Oncolytic viral therapy for prostate cancer: efficacy of reovirus as a biological therapeutic.
Reovirus is a nonattenuated double-stranded RNA virus that exploits aberrant signaling pathways allowing selective cytotoxicity against multiple cancer histologies. The use of reovirus as a potential treatment modality for prostate cancer has not previously been described, and in this study evidence of in vitro and in vivo activity against prostate cancer was seen both in preclinical models and in six patients. The human prostate carcinoma cell lines PC-3, LN-CaP, and DU-145 exposed to replication-competent reovirus showed evidence of infection as illustrated by viral protein synthesis, cytopathic effect, and release of viral progeny. This oncolytic effect was found to be manifested through apoptosis, as DNA fragmentation, Apo 2.7 expression, Annexin V binding, and poly(ADP-ribose) polymerase cleavage were observed in live reovirus-infected cells, but not in uninfected or dead virus-treated cells. In vivo, hind flank severe combined immunodeficient/nonobese diabetic murine xenograft showed reduction in tumor size when treated with even a single intratumoral injection of reovirus. Finally, intralesional reovirus injections into a cohort of six patients with clinically organ-confined prostate cancer resulted in minimal side effects and evidence of antitumor activity. Histologic analysis after prostatectomy found a significant CD8 T-cell infiltration within the reovirus-injected areas as well as evidence of increased caspase-3 activity. These findings suggest that reovirus therapy may provide a promising novel treatment for prostate cancer and also imply a possible role for viral immune targeting of tumor.
Thirukkumaran
Chandini M
CM
Departments of Oncology, University of Calgary, Calgary, Alberta, Canada.
Nodwell
Michael J
MJ
Hirasawa
Kensuke
K
Shi
Zhong-Qiao
ZQ
Diaz
Roman
R
Luider
Joanne
J
Johnston
Randal N
RN
Forsyth
Peter A
PA
Magliocco
Anthony M
AM
Lee
Patrick
P
Nishikawa
Sandra
S
Donnelly
Bryan
B
Coffey
Matt
M
Trpkov
Kiril
K
Fonseca
Kevin
K
Spurrell
Jason
J
Morris
Don G
DG
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D023041:Xenograft Model Antitumor Assays