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Abstract
Background. Successful tumor targeting of systemically administered oncolytic adenoviruses may be hindered by interactions with blood components.
Materials and 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.
Conclusion. 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.
Acknowledgements
We thank personnel at International Comprehensive Cancer Center Docrates and Eira Hospital, Helsinki, Finland for help with clinical work. Risto Renkonen and Hannu Kalimo are acknowledged for their helpful assistance. The non-clinical part of this study was supported by the European Research Council, Academy of Finland, EU FP6 APOTHERAPY and THERADPOX, ASCO Foundation, HUCH Research Funds (EVO), Sigrid Juselius Foundation, K. Albin Johansson Foundation, Biocentrum Helsinki, and Helsinki University Research Fund. Akseli Hemminki is K. Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute.
This work was done in Helsinki, Finland. Anna Kanerva and Akseli Hemminki contributed equally to this study.
Declaration of interest: Akseli Hemminki is co-founder and shareholder in Oncos Therapeutics, Inc. Timo Joensuu is joint owner of Docrates clinic. Elina Haavisto, Aila Karioja-Kallio, and Lotta Kangasniemi are employed by Oncos Therapeutics. The other authors declare no competing financial interests.