title: Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients.
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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. morse004@mc.duke.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Arvind
authors.initials: A
authors.lastname: Chaudhry
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gabitzsch
authors.forename: Amy C
authors.initials: AC
authors.lastname: Hobeika
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Burnett
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
authors.forename: David S
authors.initials: DS
authors.lastname: Hsu
authors.forename: Younong
authors.initials: Y
authors.lastname: Xu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Balcaitis
authors.forename: Rajesh
authors.initials: R
authors.lastname: Dua
authors.forename: Susan
authors.initials: S
authors.lastname: Nguyen
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Balint
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jones
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C000602305:Ad5(E1-,E2b-)-CEA(6D) vaccine; D057134:Antibodies, Neutralizing; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D007371:Interferon-gamma