Original Article

Cancer Immunology, Immunotherapy

, Volume 62, Issue 8, pp 1293-1301

First online:

Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients

  • Michael A. MorseAffiliated withDepartment of Medicine, Duke University Medical CenterDuke Cancer Institute Email author 
  • , Arvind ChaudhryAffiliated withMedical Oncology Associates
  • , Elizabeth S. GabitzschAffiliated withEtubics Corporation
  • , Amy C. HobeikaAffiliated withDepartment of Surgery, Duke University Medical Center
  • , Takuya OsadaAffiliated withDepartment of Surgery, Duke University Medical Center
  • , Timothy M. ClayAffiliated withR&D Immunotherapeutics, GlaxoSmithKline Biologicals
  • , Andrea AmalfitanoAffiliated withMichigan State University
  • , Bruce K. BurnettAffiliated withDuke Cancer Institute
  • , Gayathri R. DeviAffiliated withDepartment of Surgery, Duke University Medical Center
    • , David S. HsuAffiliated withDepartment of Medicine, Duke University Medical CenterDuke Cancer Institute
    • , Younong XuAffiliated withEtubics Corporation
    • , Stephanie BalcaitisAffiliated withEtubics Corporation
    • , Rajesh DuaAffiliated withEtubics Corporation
    • , Susan NguyenAffiliated withEtubics Corporation
    • , Joseph P. BalintJr.Affiliated withEtubics Corporation
    • , Frank R. JonesAffiliated withEtubics Corporation
    • , H. Kim LyerlyAffiliated withDepartment of Surgery, Duke University Medical CenterDuke Cancer Institute

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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.

Keywords

Immunotherapy Ad5 vector CEA Cell-mediated immunity