In vivo and in vitro distribution of type 5 and fiber-modified oncolytic adenoviruses in human blood compartments.
BACKGROUND
Successful tumor targeting of systemically administered oncolytic adenoviruses may be hindered by interactions with blood components.


METHODS
Blood distribution of oncolytic adenoviruses featuring type 5 adenovirus fiber, 5/3 capsid chimerism, or RGD-4C in the fiber knob was investigated in vitro and in patients with refractory solid tumors.


RESULTS
Virus titers and prevalence in serum of patients increased over the first post-treatment week, suggesting replication. Detection of low virus loads was more sensitive in blood clots than in serum, although viral levels > 500 viral particles/mL did not differ significantly between both sample types. While adenovirus bound to erythrocytes, platelets, granulocytes, and peripheral blood mononuclear cells in vitro, the virus was mainly detectable in erythrocytes and granulocytes in cancer patients. Taken together with a temporary post-treatment decrease in thrombocyte counts, platelet activation by adenovirus and subsequent clearance seem likely to occur in humans. Fiber modifications had limited observed effect on virus distribution in blood cell compartments. Neutrophils, monocytes and cytotoxic T lymphocytes were the major leukocyte subpopulations interacting with adenoviruses.


CONCLUSIONS
Serum and blood clots are relevant to estimate oncolytic adenovirus replication. Insight into viral interactions with blood cells may contribute to the development of new strategies for tumor delivery.
Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Finland.
Sophie
S
Escutenaire
Vincenzo
V
Cerullo
Iulia
I
Diaconu
Laura
L
Ahtiainen
Päivi
P
Hannuksela
Minna
M
Oksanen
Elina
E
Haavisto
Aila
A
Karioja-Kallio
Sirkka-Liisa
SL
Holm
Lotta
L
Kangasniemi
Camilla
C
Ribacka
Satu
S
Kauppinen
Timo
T
Joensuu
T Petteri
TP
Arstila
Sari
S
Pesonen
Anna
A
Kanerva
Akseli
A
Hemminki
D000256:Adenoviridae / Q000378:metabolism*; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D009504:Neutrophils / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014779:Virus Replication