Virotherapy

Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents.

There are three main branches of virotherapy:
1. anti-cancer oncolytic viruses
An oncolytic virus is a virus that preferentially infects and kills cancer cells… Oncolytic viruses are thought
not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune
system response (see 3)
2. viral vectors for gene therapy
Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells...
3. viral immunotherapy.
Immunotherapy is the treatment of disease by activating or suppressing the immune system.
Oncolytic viruses (Ovs) are therapeutically useful anticancer viruses that will selectively infect and damage / kill
cancerous tissues without causing harm to normal tissues.
In contrast to gene therapy where a virus is used as a mere carrier for transgene delivery, oncolytic virus therapy
uses the virus itself as an active drug reagent.
OVs can also stimulate the immune system. The delivery of OVs into the tumor wakes up the immune system so
that it can facilitate a strong and durable response against the tumor itself.
Oncolytic viruses are selected or designed to launch a multipronged attack on cancer cells: after reaching a tumor,
they
 enter, selectively replicate and lyse the infected cell,
 spread to neighboring cells and release local inflammatory signals, including tumor antigens. These switch
on immune surveillance, potentially triggering both adaptive and innate systemic immune responses
against the cancer.
A combination with immune checkpoint inhibitors or chemotherapy may enhance the efficacy of oncolytic virus
therapy. Arming oncolytic viruses with immunostimulatory gene(s) or cancer therapeutic genes may also be
beneficial.
Checkpoint inhibitors are antibodies who block the negative regulators of T cell function thereby increasing T-cell
activation. When these checkpoints are blocked, the “brakes” on the immune system are released and T cells are
able to kill cancer cells better. Examples of checkpoint inhibitors currently approved are:
 ipilimumab (Yervoy®, Bristol-Myers Squibb) blocks a checkpoint protein called CTLA-4,
 pembrolizumab (Keytruda®; Merck / MSD) and nivolumab (Opdivo®, Bristol-Myers Squibb), target another
checkpoint protein called PD-1,
 atezolizumab (Tecentriq®, Roche), targets one called PD-L1
To date, two genetically engineered oncolytic viruses have been approved for marketing as drugs.
 One is Oncorine(Shanghai Sunway Biotech) , an E1B-deleted adenovirus, which was approved in China for
head and neck cancer and esophagus cancer in 2005.
 The other is T-Vec (IMLYGIC, Amgen) which was approved for melanoma by the FDA in the USA in October
2015 and was subsequently approved in Europe in January 2016 and in Australia in May 2016. T-Vec is a
double-mutated HSV-1 with deletions in the c34.5 and a47 genes, and the human granulocyte-
macrophage colony-stimulating factor (GM-CSF) gene inserted into the deleted c34.5 loci .
Other oncolytic viruses are coming through the pipeline including SillaJen/Transgene’s Pexa-Vec, Targovax’
mesothelioma candidate ONCOS-102. Another virus – Viralytics’ Cavatak – showed promise in a phase I trial as a
combination with Keytruda in melanoma, piquing Merck’s interest and prompting a $394m takeover deal earlier
this year.

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Meanwhile, AbbVie and Johnson & Johnson have both struck deals this year with biotechs in this field: Turnstone
Biologics and BeneVir Biopharm respectively – suggesting the oncolytic virus sector is heating up.
Selected oncolytic virus deals
Date Source Buyer Deal type Up-front Note
($m)
Sep 2018 Viratherapeutics Boehringer Acquisition 245 VSV-GP project, preclinical
Ingelheim
May Benevir Johnson & Johnson Acquisition 140 Preclinical technology
2018
Feb 2018 Viralytics Merck & Co Acquisition 394 Cavatak, phase II asset
Nov Oncolytics Adlai Norte Licensing 5 Far East development of Reolysin
2017
Oct 2017 Turnstone Biologics Abbvie Licensing Undisclosed Ad-MG1-MAGEA3, phase I/II asset
Dec 2016 Ignite Pfizer Acquisition Undisclosed 50% stake
Immunotherapy
Dec 2016 Psioxus Bristol-Myers Squib Licensing Undisclosed NG-348, preclinical asset
Dec 2016 Takara Bio Otsuka Licensing Undisclosed Japan rights to HF10
Nov Virttu Biologics Sorrento Acquisition 25 (equity) Seprehvir, phase II asset
2016
Jun 2016 Psioxus Bristol-Myers Squib Licensing 10 Enadenotucirev, phase I
collaboration
Jun 2015 Oncos Targovax Acquisition Undisclosed Structured as a 50/50 merger
Jan 2015 Omnis Astrazeneca Licensing Undisclosed VSV project, phase II
Nov Jennerex Sillajen Acquisition Undisclosed $150m biodollar value
2013
Jan 2011 Biovex Amgen Acquisition 424 Imlygic, approved for melanoma in
2015
Source: https://www.evaluate.com/vantage/articles/news/oncolytics-prepares-tap-us-investors

Virus manufacturing for viro and gene therapy is probably the most complex and resource-intensive process in
biologics manufacturing
 scaling up often requires switching virus expression hosts from adherent to suspension cell lines
 purification methods must be equally scalable, strict quality control assays are mandatory to ensure that
product quality remains unchanged
 down-stream processing and formulation conditions must be matched carefully to the features of each
virus
 Quality Assurance and Quality Control (QA/QC) are at the heart of GMP production
This is a boost for contract development and manufacturing organizations (CDMOs) like Vibalogics GmbH in
Germany.
 Private Equity Groups have been shaping this industry. They seem to have continued confidence in the
sector, increasing the value of their individual bets.
 Large CDMOs have snapped up smaller ones with expertise in these fields so they have an offering as
biotechs look for contractors to help them develop and manufacture their products.
The largest CDMOs are particularly attractive to sizable clients because they offer broader, large-scale
infrastructure, and more specialized bioprocessing and regulatory expertise. These CDMOs generally handle all
services, from cell line development through fill-finish and packaging:

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 Source:
https://bourne-partners.com/sector-reports/

Source: https://bourne-partners.com/sector-reports/

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Mehr / further reading / sources:
 https://www.medizin.uni-
tuebingen.de/uktmedia/EINRICHTUNGEN/Kliniken/Medizinische+Klinik/Innere+Medizin+VIII/PDF_Archiv/2018_Beil_Lauer_OH118_fi
nale+Druckversion-port-10443-p-92950.pdf
 https://www.spektrum.de/news/mit-viren-gegen-krebs/1579542
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888062/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932159/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234197/
 https://onlinelibrary.wiley.com/doi/full/10.1111/cas.13027
 http://www.hsj.gr/medicine/oncolytic-viruses-a-gene-therapy-for-treatment-of-cancer-in-companion-animals.php?aid=23108
 https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0458-z
 https://www.phrma.org/report/list-of-2018-medicines-in-development-for-cell-and-gene-therapy
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417845/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084676/
 http://www.genetherapynet.com/gene-therapy-products-on-the-market.html
 https://www.creative-biolabs.com/oncolytic-virus/oncolytic-virus-therapy-clinical-trials-overview.htm
 https://en.wikipedia.org/wiki/Virotherapy
 https://labiotech.eu/sponsored/manufacturing-gene-therapy-bottleneck/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822647/
 https://www.nature.com/articles/1209045
 https://www.biopharma-reporter.com/Article/2019/05/09/Vibalogics-invests-in-drug-product-virus-manufacturing
 https://www.fiercepharma.com/manufacturing/viral-vector-cdmo-vibalogics-latest-private-equity-target
 https://bourne-partners.com/sector-reports/
 http://www.pmlive.com/pharma_intelligence/Cancer_immunotherapy_Whats_on_the_horizon_1245525
 https://www.evaluate.com/vantage/articles/news/oncolytics-prepares-tap-us-investors

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