Clinical Research Papers:
Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer
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Michal Podrazil1,*, Rudolf Horvath1,7,*, Etienne Becht4,5,6, Daniela Rozkova2, Pavla Bilkova2, Klara Sochorova1,2, Hana Hromadkova1, Jana Kayserova1, Katerina Vavrova1, Jan Lastovicka1, Petra Vrabcova1, Katerina Kubackova3, Zdenka Gasova8, Ladislav Jarolim9, Marek Babjuk9, Radek Spisek1,2, Jirina Bartunkova1,2, Jitka Fucikova1,2
1Department of Immunology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
2Sotio, Prague, Czech Republic
3Department of Oncology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
4Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, Paris, France
5Université Pierre et Marie Curie-Paris, Paris, France
6Université Paris Descartes, Paris, France
7Department of Pediatric and Adult Rheumatology, University Hospital Motol, Prague, Czech Republic
8Institute of Hematology and Blood Transfusion, Prague, Czech Republic
9Department of Urology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
*These authors have contributed equally to this work
Jitka Fucikova, e-mail: firstname.lastname@example.org
Keywords: immunotherapy, dendritic cell, prostate cancer, overall survival, castration-resistant prostate cancer
Received: February 10, 2015 Accepted: May 15, 2015 Published: May 29, 2015
Purpose: 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.
Experimental design: 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.
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