title: Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients.
abstract: OBJECTIVE
  The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self-antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity.
  
  
  METHODS
  Two phase I studies were conducted with CDX-1307, a vaccine composed of human chorionic gonadotropin beta-chain (hCG-β) fused to an MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose escalation of single-agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC.
  
  
  RESULTS
  CDX-1307 induced consistent humoral and T-cell responses to hCG-β when coadministered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and nonelevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions.
  
  
  CONCLUSIONS
  APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer immunotherapy.
authors.affiliation: 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: Robert
authors.initials: R
authors.lastname: Chapman
authors.forename: John
authors.initials: J
authors.lastname: Powderly
authors.forename: Kimberly
authors.initials: K
authors.lastname: Blackwell
authors.forename: Tibor
authors.initials: T
authors.lastname: Keler
authors.forename: Jennifer
authors.initials: J
authors.lastname: Green
authors.forename: Renee
authors.initials: R
authors.lastname: Riggs
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: He
authors.forename: Venky
authors.initials: V
authors.lastname: Ramakrishna
authors.forename: Laura
authors.initials: L
authors.lastname: Vitale
authors.forename: Biwei
authors.initials: B
authors.lastname: Zhao
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Butler
authors.forename: Amy
authors.initials: A
authors.lastname: Hobeika
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Thomas
authors.initials: T
authors.lastname: Davis
authors.forename: Timothy
authors.initials: T
authors.lastname: Clay
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000097:blood / Q000276:immunology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D008297:Male; D009367:Neoplasm Staging; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D001324:Autoantigens; C568617:CDX 1307; D019496:Cancer Vaccines; D018997:Chorionic Gonadotropin, beta Subunit, Human; D011993:Recombinant Fusion Proteins; D051193:Toll-Like Receptors