title: Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome.
abstract: OBJECTIVE
  Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen).
  
  
  METHODS
  Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels.
  
  
  RESULTS
  In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥ 2-fold elevation posttreatment) occurred in ≥ 25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P ≤ 0.05).
  
  
  CONCLUSIONS
  Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. See related commentary by Hellstrom and Hellstrom, p. 3581.
authors: Dendreon Corporation, Seattle, Washington.
authors: Debraj
authors: D
authors: GuhaThakurta
authors: Dendreon Corporation, Seattle, Washington.
authors: Nadeem A
authors: NA
authors: Sheikh
authors: Dendreon Corporation, Seattle, Washington.
authors: Li-Qun
authors: LQ
authors: Fan
authors: Dendreon Corporation, Seattle, Washington.
authors: Harini
authors: H
authors: Kandadi
authors: Dendreon Corporation, Seattle, Washington.
authors: T Craig
authors: TC
authors: Meagher
authors: Mount Sinai School of Medicine, New York, New York.
authors: Simon J
authors: SJ
authors: Hall
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors: Philip W
authors: PW
authors: Kantoff
authors: University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Celestia S
authors: CS
authors: Higano
authors: University of California, San Francisco, San Francisco, California.
authors: Eric J
authors: EJ
authors: Small
authors: Indiana University Simon Cancer Center, Indianapolis, Indiana.
authors: Thomas A
authors: TA
authors: Gardner
authors: Dendreon Corporation, Seattle, Washington.
authors: Kate
authors: K
authors: Bailey
authors: Dendreon Corporation, Seattle, Washington.
authors: Tuyen
authors: T
authors: Vu
authors: Dendreon Corporation, Seattle, Washington.
authors: Todd
authors: T
authors: DeVries
authors: Dendreon Corporation, Seattle, Washington.
authors: James B
authors: JB
authors: Whitmore
authors: Dendreon Corporation, Seattle, Washington.
authors: Mark W
authors: MW
authors: Frohlich
authors: Dendreon Corporation, Seattle, Washington. cdrake@jhmi.edu jtrager@dendreon.com.
authors: James B
authors: JB
authors: Trager
authors: Johns Hopkins University School of Medicine, the Brady Urological Institute, Baltimore, Maryland. cdrake@jhmi.edu jtrager@dendreon.com.
authors: Charles G
authors: CG
authors: Drake
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood* / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D007167:Immunotherapy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D014020:Tissue Extracts / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D014020:Tissue Extracts; C511774:sipuleucel-T; D017430:Prostate-Specific Antigen
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