Original Article

Cancer Gene Therapy (2009) 16, 673–682; doi:10.1038/cgt.2009.17; published online 20 February 2009

Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity

T Osada1, X Y Yang1, Z C Hartman1, O Glass1, B L Hodges2, D Niedzwiecki3, M A Morse3,4, H K Lyerly1,3,5, A Amalfitano6,7 and T M Clay1,3,7

  1. 1Department of Surgery, Duke University Medical Center, Durham, NC, USA
  2. 2Prothelia Inc., Milford, MA, USA
  3. 3Duke Comprehensive Cancer Center, Durham, NC, USA
  4. 4Department of Medicine, Durham, NC, USA
  5. 5Department of Immunology, Durham, NC, USA
  6. 6Department of Microbiology and Molecular Genetics and Pediatrics, Michigan State University, East Lansing, MI, USA

Correspondence: Dr TM Clay, Department of Experimental Surgery, Duke University Medical Center, Rm 433 MSRB 1 Box 2606, Durham, NC 27710, USA. E-mail: tim.clay@duke.edu

7These authors contributed equally to this work.

Received 19 October 2008; Accepted 24 December 2008; Published online 20 February 2009.

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Abstract

Recombinant serotype 5 adenovirus (Ad5) vectors lacking E1 expression induce robust immune responses against encoded transgenes in pre-clinical models, but have muted responses in human trials because of widespread pre-existing anti-adenovirus immunity. Attempts to circumvent Ad5-specific immunity by using alternative serotypes or modifying capsid components have not yielded profound clinical improvement. To address this issue, we explored a novel alternative strategy, specifically reducing the expression of structural Ad5 genes by creating E1 and E2b deleted recombinant Ad5 vectors. Our data show that [E1−, E2b−]vectors retaining the Ad5 serotype are potent immunogens in pre-clinical models despite the presence of significant Ad5-specific immunity, in contrast to [E1−] vectors. These pre-clinical studies with E1 and E2b-deleted recombinant Ad5 vectors suggest that anti-Ad immunity will no longer be a limiting factor, and that clinical trials to evaluate their performance are warranted.

Keywords:

adenovirus, Ad5 vectors, immunotherapy