the trial is progression-free survival in 12-14 of a targeted 63
melanoma patients.
Viralytics also holds the patents to EVATAK, its proprietary formulation of Echovirus
Type 1 (EV1). EVI uses a different cell surface receptor to bind and infect cancer cells.
In Latvia
«Oncotropism of Viruses
and the Problem of
Virotherapy of
Malignant Tumours»
by A. Muceniece
published in Riga in 1972
Viral Oncolysis
in a Model of
Mouse Xenografts of
Human Angiosarcoma
(R. Bruvere 1968)
2 days after virus i/m
3 days after virus i/m
4 days after virus i/m
9 days after virus i/m
Control
Late Alterations in Melanoma Tissue
(R. Bruvere 1969)
Before therapy
Subcutaneous mts of MM
3 months after therapy
with Rigvir
(apoptotic tumour cells,
lymphocytes, plasma cells)
Antibody to Rigvir during the therapy
(A. Volrate, R. Garklava 1968)
Rigvir
ECHO-7 containing
medicine
for treatment of
malignant melanoma
was registered
in 2004 in Latvia
Patients (%) with elevated number of
CD16+ cells during the therapy with Rigvir
Pts (n)
1 Month
3 Months
6 Months
12 Months
49
37
27
25
Patients (%) with elevated number of
CD8+ cells during the therapy with Rigvir
Pts (n)
27
64
25
32
Patients (%) with elevated number of
CD38+ cells during the therapy with Rigvir
Pts (n)
1 Month
3 Months
6 Months
12 Months
47
43
27
35
CD 3+ between malignant
melanocytes
IHC after injection of Rigvir
(l/n, Dako, 400х 23/05/2013)
.
CD8+ in the lymph node after
injections of Rigvir
Vacuolisation and picnosis of nuclei of malignant melanocytes.
H/E. 400x. 23.05. 13.
Melanoma cutis femoris dxt. T4A N0 M0
Clark V, Breslow 9mm
of immunocompetent cellsклеток
кол-о no.
иммуннокомпетентных
Female, 62
2500
2000
Ly
CD3+
1500
CD4+
CD95+
1000
CD8+
CD38+
500
0
CD16+
CD19+
перeд Rigvir
1 месяц
3 месяца
6 месяцев
12 месяцев
Ly
1930
1910
1790
2040
2450
CD3+
1583
1509
1424
1737
2009
CD4+
830
745
659
943
1299
CD8+
714
707
694
712
784
CD38+
521
516
481
592
686
CD16+
309
267
249
250
220
CD19+
97
96
142
161
172
CD95+
844
840
961
996
1152
Before the therapy with RIGVIR
Melanoma cutis dorsi
T4b N2c M0
Feb 14, 2008
IFN
During the therapy with RIGV
Apr 29, 2010
RIGVIR
Male, Melanoma cutis dorsi T4b N2c M0
Melanoma cell culture (patient A.S.)
D. Pjanova et col. 2014
Control 24 and 48 h
Rigvir 24 and 48 h
Cell viability 24h and 48h after treatment with Rigvir
MTT - (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test
(p<0.05)
D. Pjanova et col. 2014
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Predictive markers?
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Immune monitoring?
Months
0
6
12
18
24
30
36
42
Rigvir
65
59
52
42
33
22
16
6
Observation
45
38
26
19
12
8
4
2
p=0.001 (Log-Rank test)
Summary
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Oncolytic virus therapy has been well tolerated, with largely minor
and expected toxicity, and no evidence of uncontrolled or latent
infection.
A number of clinical trials have combined oncolytic viruses with a
second form of therapy.
Further investigation will need to focus on optimal selection of
viruses, tumor types and stages of disease, viral dose and
schedules, routes of delivery.
Our data suggest that ECHO-7 containing medicine- Rigvir- is well
tolerated and no remarkable side-effects were documented, and
significantly better relapse free suvival for stage IB - IIA patients was
observed in Rigvir treated group in our retrospective study.