Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

Harm Westdorp, Jeroen H A Creemers, Inge M van Oort, Gerty Schreibelt, Mark A J Gorris, Niven Mehra, Michiel Simons, Anna L de Goede, Michelle M van Rossum, Alexandra J Croockewit, Carl G Figdor, J Alfred Witjes, Erik H J G Aarntzen, Roel D M Mus, Mareke Brüning, Katja Petry, Martin Gotthardt, Jelle O Barentsz, I Jolanda M de Vries, Winald R Gerritsen, Harm Westdorp, Jeroen H A Creemers, Inge M van Oort, Gerty Schreibelt, Mark A J Gorris, Niven Mehra, Michiel Simons, Anna L de Goede, Michelle M van Rossum, Alexandra J Croockewit, Carl G Figdor, J Alfred Witjes, Erik H J G Aarntzen, Roel D M Mus, Mareke Brüning, Katja Petry, Martin Gotthardt, Jelle O Barentsz, I Jolanda M de Vries, Winald R Gerritsen

Abstract

Background: Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs).

Methods: In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria.

Results: Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity.

Conclusions: Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome.

Trial registration: ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.

Keywords: Castration-resistant prostate cancer; Dendritic cell vaccination; Immunotherapy.

Conflict of interest statement

IMvO has received grants, personal fees and non-financial support from Astellas; grants and personal fees from Janssen-Cilag; grants and personal fees from Bayer and personal fees from Sanofi (all outside the submitted work). NM reports personal fees from Bayer, grants and personal fees from Jansen-Cilag, personal fees from Merck Sharp & Dohme, grants and personal fees from Roche, grants and personal fees from Astellas, grants and personal fees from Sanofi (all outside the submitted work). JAW reports personal fees from Sanofi, Merck Sharp & Dohme, Bristol-Myers Squibb and Roche (all outside the submitted work). MB is employed as a Project Manager R&D at Miltenyi Biotec GmbH. KP is employed as a Senior Clinical Project Manager at Miltenyi Biotec GmbH. MG has received grants from Astellas and Sanofi, personal fees from Boehringer Ingelheim, Sanofi and Sandoz (all outside the submitted work). JOB is an advisor for SPL Medical and Soteria Medical. WRG reports personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen-Cilag, Bayer, Astellas, Bavarian Nordic, Sanofi, Amgen, Curevac, IQVIA, Dendreon, Morphosys, ORCA Pharmaceuticals and Sotio (all outside the submitted work).

Figures

Fig. 1
Fig. 1
Immunological responses in the DTH skin-test and in blood. a Example of flow cytometric analysis of SKILs of patients combiDC-04. SKILs were stained with dextramers encompassing HLA-A0201-specific peptides of NY-ESO-1, MAGE-C2 and Mucin-1 (MUC1) or with a negative control (HLA-B*0801) and with anti-CD8. Tumor antigen-specific T cells were detected against all 3 tumor-associated antigens. b Tumor-associated antigen-specific responses in DTH skin-tests. NY-ESO-1-, MAGE-C2 and MUC1-specific T cell responses are presented per study arm and in total. c Number of antigen-specific responses in DTH skin-tests and in blood. Results are presented per vaccination cycle and in total. d Radiological non-progressive patients (n = 13) are defined as patients with the absence of disease progression within 6 months. Radiological progressive patients (n = 8) are defined as patients with progressive disease within 6 months. Presented are percentages of non-progressive and progressive patients with a positive DTH skin-test (tetramer/dextramer positive, dm+) for at least one epitope, IFN-y producing SKILs (IFN-y+), presence of both dm+ and IFN-y+ SKILs, and dominant IL-5+- or IL-10+-skewed immune responses, demonstrated by higher IL-5 or IL-10 production compared to IFN-y production in supernatant of antigen-challenged SKILs. e The presence of dm+ antigen-specific T cells and IFN-y-producing (IFN-y+) SKILs are shown for patients with non-progressive disease (n = 13) and progressive patients (n = 8). +: 1 epitope; ++: 2 epitopes; +++: 3 epitopes recognized. DTH: delayed-type hypersensitivity; dm: dextramer; PBMCs: peripheral blood mononuclear cells; PE: phyco erytrin; SKILs: skin-test infiltrating lymphocytes
Fig. 2
Fig. 2
Radiological progression-free survival and biochemical responses. a Kaplan-Meier analysis of rPFS of all patient determined by a log-rank test. b Kaplan-Meier analysis of rPFS of patients with (dm+ and IFN-y+) or without (dm− or IFN-y−) the presence of functional antigen-specific T cells in skin biopsies was determined by a log-rank test. c PSA doubling tome during DC vaccination therapy in dm+ and IFN-y+ patients (n = 5) and dm− or IFN-y− patients (n = 16)
Fig. 3
Fig. 3
Biochemical and radiological response upon first DC vaccination cycle of patient combiDC-07. a Biochemical analysis shows a PSA normalization upon the first cycle of DC vaccinations. b Fused 68Ga-prostate-specific membrane antigen PET/CT images showed a significant reduction of bilateral para-iliac and para-aortic lymph node metastases, right inguinal node metastases and a left supraclavicular lymph node metastasis after the 1st cycle of DC vaccinations. Lymph nodes are indicated with white arrows. c Maximal intensity projection images. Lymph nodes are indicated with red arrows
Fig. 4
Fig. 4
Expression of NY-ESO-1, MAGE-C2 and MUC1 and its relation to antigen-specific T cells in skin biopsies. a-d Representative immunohistochemical images showing (a) haematoxylin and eosin stain (H&E stain) and the expression of (b) NY-ESO-1, (c) MAGE-C2 and (d) MUC1. e Kaplan-Meier curve of rPFS in patients with or without the presence of antigen-specific T cells (dm+) in skin biopsies and expression of the same tumor-associated antigen in the tumor (dm+ and tumor+)

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.
    1. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–1512. doi: 10.1056/NEJMoa040720.
    1. 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. J Clin Oncol. 2008;26(2):242–245. doi: 10.1200/JCO.2007.12.4008.
    1. Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513–1520. doi: 10.1056/NEJMoa041318.
    1. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005. doi: 10.1056/NEJMoa1014618.
    1. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197. doi: 10.1056/NEJMoa1207506.
    1. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152–160. doi: 10.1016/S1470-2045(14)71205-7.
    1. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–433. doi: 10.1056/NEJMoa1405095.
    1. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–422. doi: 10.1056/NEJMoa1001294.
    1. Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–223. doi: 10.1056/NEJMoa1213755.
    1. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147–1154. doi: 10.1016/S0140-6736(10)61389-X.
    1. Eisenberger M, Hardy-Bessard AC, Kim CS, Geczi L, Ford D, Mourey L, et al. Phase III study comparing a reduced dose of Cabazitaxel (20 mg/m(2)) and the currently approved dose (25 mg/m(2)) in Postdocetaxel patients with metastatic castration-resistant prostate Cancer-PROSELICA. J Clin Oncol. 2017;35(28):3198–3206. doi: 10.1200/JCO.2016.72.1076.
    1. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet oncol. 2012;13(10):983–992. doi: 10.1016/S1470-2045(12)70379-0.
    1. Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, et al. Randomized, double-blind, phase III trial of Ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate Cancer. J Clin Oncol. 2017;35(1):40–47. doi: 10.1200/JCO.2016.69.1584.
    1. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700–712. doi: 10.1016/S1470-2045(14)70189-5.
    1. EMA Human Medicine European Public Assessment Report (EPAR) of Provenge (last updated 19/05/2015); EMA website: .
    1. Sheikh NA, Petrylak D, Kantoff PW, Dela Rosa C, Stewart FP, Kuan LY, et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol Immunother. 2013;62(1):137–147. doi: 10.1007/s00262-012-1317-2.
    1. Burch PA, Breen JK, Buckner JC, Gastineau DA, Kaur JA, Laus RL, et al. Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res. 2000;6(6):2175–2182.
    1. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–252. doi: 10.1038/32588.
    1. Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med. 2004;10(5):475–480. doi: 10.1038/nm1039.
    1. Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity. 2013;39(1):38–48. doi: 10.1016/j.immuni.2013.07.004.
    1. Bol KF, Figdor CG, Aarntzen EH, Welzen ME, van Rossum MM, Blokx WA, et al. Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients. Oncoimmunology. 2015;4(8):e1019197. doi: 10.1080/2162402X.2015.1019197.
    1. Tel J, Aarntzen EH, Baba T, Schreibelt G, Schulte BM, Benitez-Ribas D, et al. Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients. Cancer Res. 2013;73(3):1063–1075. doi: 10.1158/0008-5472.CAN-12-2583.
    1. Schreibelt G, Bol KF, Westdorp H, Wimmers F, Aarntzen EH, Duiveman-de Boer T, et al. Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells. Clin Cancer Res. 2016;22(9):2155–2166. doi: 10.1158/1078-0432.CCR-15-2205.
    1. MacDonald KP, Munster DJ, Clark GJ, Dzionek A, Schmitz J, Hart DN. Characterization of human blood dendritic cell subsets. Blood. 2002;100(13):4512–4520. doi: 10.1182/blood-2001-11-0097.
    1. Piccioli D, Sammicheli C, Tavarini S, Nuti S, Frigimelica E, Manetti AG, et al. Human plasmacytoid dendritic cells are unresponsive to bacterial stimulation and require a novel type of cooperation with myeloid dendritic cells for maturation. Blood. 2009;113(18):4232–4239. doi: 10.1182/blood-2008-10-186890.
    1. Nizzoli G, Krietsch J, Weick A, Steinfelder S, Facciotti F, Gruarin P, et al. Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. Blood. 2013;122(6):932–942. doi: 10.1182/blood-2013-04-495424.
    1. Bakdash G, Schreurs I, Schreibelt G, Tel J. Crosstalk between dendritic cell subsets and implications for dendritic cell-based anticancer immunotherapy. Expert Rev Clin Immunol. 2014;10(7):915–926. doi: 10.1586/1744666X.2014.912561.
    1. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol. 2000;165(11):6037–6046. doi: 10.4049/jimmunol.165.11.6037.
    1. Bol KF, Schreibelt G, Rabold K, Wculek SK, Schwarze JK, Dzionek A, et al. The clinical application of cancer immunotherapy based on naturally circulating dendritic cells. J Immunother Cancer. 2019;7(1):109. doi: 10.1186/s40425-019-0580-6.
    1. van Beek JJ, Gorris MA, Skold AE, Hatipoglu I, Van Acker HH, Smits EL, et al. Human blood myeloid and plasmacytoid dendritic cells cross activate each other and synergize in inducing NK cell cytotoxicity. Oncoimmunology. 2016;5(10):e1227902. doi: 10.1080/2162402X.2016.1227902.
    1. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65(2):467–479. doi: 10.1016/j.eururo.2013.11.002.
    1. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of hybrid (6)(8)Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56(5):668–674. doi: 10.2967/jnumed.115.154153.
    1. Heesakkers RA, Hovels AM, Jager GJ, van den Bosch HC, Witjes JA, Raat HP, et al. MRI with a lymph-node-specific contrast agent as an alternative to CT scan and lymph-node dissection in patients with prostate cancer: a prospective multicohort study. Lancet Oncol. 2008;9(9):850–856. doi: 10.1016/S1470-2045(08)70203-1.
    1. Fortuin Ansje S., Brüggemann Roger, van der Linden Janine, Panfilov Ilia, Israël Bas, Scheenen Tom W.J., Barentsz Jelle O. Ultra-small superparamagnetic iron oxides for metastatic lymph node detection: back on the block. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 2017;10(1):e1471.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45(2):228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate Cancer clinical trials working group. J Clin Oncol. 2008;26(7):1148–1159. doi: 10.1200/JCO.2007.12.4487.
    1. Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, et al. A clinical development paradigm for cancer vaccines and related biologics. J Immunother. 2007;30(1):1–15. doi: 10.1097/.
    1. Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102(18):1388–1397. doi: 10.1093/jnci/djq310.
    1. Hoos A. Evolution of end points for cancer immunotherapy trials. Ann Oncol. 2012;23(Suppl 8):viii47–viii52. doi: 10.1093/annonc/mds263.
    1. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143–ee52. doi: 10.1016/S1470-2045(17)30074-8.
    1. de Vries IJ, Bernsen MR, Lesterhuis WJ, Scharenborg NM, Strijk SP, Gerritsen MJ, et al. Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome. J Clin Oncol. 2005;23(24):5779–5787. doi: 10.1200/JCO.2005.06.478.
    1. Westdorp H, Skold AE, Snijer BA, Franik S, Mulder SF, Major PP, et al. Immunotherapy for prostate cancer: lessons from responses to tumor-associated antigens. Front Immunol. 2014;5:191. doi: 10.3389/fimmu.2014.00191.
    1. Skold AE, van Beek JJ, Sittig SP, Bakdash G, Tel J, Schreibelt G, et al. Protamine-stabilized RNA as an ex vivo stimulant of primary human dendritic cell subsets. Cancer Immunol Immunother. 2015;64(11):1461–1473. doi: 10.1007/s00262-015-1746-9.
    1. Aarntzen EH, Bol K, Schreibelt G, Jacobs JF, Lesterhuis WJ, Van Rossum MM, et al. Skin-test infiltrating lymphocytes early predict clinical outcome of dendritic cell-based vaccination in metastatic melanoma. Cancer Res. 2012;72(23):6102–6110. doi: 10.1158/0008-5472.CAN-12-2479.
    1. Benitez-Ribas D, Adema GJ, Winkels G, Klasen IS, Punt CJ, Figdor CG, et al. Plasmacytoid dendritic cells of melanoma patients present exogenous proteins to CD4+ T cells after fc gamma RII-mediated uptake. J Exp Med. 2006;203(7):1629–1635. doi: 10.1084/jem.20052364.
    1. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–148. doi: 10.1056/NEJMoa1209096.
    1. Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate Cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71(2):151–154. doi: 10.1016/j.eururo.2016.07.032.
    1. Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J Clin Oncol. 2013;31(23):2963–2969. doi: 10.1200/JCO.2013.49.5283.
    1. Boudewijns S, Westdorp H, Koornstra RH, Aarntzen EH, Schreibelt G, Creemers JH, et al. Immune-related adverse events of dendritic cell vaccination correlate with Immunologic and clinical outcome in stage III and IV melanoma patients. J Immunother. 2016;39(6):241–248. doi: 10.1097/CJI.0000000000000127.
    1. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate Cancer: updated recommendations from the prostate Cancer clinical trials working group 3. J Clin Oncol. 2016;34(12):1402–1418. doi: 10.1200/JCO.2015.64.2702.
    1. Scarpelli M, Zahm C, Perlman S, McNeel DG, Jeraj R, Liu G. FLT PET/CT imaging of metastatic prostate cancer patients treated with pTVG-HP DNA vaccine and pembrolizumab. J Immunother Cancer. 2019;7(1):23. doi: 10.1186/s40425-019-0516-1.
    1. von Boehmer L, Keller L, Mortezavi A, Provenzano M, Sais G, Hermanns T, et al. MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer. PLoS One. 2011;6(7):e21366. doi: 10.1371/journal.pone.0021366.
    1. Fossa A, Berner A, Fossa SD, Hernes E, Gaudernack G, Smeland EB. NY-ESO-1 protein expression and humoral immune responses in prostate cancer. Prostate. 2004;59(4):440–447. doi: 10.1002/pros.20025.
    1. Wong N, Major P, Kapoor A, Wei F, Yan J, Aziz T, et al. Amplification of MUC1 in prostate cancer metastasis and CRPC development. Oncotarget. 2016;7(50):83115–83133. doi: 10.18632/oncotarget.13073.
    1. Prue RL, Vari F, Radford KJ, Tong H, Hardy MY, D'Rozario R, et al. A phase I clinical trial of CD1c (BDCA-1)+ dendritic cells pulsed with HLA-A*0201 peptides for immunotherapy of metastatic hormone refractory prostate cancer. J Immunother. 2015;38(2):71–76. doi: 10.1097/CJI.0000000000000063.
    1. Aarntzen EH, Srinivas M, Bonetto F, Cruz LJ, Verdijk P, Schreibelt G, et al. Targeting of 111In-labeled dendritic cell human vaccines improved by reducing number of cells. Clin Cancer Res. 2013;19(6):1525–1533. doi: 10.1158/1078-0432.CCR-12-1879.
    1. Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016;7(33):52810–52817. doi: 10.18632/oncotarget.10547.
    1. Mehra N, Gerritsen W. Now the dust has settled over immune checkpoint blockade in metastatic prostate cancer. Ann Oncol. 2018;29(8):1620–1622. doi: 10.1093/annonc/mdy239.
    1. Higano CSF, Somer B, Curti B, Petrylak DP, Drake CG, et al. A phase III trial of GVAX immunotherapy for prostate cancer vs docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC). . Genitourinary Cancer Symposium: Proc Am Soc Clin Oncol, 2009 (abstract #LBA150). 2009.
    1. Small EJDT, Gerritsen WR et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). Genitourinary Cancer Symposium: Proc Am Soc Clin Oncol, 2009 (abstract 7). 2009.
    1. Gulley JL, Borre M, Vogelzang NJ, Ng S, Agarwal N, Parker CC, et al. Phase III trial of PROSTVAC in asymptomatic or minimally symptomatic metastatic castration-resistant prostate Cancer. J Clin Oncol. 2019;37(13):1051–1061. doi: 10.1200/JCO.18.02031.
    1. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–567. doi: 10.1038/nature14011.
    1. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545(7652):60–65. doi: 10.1038/nature22079.
    1. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–571. doi: 10.1038/nature13954.
    1. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108–119. doi: 10.1038/s41590-017-0022-x.
    1. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36(4):265–276. doi: 10.1016/j.it.2015.02.008.
    1. Gulley JL, Madan RA, Pachynski R, Mulders P, Sheikh NA, Trager J, et al. Role of Antigen Spread and Distinctive Characteristics of Immunotherapy in Cancer Treatment. J Natl Cancer Inst. 2017;109(4).

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