Lidia Rodríguez García

Lidia Rodríguez García
[email protected]
Bachelor’s degree final project-Biochemistry, Faculty of Biosciences, Universitat Autònoma de Barcelona, June 2014
INTRODUCTION- Oncolytic Virotherapy
Cancer is the main cause of death of the world. The main
goal of the investigation in cancer field is to find less
aggressive and more effective and specific treatments.
A century ago, viruses began to have considerable
interest as possible agents of tumor destruction since
some clinical remissions were seen in cancer patients
during naturally acquired virus infections. Viral therapy is
based on the ability of certain viruses to replicate
selectively and kill cancer cells without causing
harm to normal tissues. The initial dose is
self-amplified in tumor sites and viral
progeny produced within the dying
cancer cell is released and infect
adjacent and/or distant cancer
cells.
Tumor selective
replication and
cell lysis
ONCOLYITIC ADENOVIRUS AND STRUCTURE
– Are mildly pathogenic in human→ safety profile
– Infect quiescent and dividing cells
– Cause lysis on the infected cells
– Are not integrative
– Are genetically stable
– Can be easily manipulated
Fiber
– Can be produced at large scale
Hexon
Infection of
tumor cell
Viral
dispersion
SELECTIVE - REPLICATION
Adenoviruses are genetically
modified to redirect its tropism and
achieve selective replication in tumor
cells by using three strategies:
1. Deletion of viral functions that confer
tumor selectivity thanks to the phenotypic
differences between tumor and normal cells.
2. Control of protein expression under tumor-specific
promoters (transcriptional and translational targeting).
3. Modification of the capsid proteins to redirect
adenovirus tropism (transductional targeting).
ITR
E1A
promoters
E1B
2.
1.
Penton
base
hexon/fiber
LIMITATIONS
Poor tumor targeting after
intravenous administration:
•
•
Reinfection and
elimination of
cancer cells
Interaction with blood cells and
complement → neutralization
Accumulation in non-target organs
→ liver and spleen sequestration.
Capsid modifications
•
ITR
Deficient intratumoral spread:
Stroma barriers and high intersticial
pressure →no extravasation.
Express matrix degrading enzymes
3.
SOME EXAMPLES
ONYX-015 replicate specifically in p53-deficient tumors thanks to the lack of E1B-55 kb gene, whose protein
binds and inactivates the pro-apoptotic p53 protein (Figure). Its derivate H101, was the first approved and
commercialized oncolytic adenovirus (2005).
CG0070 is the most promising oncolytic adenovirus of the moment, which replicates in Rb-pathway defective
tumor cells and express an immunostimulatory gene to enhance immune response against the tumor.
CONCLUSIONS
1. Virotherapy is a good alternative of the currenly used treatments.
2. Adenovirus can now be genetically engineered to redirect its tropism and selectively replicate in
tumor cells without causing toxicity in other organs.
3. Replication in cancer cells will amplify the input virus potentially leading to spread of the virus
and the amplification of the initial dose in tumor site.
4. Oncolytic adenoviruses can be armed with transgenes which helps in the dissemination through
the tumor and with immunostimulatory genes, to generate a systemic immune response against
the tumor.
5. Combination with convecional cancer therapies (chemotherapy and radiotherapy) improves the
antitumor activity of oncolytic agents.
REFERENCES
[1] Stephen J Russell, Kah Whye Peng, John C Bell (2012).
Oncolytic virotherapy. Nature Biotechnology 30: 1-13.
[2] Elizabeth Kelly, Stephen J Russell (2007). History of Oncolytic
Viruses: Genesis to Genetic Engineering. Molecular Therapy 15:
651-659
[3] Roland L. Chu, Dawn E. Post, Fadlo R. Khuri, et al. (2004). Use
of Replicating Oncolytic Adenoviruses in Combination Therapy for
Cancer. Clin Cancer Res,10: 5299-5312.
[4] T-C Liu, D Kirn (2008). Gene therapy progress and prospects
cancer: oncolytic viruses. Gene Therapy 15: 877-884.