title: Immunization with N-propionyl polysialic acid-KLH conjugate in patients with small cell lung cancer is safe and induces IgM antibodies reactive with SCLC cells and bactericidal against group B meningococci.
abstract: OBJECTIVE
  Polysialic acid (polySA) is a polymer side chain bound to the neural cell adhesion molecule that is extensively expressed on the surface of small cell lung cancer (SCLC) cells. In our previous study, a robust antibody response was noted in patients with SCLC after vaccination with 30 μg of keyhole limpet hemocyanin (KLH)-conjugated N-propionylated (NP-) polySA, but peripheral neuropathy and ataxia were detected in several vaccinated patients. The objectives of the current trial were to establish the lowest optimal dose and to confirm the safety of the induction of antibodies against polySA with the NP-polySA vaccine.
  
  
  METHODS
  Patients with SCLC who completed initial treatment and had no evidence of disease progression were injected with either 10 or 3 μg of NP-polySA conjugated to KLH and mixed with 100 μg of immunologic adjuvant (QS-21) at weeks 1, 2, 3, 4, 8, and 16.
  
  
  RESULTS
  Nine patients were enrolled at each of the two dose levels. Prior to vaccination, one patient in each group had low-titer antibodies against polysialic acid. All patients at the 10 μg vaccine dose level responded to vaccination with IgM antibody titers against polysialic acid (median titer 1/1,280 by ELISA), and all but one patient made IgM and IgG antibodies against the artificial vaccine immunogen, NP-polysialic acid (median titer 1/10,240). The antibody responses at the 3 μg vaccine dose level were lower; six of nine patients developed antibodies against polysialic acid (median titer 1/160). Post-vaccination sera from 6/9 and 3/9 patients in the 10 and 3 μg groups reacted strongly with human SCLC cells by fluorescent-activated cell sorting (FACS). Sera from all patients in the 10 μg dose group also had bactericidal activity against group B meningococci with rabbit complement. Self-limited grade 3 ataxia of unclear etiology was seen in 1 of 18 patients.
  
  
  CONCLUSIONS
  Vaccination with NP-polySA-KLH resulted in consistent high-titer antibody responses, with the 10 μg dose significantly more immunogenic than the 3 μg dose. This study establishes the lowest optimally immunogenic dose of NP-polysialic acid in this NP-polysialic acid-KLH conjugate vaccine to be at least 10 μg, and it establishes the vaccine's safety. We plan to incorporate NP-polySA into a polyvalent vaccine against SCLC with four glycolipid antigens also widely expressed in SCLC-GD2, GD3, fucosylated GM1, and globo H.
authors.affiliation: Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, 1275 York Ave., New York, NY 10065, USA. krugl@mskcc.org
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.forename: Govind
authors.initials: G
authors.lastname: Ragupathi
authors.forename: Chandra
authors.initials: C
authors.lastname: Hood
authors.forename: Constantine
authors.initials: C
authors.lastname: George
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Lauren
authors.initials: L
authors.lastname: Abrey
authors.forename: Harold J
authors.initials: HJ
authors.lastname: Jennings
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Philip O
authors.initials: PO
authors.lastname: Livingston
mesh_terms: D000368:Aged; D000818:Animals; D001770:Blood Bactericidal Activity / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D006433:Hemocyanins / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000276:immunology; D008175:Lung Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D038541:Neisseria meningitidis, Serogroup B / Q000276:immunology; D011817:Rabbits; D012794:Sialic Acids / Q000276:immunology / Q000627:therapeutic use*; D055752:Small Cell Lung Carcinoma / Q000097:blood / Q000276:immunology / Q000628:therapy*; D016019:Survival Analysis
chemical_list: D019496:Cancer Vaccines; D007075:Immunoglobulin M; D012794:Sialic Acids; C021319:polysialic acid; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin