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.

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Oncology 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

Department of Urology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Institut National de la Santé et de la Recherche Médicale Centre de Recherche des Cordeliers Paris France

Institute of Hematology and Blood Transfusion Prague Czech Republic

Sotio Prague Czech Republic

Université Paris Descartes Paris France

Université Pierre et Marie Curie Paris Paris France

Zobrazit více v PubMed

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians. 2014;64:9–29. PubMed

Ross RW, Xie W, Regan MM, Pomerantz M, Nakabayashi M, Daskivich TJ, Sartor O, Taplin ME, Kantoff PW, Oh WK. Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect. Cancer. 2008;112:1247–1253. PubMed

Beltran H, Beer TM, Carducci MA, de Bono J, Gleave M, Hussain M, Kelly WK, Saad F, Sternberg C, Tagawa ST, Tannock IF. New therapies for castration-resistant prostate cancer: efficacy and safety. European urology. 2011;60:279–290. PubMed

Maluf FC, Smaletz O, Herchenhorn D. Castration-resistant prostate cancer: systemic therapy in 2012. Clinics. 2012;67:389–394. PubMed PMC

Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. The New England journal of medicine. 2004;351:1513–1520. PubMed

Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26:242–245. PubMed

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Flechon A, Mainwaring P, Fleming M, Hainsworth JD, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England journal of medicine. 2012;367:1187–1197. PubMed

de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, et al. Abiraterone and increased survival in metastatic prostate cancer. The New England journal of medicine. 2011;364:1995–2005. PubMed PMC

Harrison MR, Wong TZ, Armstrong AJ, George DJ. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer management and research. 2013;5:1–14. PubMed PMC

Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nature reviews Cancer. 2002;2:389–396. PubMed PMC

Galluzzi L, Vacchelli E, Bravo-San Pedro JM, Buque A, Senovilla L, Baracco EE, Bloy N, Castoldi F, Abastado JP, Agostinis P, Apte RN, Aranda F, Ayyoub M, Beckhove P, Blay JY, Bracci L, et al. Classification of current anticancer immunotherapies. Oncotarget. 2014;5:12472–12508. PubMed PMC

Sheikh NA, Petrylak D, Kantoff PW, Dela Rosa C, Stewart FP, Kuan LY, Whitmore JB, Trager JB, Poehlein CH, Frohlich MW, Urdal DL. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer immunology, immunotherapy : CII. 2013;62:137–147. PubMed PMC

Lesterhuis WJ, Haanen JB, Punt CJ. Cancer immunotherapy—revisited. Nature reviews Drug discovery. 2011;10:591–600. PubMed

Butterfield LH. Dendritic Cells in Cancer Immunotherapy Clinical Trials: Are We Making Progress? Frontiers in immunology. 2013;4:454. PubMed PMC

de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nature reviews Cancer. 2006;6:24–37. PubMed

Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–148. PubMed

Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nature reviews Drug discovery. 2012;11:215–233. PubMed

Hodge JW, Garnett CT, Farsaci B, Palena C, Tsang KY, Ferrone S, Gameiro SR. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. International journal of cancer. 2013;133:624–636. PubMed PMC

Carson WE, 3rd, Shapiro CL, Crespin TR, Thornton LM, Andersen BL. Cellular immunity in breast cancer patients completing taxane treatment. Clinical cancer research: an official journal of the American Association for Cancer Research. 2004;10:3401–3409. PubMed

Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16:4583–4594. PubMed PMC

Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Frontiers in bioscience: a journal and virtual library. 2007;12:4957–4971. PubMed

Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862–2868. PubMed

Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V. Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer research. 2003;63:8408–8413. PubMed

Schiavoni G, Mattei F, Di Pucchio T, Santini SM, Bracci L, Belardelli F, Proietti E. Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer. Blood. 2000;95:2024–2030. PubMed

Rozkova D, Tiserova H, Fucikova J, Last'ovicka J, Podrazil M, Ulcova H, Budinsky V, Prausova J, Linke Z, Minarik I, Sediva A, Spisek R, Bartunkova J. FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer. Clinical immunology. 2009;131:1–10. PubMed

Fucikova J, Rozkova D, Ulcova H, Budinsky V, Sochorova K, Pokorna K, Bartunkova J, Spisek R. Poly I: C-activated dendritic cells that were generated in CellGro for use in cancer immunotherapy trials. Journal of translational medicine. 2011;9:223. PubMed PMC

Fucikova J, Moserova I, Truxova I, Hermanova I, Vancurova I, Partlova S, Fialova A, Sojka L, Cartron PF, Houska M, Rob L, Bartunkova J, Spisek R. High hydrostatic pressure induces immunogenic cell death in human tumor cells. International journal of cancer. 2014;135:1165–1177. PubMed

Fialova A, Partlova S, Sojka L, Hromadkova H, Brtnicky T, Fucikova J, Kocian P, Rob L, Bartunkova J, Spisek R. Dynamics of T-cell infiltration during the course of ovarian cancer: the gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells. International journal of cancer. 2013;132:1070–1079. PubMed

Halabi S, Small EJ, Kantoff PW, Kattan MW, Kaplan EB, Dawson NA, Levine EG, Blumenstein BA, Vogelzang NJ. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003;21:1232–1237. PubMed

Smaletz O, Scher HI, Small EJ, Verbel DA, McMillan A, Regan K, Kelly WK, Kattan MW. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2002;20:3972–3982. PubMed

Drake CG. Prostate cancer as a model for tumour immunotherapy. Nature reviews Immunology. 2010;10:580–593. PubMed PMC

Vacchelli E, Vitale I, Eggermont A, Fridman WH, Fucikova J, Cremer I, Galon J, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology. 2013;2:e25771. PubMed PMC

Thomas-Kaskel AK, Waller CF, Schultze-Seemann W, Veelken H. Immunotherapy with dendritic cells for prostate cancer. International journal of cancer. 2007;121:467–473. PubMed

Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007;450:903–907. PubMed

Spisek R. Immunoprevention of cancer: time to reconsider timing of vaccination against cancer. Expert Rev Anticancer Ther. 2006;6:1689–1691. PubMed

Spisek R, Dhodapkar MV. Immunoprevention of cancer. Hematology/oncology clinics of North America. 2006;20:735–750. PubMed

Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annual review of immunology. 2013;31:51–72. PubMed

Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature medicine. 2007;13:54–61. PubMed

Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob L, Bartunkova J, Spisek R. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer research. 2011;71:4821–4833. PubMed

Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood. 2007;109:4839–4845. PubMed PMC

Walsh PC, DeWeese TL, Eisenberger MA. Clinical practice. Localized prostate cancer. The New England journal of medicine. 2007;357:2696–2705. PubMed

Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer immunology, immunotherapy: CII. 2009;58:823–830. PubMed PMC

Nouri-Shirazi M, Banchereau J, Fay J, Palucka K. Dendritic cell based tumor vaccines. Immunol Lett. 2000;74:5–10. PubMed

Vergati M, Cereda V, Madan RA, Gulley JL, Huen NY, Rogers CJ, Hance KW, Arlen PM, Schlom J, Tsang KY. Analysis of circulating regulatory T cells in patients with metastatic prostate cancer pre- versus post-vaccination. Cancer immunology, immunotherapy: CII. 2011;60:197–206. PubMed PMC

Schweizer MT, Drake CG. Immunotherapy for prostate cancer: recent developments and future challenges. Cancer metastasis reviews. 2014;33:641–655. PubMed PMC

LL-37 as a Powerful Molecular Tool for Boosting the Performance of Ex Vivo-Produced Human Dendritic Cells for Cancer Immunotherapy

Immune activation of the monocyte-derived dendritic cells using patients own circulating tumor cells

Mast Cells and Dendritic Cells as Cellular Immune Checkpoints in Immunotherapy of Solid Tumors

Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial

Safety and efficacy of dendritic cell-based immunotherapy DCVAC/OvCa added to first-line chemotherapy (carboplatin plus paclitaxel) for epithelial ovarian cancer: a phase 2, open-label, multicenter, randomized trial

SARS-CoV-2 spike glycoprotein-reactive T cells can be readily expanded from COVID-19 vaccinated donors

CD4+ T Cells of Prostate Cancer Patients Have Decreased Immune Responses to Antigens Derived From SARS-CoV-2 Spike Glycoprotein

Quo Vadis Advanced Prostate Cancer Therapy? Novel Treatment Perspectives and Possible Future Directions

Thapsigargin-Stimulated LAD2 Human Mast Cell Line Is a Potent Cellular Adjuvant for the Maturation of Monocyte-Derived Dendritic Cells for Adoptive Cellular Immunotherapy

Induction of Tolerance and Immunity by Dendritic Cells: Mechanisms and Clinical Applications

Phase I/II trial of dendritic cell-based active cellular immunotherapy with DCVAC/PCa in patients with rising PSA after primary prostatectomy or salvage radiotherapy for the treatment of prostate cancer

Caspase-2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure-induced cancer cell death

Personalized ex vivo multiple peptide enrichment and detection of T cells reactive to multiple tumor-associated antigens in prostate cancer patients

Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure inhibit prostate tumor growth in TRAMP mice

Expression of tumor antigens on primary ovarian cancer cells compared to established ovarian cancer cell lines

Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure induce strong immune responses and display therapeutic effects both in murine TC-1 and TRAMP-C2 tumors when combined with docetaxel chemotherapy