Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients |
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Authors: | Michael A. Morse Arvind Chaudhry Elizabeth S. Gabitzsch Amy C. Hobeika Takuya Osada Timothy M. Clay Andrea Amalfitano Bruce K. Burnett Gayathri R. Devi David S. Hsu Younong Xu Stephanie Balcaitis Rajesh Dua Susan Nguyen Joseph P. Balint Jr. Frank R. Jones H. Kim Lyerly |
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Affiliation: | 1. Department of Medicine, Duke University Medical Center, Rm 403 MSRB 1, Box 3233, Durham, NC, 27710, USA 4. Duke Cancer Institute, Durham, NC, 27710, USA 2. Medical Oncology Associates, Spokane, WA, 99208, USA 6. Etubics Corporation, Seattle, WA, 981119, USA 3. Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA 7. R&D Immunotherapeutics, GlaxoSmithKline Biologicals, Rue de l′Institut 89, 1300, Rixensart, Belgium 5. Michigan State University, East Lansing, MI, 48824, USA
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Abstract: | First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen carcinoembryonic antigen (CEA), induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of preexisting or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of preexisting Ad5 immunity in a majority (61.3 %) of patients. Importantly, there was minimal toxicity, and overall patient survival (48 % at 12 months) was similar regardless of preexisting Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity. |
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