This seminar presentation summarizes current developments in adenovirus-based cancer gene therapy. Adenoviruses were first isolated from adenoid tissues and function as vectors for gene delivery. They enter cells through endocytosis and release their genome into the nucleus. Cancers form through DNA damage and mutations that allow damaged cells to proliferate. Adenoviruses can be used for virotherapy by arming them with genes to target cancer cells. Challenges include immune responses, low replication of deficient viruses, and downregulation of viral receptors on cancer cells. Researchers are developing serotype chimeras and capsid modifications to overcome these challenges, along with combination therapies. Resistance remains an issue but may be addressed through

1. A SEMINAR PRESENTATION
ON
CURRENT DEVELOPMENTS IN ADENOVIRUS-
BASED CANCER GENE THERAPY
MAKINDE, OLATUNDUN YETUNDE
BCH/2009/084

2. ADENOVIRUSES IN CANCER GENE THERAPY
 Isolation: Adenoviruses were first Isolated from Adenoid
tissues..
 Structure and Characteristics: Double Stranded,
Icosahedral..(Martin et al., 2007)
 Function: They function as Vectors

3. Cell Division Cycle
 G1 Phase: Growth and development of the cell
 S phase: Chromosomes (DNA) are doubled, proteins and other essential components needed
by the daughter cells are produced.
 G2 Phase: Prepares the Cells for division. Note: Checkpoints
 M Phase: Actual cell division takes place
G2
M
G1 G0
S

4. HOW ARE CANCERS FORMED?
DNA Damage
Monitoring kinases
Other kinases
p53
Increased Conc. of p53
Activates waf 1 of cif 1
gene
More p21 is produced
Inhibits G1 and G1/S Cd KinasesPrevents Phosphorylation
of Rb Protein
Unphosphorylated protein
retains bound E2F.
Retainment of bound E2F
prevents cells with damaged
DNA from entering Sphase
Mutated Cells
Proliferate
Metastasis
Secondary Tumor/
CANCER
Primary Tumor

5. VIROTHERAPY: MECHANISM OF ACTION OF ADENOVIRUSES
 Entry and Internalization
 Endocytosis and release of viral genome into the nucleus

6. VIROTHERAPY AND ITS CHALLENGES
 Definition: An aspect of oncology that deals with the treatment
of cancers using adenoviruses
 Over the years, challenges have been met while using
Oncolytic Immunotherapy. Including:
Immune Response,
 Low efficacy of replication deficient Adenoviruses.
Conditionally Replicating Adenoviruses are now been
used.(Howe et al., 2000)
 Liver Tropism/ Toxicity. This was solved by transductional
targeting. This ensures safety of the patients
 Downregulation of CAR (Coxsackie Adenovirus Receptor) on
cell surface in malignant tumor conditions. Serotype
chimerism was been used to overcome this problem

7. SEROTYPE CHIMERISM
 Approach is used to combact the problem of downregulation
of CAR (Coxsackie Adenovirus Receptor)
K nob
Shaft
Tail
Serotype X
K nob
Ad 5 Shaft
A d 5 T ail
Serotype X
K nob
Serotype X
Shaft
A d5 T ail

8. CAPSID MODIFICATIONS
 An adenovirus was armed with Granulocyte-macrophage
colony stimulating factor, GMCSF.
 The already modified adenovirus was further armed by
serotype chimerism leading to the formation of a Chimera.
 Further modification was done to improve on the Ad5/3
Chimer by anchoring it with monoclonal antibodies.
 Ad5/3 Chimera was further modified by combining a tumor
specific promoter(E2F) and “delta-24” with the GMCSF
expression. This gave rise to a Quadruple Modification Design
(Ad5/3-D24-GMCSF also called CGTG-102). A large
proportion of Cancer Patients were treated.

9. SYNERGISTIC/ COCKTAILAPPROACHES
 Radiotherapy + Chemotherapy
 Low dose Cyclophosphamide
 Low dose pulse temozolomide.
 These drugs can be used along side CTGT-102 for best effects
(Cerullo et al., 2011)

10. RESISTANCE TO VIROTHERAPY!
 Research shows that interferon response by tumor stroma
resulted in tumor becoming Refractory. (Moerdyk et al., 2013;
Liikanen et al., 2011). This problem can be overcome by
treating the cancer in its early phase or by arming CTGT-102
with anti-interferons.

11. REFERENCES
 Howe, J. A., Demers, G. W., Johnson, D. E., Neugebauer, S. E., Perry, S.
T, Vaillancourt, M. T and Fahaab. (2000). Evaluation of E1-mutant
adenoviruses as conditionally replicating agents for cancer therapy.
MolTher. 2(5): 485-95.
 Matin A. M., Knipe D. M., Fields B. N., Howley P. M., Griffin D. and
Lamb R. (2007) Fields Virology. Philadelphia: Wolter Kluwer
Health/Lippincott Williams & Wilkins, 2007, Page 2395.
 Cerullo V., Pesonen S. and Diaconu I. (2010) “Oncolytic Adenovirus
coding for granulocyte macrophage colony stimulating factor induces
antitumoral immunity in cancer patients”, Cancer Research , vol 70, no
11, page 4297-2309.
 Hemminki A., (2012) “Portrait of a leader in immunotherapeutics:
Oncolyic virusses for treatment of cancer”, Human vaccines and
Immunotherapeutics, vol 8, no. 8, page 1018-1021.
 Liikanen I., Monsurro V. and Ahtiainen L. (2011) “Induction of
interfeon pathways mediates in vivo resistanceto oncolytic adenovirus”,
Molecular Therapy, vol. 19, no. 10, page 1858-1866.