title: An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer.
abstract: Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. morse004@mc.duke.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Amy C
authors.initials: AC
authors.lastname: Hobeika
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Peter
authors.initials: P
authors.lastname: Berglund
authors.forename: Bolyn
authors.initials: B
authors.lastname: Hubby
authors.forename: Sarah
authors.initials: S
authors.lastname: Negri
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Burnett
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Jonathan
authors.initials: J
authors.lastname: Smith
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D000328:Adult; D000368:Aged; D000524:Alphavirus / Q000235:genetics* / Q000276:immunology; D057134:Antibodies, Neutralizing; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D012093:Replicon; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen