Download Toan Mon 1500

2015 Asia Pacific Military Health Exchange
Combination of Vaccine-derived Measles and
Mumps Virus Enhanced anti-tumor Effects: Special
Focus on Acute Leukemia and Prostate Cancer
Sen. Colonel A/Pr. Dr. Nguyen Linh Toan1$, Ho Anh Son1#, LiFeng Zhang3#,
Bui Khac Cuong1, Hoang Van Luong2, Naoki Yamamoto3$, et al.
1Vietnam
Military Medical University, Vietnam.
2Department of Microbiology, NUS, Singapore.
Da Nang - 2015
Nguyen Linh Toan - VMMU - Vietnam
BACKGROUND
Cancer is major leading cause of death in worldwide.
14.1 million new cancer cases & 8.2 million cancer deaths, 2012
(Torre LA et al. CA Cancer J Clin. 2015).
Lung and breast cancer are the most frequently and the leading causes
of cancer death in men and women worldwide .
However, prostate cancer is the second most frequently diagnosed
cancer in men worldwide, with 1.1mil. new cases to occurred in 2012
(Torre LA et al. CA Cancer J Clin. 2015).
Despite the considerable progress accomplished in
recently years, most advanced cancers remain incurable
prompting the need for novel, less toxic and more targeted
therapy.
Oncolytic virotherapy (OLV)
OLV is a novel
treatment approach
that exploits the ability
of viruses to selectively
infected and destroy
cancer cells. OLV
replication, cell killing,
virus release and
spread within cancer
cells but not normal
cells
CD46
Nectin 4
CSC: cancer stem cells
Freidman et al., Pediatric
Research (2012)
CD150: B,T, M, DC
CD46
Nectin 4
Kirn D et al. (2001). Nat Med
Liu T-C et al. (2007) Nat Clin Pract Oncol
5
Summay: phase I-III clinical trials of OLV
(Buijs PR et al. 2015; Lapp et al. 2014; Msaouel et al. 2013)
Our strategy is to exploit Viral Synergy
It is highly anticipated that the oncolytic activity of
combined OLVs should be improved quantitatively
as well as qualitatively. This situation is rather
reminiscent of drug therapy in the clinical settings.
1) Improved targeting
2) Synergy and complementation of multiple viruses
3) Produces enhanced anti-tumor effects
Nguyen Linh Toan - VMMU - Vietnam
8
Cytopathic effects (CPE) were observed in a wide range of human
solid malignancy cell lines infected with the MMR viruses
MMR:
Measles
Mumps
Rubella
PC-3
(prostate)
MCF-7
(Breast)
HepG2
(Liver)
Mock
MMR-Infected
HCT116
(Colorectal)
H358
(Lung)
HK1
(Nasopharyngeal)
EC109
(Esohageal)
Mock
MMR-Infected
9
Cytopathic effects (CPE) was observed in a wide range of hematological
malignancy cell lines infected with the MMR viruses
Leukemia cell lines
U937
Lymphoma cell lines
Jurkat
Raji
Mock
MMR-Infected
HL-60
KI-4
HuT 102
Mock
MMR-Infected
(Zhang….. Toan. ..et al, Cancer Letter, 2014)
10
The MM targeted a wider range of solid cancer cell lines and displayed
greater oncolytic effect on several cell lines compared with single virus
MeV
MuV
MM
Huc-Fm
PC-3
MCF-7
KATO III
HEPG2
HUH4
H358
H1299
HELA
SIHA
HK-1
HONE-1
EC109
KYSE70
HT29
HCT116
Post infection (P.I.)
PC3:Prostate C., MCF-7: Breast C., KATO III: Gastric C., HepG2, HuH4: Liver C., H358, H1299: Lung C.,
Hela and SiHa: cervix C. HK-1:NPC, HONE-2 EC109: Esohageal, KYSE70, HT29 and HCT166: Colorectal C.,
11
The MM targeted a wider range of hematological cancer cell lines and displayed
greater oncolytic effect on several cell lines compared with single virus
MeV
MuV
MM
(Zhang….. Toan. ..et al, Cancer Letter, 2014)
Oncolytic effects between MeV, MuV and MM on human hematological malignant
cell lines.
U937
MeV
MuV
THP-1
MM
MeV
Jurkat
MeV
MuV
MuV
HL-60
MM
MeV
KI-4
MM
MeV
MuV
MuV
MM
HuT 102
MM
MeV
MuV
MM
The oncolytic effect of the MM compared with single virus was significantly enhanced in
U937, THP-1, HL-60, Jurkat, KI-4 and HuT102 cell lines.
(Zhang….. Toan. ..et al, Cancer Letter, 2014)
14
Nude Mice bearing human solid tumors
Larynx cancer (Hep2)
Liver cancer (Hep 3B)
Lung cancer (H211)
PC tissue with
prostate tubes
Muscles
PC invaded venous
system
Colon cancer
(HT 29)
Prostate Cancer (PC-3)
15
Dose of intra-tumoral injections
Groups
Virus
concentration
Frequency
Inoculation
site
Negative
control
M199 medium
1 time or
2 time/wk x 3wks
Intra-tumor
Me
106pfu/100ul
1 time or
2 time/wk x 3wks
Intra-tumor
Mu
106pfu/100ul
1 time or
2 time/wk x 3wks
Intra-tumor
Me+Mu
106pfu/100ul +
106pfu/100ul
1 time or
2 time/wk x 3wks
Intra-tumor
OLV were inoculated intra-tumor when PC-3 tumors reached 0.5 mm3 volume
16
MM enhances killing human PC-3 tumor xenograft
* P<0.05
Tumor size (mm3)
Tumor size (mm3)
* P<0.05
*
Time (day)
Single dose
*
*
*
Time (day)
Multi-dose
17
Percent Survival
Percent Survival
MM combination prolonging survival time
Survival time (day)
Single dose
Multi-dose
18
Enhanced killing of U937 cells and prolonged mice survival by MM treatment
in nude mice bearing U937 tumors
a. Tumor volume
b. Survival
Days post treatment
Days post treatment
(Zhang….. Toan. ..et al, Cancer Letter, 2014)
19
Mechanistic studies: Involvement in apoptosis of U937
and THP-1 cells induced by MM infection.
Mock
Kp7-6 (1mg/ml)
1.2%
1.6%
MM
Kp7-6 (1mg/ml)
MM
8.6%
6.9%
2.9%
2.3%
27.9%
21.7%
1.4%
1.0%
6.9%
7.9%
THP-1
U937
2.2%
2.7%
41.1%
31.1%
Annexin V
(Zhang….. Toan. ..et al, Cancer Letter, 2014)
SUMMARY
In vitro MM displayed a more potent oncolytic
effect than single virus on human solid and
hematological cancer cell lines
In vivo, MM displayed significant tumor
suppression and prolonged survival, compared
to single virus, in a PC-3 and U937 xenograft
tumor models.
Our results demonstrate that MM is a promising
candidate for the treatment human cancers.
ACKNOWLEDGMENTS
Centre Biomedical & Pharmaceutical Lab.,
VMMU, Vietnam
Department of Microbiology, NUS, Singapore
NUS-VMMU collaboration project;
Vietnam NAFOSTED project, Viet Nam
VIETNAM MILITARY MEDICAL UNIVERSITY