Nowadays, oncolytic virotherapy has gradually become a powerful immunotherapeutic modality for cancer treatment. Immunogenicity manipulation is quite necessary, and with genetic modifications, oncolytic viruses are able to improve the oncolytic effects on tumor cells and stimulate antitumor immunity. https://www.creative-biolabs.com/oncolytic-virus/immunogenicity-manipulation.htm

1. Immunogenicity Manipulation
Nowadays, oncolytic virotherapy has gradually become a powerful immunotherapeutic
modality for cancer treatment. However, the anti-tumor effect of oncolytic virus is
often limited by the immunogenicity of virus which may induce neutralization
antibody to inactivate the virus and decrease viral load in patients. Thus,
immunogenicity manipulation is quite necessary, and with genetic modifications,
oncolytic viruses are able to improve the oncolytic effects on tumor cells and stimulate
antitumor immunity.
Fig 1. Schematic diagram of barriers to effective OV therapy. (Marchini, A., 2016)
Modification of the Capsid
Adenoviruses are excellent oncolytic virus candidates owing to their special
characteristics, such as relatively easy production of recombinants, feasible large-scale
production, as well as greatly efficient gene transfer and expression in dividing and
quiescent. Nevertheless, the primary receptor for adenoviruses, coxsackie-adenovirus
receptor (CAR), has been demonstrated to be frequently down-regulated on many
types of cancers. In order to circumvent dependence on CAR, viruses targeted to non-
CAR receptors have been developed. Generally, there are three methods, including 5/3
serotype chimerism, incorporation of RGD-4C, and polylysine chains (pK) into the
adenovirus fiber.
Antibody Secretion

2. To solve immunogenicity problems, antibody secretion is a very useful method that
enhance the anti-tumor immune response. For example, an oncolytic group B
adenovirus EnAdenotucirev (EnAd) has been designed to express a bispecific single-
chain antibody, secreted from infected tumour cells into the microenvironment. This
strategy increases the cytotoxicity of EnAd, and it has proven that using primary
pleural effusions and peritoneal malignant ascites that infection of cancer cells with the
BiTE-expressing EnAd causes activation of endogenous T cells to kill endogenous
tumour cells. In this way, an EnAd combining both direct oncolysis and T cell-
mediated killing is performed.
Cytokine/chemokine Expression
Expressing cytokine/chemokine to attract immune cells migration to the tumor site is
also a powerful approach. Researchers have constructed two oncolytic herpes simplex
viruses (HSV) which enable to express the murine GM-CSF and murine IL-12 genes.
The two cytokine-carrying variants are contrasted with the analogous non-cytokine-
carrying control virus in the treatment of murine SCC VII squamous cell carcinoma. It
has demonstrated that the GM-CSF and IL-12 expression HSV displays a much
stronger antitumor efficacy than non-cytokine-carrying control virus.
Load with Immune Checkpoint Inhibitors
Immune system has an essential capacity to distinguish normal cells in the body and
those it considers as “foreign.” To achieve this, “checkpoints” are used, which refers to
molecules on certain immune cells needed to be activated (or inactivated) to start an
immune response. However, sometimes cancer cells find ways to utilize these
checkpoints to avoid being attacked. Thus, drugs that target these checkpoints hold
great promises as cancer treatments.
Fig 2. Combinatorial methods to overcome barriers to oncolytic virus‐induced oncolysis
and immune stimulation. (Marchini, A., 2016)

3. Reference:
1. Marchini, A., (2016). “Overcoming barriers in oncolytic virotherapy with HDAC inhibitors
and immune checkpoint blockade.” Viruses, 8(1), 9.
2. Wong, R. J., (2001). “Cytokine gene transfer enhances herpes oncolytic therapy in murine
squamous cell carcinoma.” Human gene therapy, 12(3), 253-265.