title: Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables.
abstract: OBJECTIVE
  There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients.
  
  
  METHODS
  We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture.
  
  
  RESULTS
  Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2).
  
  
  CONCLUSIONS
  Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.
authors.affiliation: Department of Oncology, St. George's Hospital Medical School, London, United Kingdom.
authors.forename: Agnieska
authors.initials: A
authors.lastname: Michael
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.forename: Nadine
authors.initials: N
authors.lastname: Quatan
authors.forename: Fatima
authors.initials: F
authors.lastname: Wushishi
authors.forename: Nick
authors.initials: N
authors.lastname: Russell
authors.forename: Joe
authors.initials: J
authors.lastname: Whelan
authors.forename: Prabir
authors.initials: P
authors.lastname: Chakraborty
authors.forename: David
authors.initials: D
authors.lastname: Leader
authors.forename: Michael
authors.initials: M
authors.lastname: Whelan
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics; D003967:Diarrhea / Q000209:etiology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D016571:Neural Networks, Computer; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D016896:Treatment Outcome; D014839:Vomiting / Q000209:etiology
chemical_list: D015703:Antigens, CD; D018931:Antineoplastic Agents, Hormonal; D019496:Cancer Vaccines; D016207:Cytokines