PT  - JOURNAL ARTICLE
AU  - John C Flickinger Jr
AU  - Jagmohan Singh
AU  - Robert Carlson
AU  - Elinor Leong
AU  - Trevor R Baybutt
AU  - Joshua Barton
AU  - Ellen Caparosa
AU  - Amanda Pattison
AU  - Jeffrey A Rappaport
AU  - Jamin Roh
AU  - Tingting Zhan
AU  - Babar Bashir
AU  - Scott A Waldman
AU  - Adam E Snook
TI  - Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity
AID  - 10.1136/jitc-2020-001046
DP  - 2020 Aug 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e001046
VI  - 8
IP  - 2
4099  - http://jitc.bmj.com/content/8/2/e001046.short
4100  - http://jitc.bmj.com/content/8/2/e001046.full
SO  - J Immunother Cancer2020 Aug 01; 8
AB  - Background Adenovirus serotype 5 (Ad5) is a commonly used viral vector for transient delivery of transgenes, primarily for vaccination against pathogen and tumor antigens. However, endemic infections with Ad5 produce virus-specific neutralizing antibodies (NAbs) that limit transgene delivery and constrain target-directed immunity following exposure to Ad5-based vaccines. Indeed, clinical trials have revealed the limitations that virus-specific NAbs impose on the efficacy of Ad5-based vaccines. In that context, the emerging focus on immunological approaches targeting cancer self-antigens or neoepitopes underscores the unmet therapeutic need for more efficacious vaccine vectors.Methods Here, we evaluated the ability of a chimeric adenoviral vector (Ad5.F35) derived from the capsid of Ad5 and fiber of the rare adenovirus serotype 35 (Ad35) to induce immune responses to the tumor-associated antigen guanylyl cyclase C (GUCY2C).Results In the absence of pre-existing immunity to Ad5, GUCY2C-specific T-cell responses and antitumor efficacy induced by Ad5.F35 were comparable to Ad5 in a mouse model of metastatic colorectal cancer. Furthermore, like Ad5, Ad5.F35 vector expressing GUCY2C was safe and produced no toxicity in tissues with, or without, GUCY2C expression. Importantly, this chimeric vector resisted neutralization in Ad5-immunized mice and by sera collected from patients with colorectal cancer naturally exposed to Ad5.Conclusions These data suggest that Ad5.F35-based vaccines targeting GUCY2C, or other tumor or pathogen antigens, may produce clinically relevant immune responses in more (≥90%) patients compared with Ad5-based vaccines (~50%).