title: Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer.
abstract: OBJECTIVE
  We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms.
  
  
  METHODS
  Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis.
  
  
  RESULTS
  No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS.
  
  
  CONCLUSIONS
  In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Podrazil
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Department of Pediatric and Adult Rheumatology, University Hospital Motol, Prague, Czech Republic.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, Paris, France.|Université Pierre et Marie Curie-Paris, Paris, France.|Université Paris Descartes, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Becht
authors.affiliation: Sotio, Prague, Czech Republic.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rozkova
authors.affiliation: Sotio, Prague, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Bilkova
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
authors.forename: Klara
authors.initials: K
authors.lastname: Sochorova
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hromadkova
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kayserova
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Vavrova
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Lastovicka
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Vrabcova
authors.affiliation: Department of Oncology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kubackova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Gasova
authors.affiliation: Department of Urology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Jarolim
authors.affiliation: Department of Urology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Babjuk
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Spisek
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartunkova
authors.affiliation: Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.|Sotio, Prague, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Fucikova
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D059250:Administration, Metronomic; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D000077143:Docetaxel; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D049451:Nomograms; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000276:immunology; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D043823:Taxoids; D000077143:Docetaxel; D003520:Cyclophosphamide; D011241:Prednisone
keywords: castration-resistant prostate cancer; dendritic cell; immunotherapy; overall survival; prostate cancer