E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models.
Oncolytic replication-selective adenoviruses constitute a rapidly growing therapeutic platform for cancer. However, the role of the host immune response and the E3 immunoregulatory genes of the human adenovirus were unknown until now. We identified four mouse carcinoma lines of variable permissivity for adenoviral gene expression, cytopathic effects and/or burst size. To determine E3 gene effects in immunocompetent tumor-bearing hosts, we injected tumors with one of three adenoviruses: Ad5 (E3 wild type), dl309 (del. E3 10.4/14.5, 14.7 kDa) or dl704 (del. E3 gp19 kDa). Compared with Ad5 and dl704, dl309 was cleared much more rapidly and/or its activity was lower in all four models. Intratumoral injection with dl309 resulted in markedly greater macrophage infiltration and expression of both tumor necrosis factor and interferon-gamma. Adenovirus replication, CD8(+) lymphocyte infiltration and efficacy were similar upon intratumoral injection with either dl704 or Ad5. E3-dependent differences were not evident in athymic mice. These findings have important implications for the design of oncolytic adenoviruses and may explain the rapid clearance of E3-10.4/14.5,14.7-deleted adenoviruses in patients.
Wang
Yaohe
Y
Viral and Genetic Therapy Program, Cancer Research UK and Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Hallden
Gunnel
G
Hill
Richard
R
Anand
Arthi
A
Liu
Ta-Chiang
TC
Francis
Jennelle
J
Brooks
Gabriel
G
Lemoine
Nick
N
Kirn
David
D
D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development* / Q000276:immunology / Q000378:metabolism*; D017503:Adenovirus E3 Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002277:Carcinoma / Q000821:virology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007121:Immunocompetence / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000378:metabolism; D014775:Virus Activation / Q000502:physiology*
D017503:Adenovirus E3 Proteins; D011994:Recombinant Proteins