Current Vaccination Strategies for Prostate Cancer

EUROPEAN UROLOGY 61 (2012) 290–306

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Collaborative Review – Prostate Cancer

Current Vaccination Strategies for Prostate Cancer Steven Joniau a,*, Per-Anders Abrahamsson b, Joaquim Bellmunt c, Carl Figdor d, Freddie Hamdy e, Paul Verhagen f, Nicholas J. Vogelzang g, Manfred Wirth h, Hendrik Van Poppel a, Susanne Osanto i a

Department of Urology, University Hospital, K.U. Leuven, Leuven, Belgium;

c

Department of Medical Oncology, Hospital Del Mar, Barcelona, Spain;

d

b

Department of Urology, Malmo¨-Lund University Hospital, Malmo¨, Sweden;

Tumour Immunology Department, UMC St. Radboud Nijmegen, Nijmegen, The

Netherlands; e Nuffield Department of Surgery, John Radcliffe Hospital, Oxford University, Oxford, UK; f Department of Urology, Erasmus Medical Centre, Rotterdam, The Netherlands; g Comprehensive Cancer Centres, Las Vegas, NV, USA; h Department of Urology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany; i Department of Oncology, Leiden University Medical Centre, Leiden, The Netherlands

Article info

Abstract

Article history: Accepted September 23, 2011 Published online ahead of print on October 3, 2011

Context: The first therapeutic cancer vaccine demonstrating effectiveness in a phase 3 study was approved by the US Food and Drug Administration on 29 April 2010. The pivotal trial demonstrated overall survival (OS) benefit in patients treated with antigen-loaded leukapheresis cells compared with a control infusion. Results of other prostate cancer (PCa) vaccination strategies are awaited, as this approach may herald a new era in the care for patients with advanced PCa. Objective: Consider effectiveness and safety of vaccination strategies in the treatment of PCa. Evidence acquisition: We searched three bibliographic databases (January 1995 through October 2010) for randomised phase 2 and 3 studies of vaccination strategies for PCa based on predetermined relevant Medical Subject Heading terms and free text terms. Evidence synthesis: Data from 3 randomised phase 3 and 10 randomised phase 2 vaccination trials are discussed with respect to clinical outcome in terms of progression-free survival and OS, toxicity, prostate-specific antigen (PSA) response, and immunologic response. Three phase 3 trials (D9901, D9902A, and D9902B) that enrolled a total of 737 patients, all controlled and double-blinded, tested the efficacy of sipuleucel-T. The largest of these three trials, called Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT), has demonstrated safety and effectiveness of sipuleucel-T (now marketed as Provenge) as measured by prolonged survival of 512 asymptomatic patients with metastatic castration-resistant PCa (mCRPC). The study showed a 4.1-mo median survival benefit in the sipuleucel-T vaccine-treated group compared with the control group (25.8 vs 21.7 mo; hazard ratio [HR]: 0.78; 95% confidence interval [CI], 0.62–0.98; p = 0.032) and extended 3-yr survival (31.7% vs 23.0%). In contrast, two phase 3 vaccination trials with a whole-tumour-cell mixture of two PCa cell lines (GVAX) and testing GVAX either alone or in combination with chemotherapy versus chemotherapy alone (VITAL1 and 2) were terminated prematurely based on futility and increased deaths. Other phase 2 vaccination trials testing different types of vaccines in castration-resistant PCa patients have been reported with variable outcomes. Notably, a controlled, double-blind, randomised phase 2 vaccine trial of PROSTVACVF, a recombinant viral vector containing complementary DNA encoding PSA, in 125 patients with chemotherapy-naı¨ve, minimally symptomatic mCRPC also demonstrated safety but no significant effect on the time to disease progression. In comparison with controls (n = 40), PROSTVAC-VF-treated patients (n = 82) experienced longer median

Keywords: Cancer vaccines Prostate neoplasms Poxvirus vector vaccine PROSTVAC-VF Sipuleucel-T

* Corresponding author. Uro-oncology and Reconstructive Urology, Department of Urology, University Hospital K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel. +32 16 34 69 45; Fax: +32 16 34 69 31. E-mail address: [email protected] (S. Joniau). 0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2011.09.020

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survival of 8.5 mo (25.1 vs 16.6 mo; HR: 0.56; 95% CI, 0.37–0.85; p = 0.0061) and extended 3-yr survival (30% vs 17%). In general, PCa vaccines are perceived to have less toxicity compared with current cytotoxic or targeted therapies. Evaluation of clinical efficacy of different vaccination strategies (eg, protein-, peptide- and DNA-based vaccines) in the context of properly designed and controlled phase 3 studies is warranted. Conclusions: Cancer vaccines represent a new paradigm in the treatment of PCa. The IMPACT trial showed improved survival but no difference in time to disease progression in mCRPC patients with minimal tumour burden. Observations in phase 2 and 3 trials pave the way for other vaccination approaches for this disease, raise questions regarding the most appropriate clinical trial designs, and underscore the importance of identifying biomarkers for antitumour effect to better implement such therapies. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

1.

Introduction

Prostate cancer (PCa) remains a significant health problem. For those with advanced or metastatic PCa, the traditional initial systemic therapy is androgen deprivation therapy. Eventually, nearly all patients progress to castrationresistant PCa (CRPC), for which the first-line treatment is limited to docetaxel-based chemotherapy. This therapy has shown a modest survival benefit of 2.4 mo and is associated with significant side effects [1]. Consequently, new, more effective, and less toxic treatments are urgently needed. Greater understanding of basic immunologic principles and advances in immunologic and molecular techniques have led to the development of therapeutic cancer vaccines for PCa. A cancer vaccine is used prophylactically to boost and harness the immune system and to mount a beneficial antitumour response to prevent the development of a tumour (ie, prophylactic vaccines) or therapeutically to enhance antitumour efficacy, leading to destruction of tumour cells or inhibition of their outgrowth (ie, therapeutic vaccines). Currently, only sipuleucel-T (Provenge), a prostatic acid phosphatase–granulocyte/macrophage– colony-stimulating factor (PAP-GM-CSF) fusion protein– loaded autologous blood cell vaccine, has been approved by the US Food an Drug Administration (FDA) for the treatment of asymptomatic or minimally symptomatic metastatic CRPC (mCRPC; April 2010) [2]. This review considers the clinical evidence supporting effectiveness and safety of vaccination strategies in the treatment of PCa. 2.

Evidence acquisition

A literature search was conducted for articles on vaccination strategies for PCa published between January 1995 and October 2010 using the following databases searched from 1995 to November 2010: PubMed, Embase, and Cochrane Library. Searches of each database included the Medical Subject Heading terms prostate neoplasms, cancer vaccines, clinical trial(s), RCT(s), randomized, and randomised and the free text terms vaccination strategies, vaccination strategy, cancer vaccine(s), cancer vaccination, Provenge, sipuleucel-T, GVAX, DVAC, and poxvirus vector vaccine(s), the substance name sipuleucel-T, and title words PCa, prostatic cancer, prostate carcinoma(s), and prostatic carcinoma(s).

Results were limited to randomised controlled trials. Only articles publishing data on humans were considered. The literature selection process is presented in Figure 1. Randomised phase 2 and 3 studies on PCa vaccines were assessed that included at least 20 patients and that reported on at least one of the following factors: overall survival (OS), cancer-specific survival, recurrence- or relapse-free survival, progression-free survival (PFS) or time to progression (TTP), prostate-specific antigen (PSA) response, toxicity, and immunologic effects on intervention or quality of life. No meta-analyses were identified. Abstracts were not included, with the exception of two American Society of Clinical Oncology abstracts from 2009 regarding the two large GVAX phase 3 studies that were terminated prematurely and were not published. Recent review papers were taken into account. Subsequent references were identified from the reference lists of retrieved articles. 2.1.

Description of clinical studies

The final list includes 16 randomised studies (3 randomised phase 3 studies and 10 randomised phase 2 studies; 3 studies were not eligible) and two notes on one randomised phase 2 study. The number of patients randomised in these peer-reviewed studies was 1342 in total. In four trials the comparative arm was control, and in four trials it was a vaccine. Other comparative arms in one trial each were nilutamide, radiotherapy, vaccine plus docetaxel, and standard-dose estramustine phosphate. The definition of CRPC was reasonably similar for all trials and was generally defined as men with advanced PCa who had failed standard hormone therapy. However, there were differences in definitions of study population because inclusion criteria in some trials were consensus PSA measurements or PSA plus a new lesion on bone scan or progression of disease as demonstrated by computed tomography (CT) scan. Six trials stated that the included patients had mCRPC, two trials had patients with CRPC, and one specified patients with nonmetastatic CRPC. The disease stage of the populations in the other trials varied: One study had subjects with advanced PCa, one had patients with PSA progression and PSA doubling time <10 mo, and one had patients with clinically localised PCa. It was not possible to accurately define the frequency of bone metastases, with the exception of the three phase

292

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[(Fig._1)TD$IG]

Medline (n=97) Embase (n=173) Cochrane (n=38)

Records after duplicates removed (n=218)

Records excluded based on screening of the abstracts

Randomised studies (n=16) Full text articles excluded due to: - study not on vaccine treatment (n=1) - one study 2 publications (n=1) - study with less than 20 patients (n=1)

Randomised phase ll vaccine therapy studies (n=10)

Randomised phase lll vaccine therapy studies (n=3) Fig. 1 – Literature selection process.

3 studies using sipuleucel-T and the double-blind phase 2 PROSTVAC-VF study, because not all trials categorised these data. 3.

Evidence synthesis

3.1.

Cancer immunology

A recent review paper by Cha and Fong nicely summarises the sequence of an adaptive immune response. First, antigen-presenting cells (APCs) are activated in the presence of a target antigen. Next, the antigen is presented in an organised way to T cells. Then the activated T cells target the antigen, and finally, T-cell response is downregulated. The goal of cancer vaccines is to promote this effector response against cancerous cells [3]. The immature APCs have the capability to take up any protein, and thus targeted antigens, derived from tumour cells and process it into small peptides. Mature and activated APCs present those peptides in their major histocompatibility complex (MHC) class II and class I

molecules, along with costimulatory molecules (B7 ligands), to CD4 and CD8+ T cells, respectively. APC maturation and activation can be enhanced by certain cytokines, such as granulocyte macrophage–colonystimulating factor (GM-CSF), and by stimulation of Tolllike receptors [3]. CD4+ cells are required for full CD8+ activation. Once fully activated, CD8+ cytotoxic T lymphocytes (CTLs) can travel through the body and efficiently destroy tumour cells when their targets are recognised. T-cell activation also turns on inhibitory pathways. These are innate immune checkpoints that are important in winding down immune responses after infections. In the presence of malignancy, however, these inhibitory pathways can abort antitumour responses. The CTL-associated receptor 4 (CTLA4) and programmed death 1 (PD-1) receptors on the surface of T cells are examples of coreceptors that negatively regulate T-cell responses [3]. Tumour cells themselves can evade the immune system by impeding the maturation of dendritic cells (DCs) or preventing the expression of costimulatory molecules

EUROPEAN UROLOGY 61 (2012) 290–306

necessary for T-cell activation. Furthermore, the ligands for PD-1 are often expressed by tumours, initiating innate immune checkpoint mechanisms and causing inhibition of immune responses [3]. These phenomena are generally fitted under the term tumour-induced immune tolerance. 3.2.

Cancer vaccines

Identification of human tumour antigens, recent insights into antigen presentation, and elucidation of the various interacting effector arms of the immune system have renewed interest in the development of cancer vaccines. Vaccines may consist of whole-tumour-cell vaccines, which contain multiple common or unique tumour antigens, or genetically modified tumour cells engineered to express tumour antigen proteins either alone or in combination with immunomodulatory molecules; tumour lysates; tumour antigens, as either proteins or peptides; or DNA-based vaccines containing genes or minigenes encoding for tumour antigens. Because optimal presentation of tumour antigens may depend on provision of appropriate costimulatory signals, it may be advantageous to administer APCs (ie, DCs) pulsed with tumour antigen protein or peptides to cancer patients. 3.2.1.

Dendritic cell preparation

DCs can be routinely prepared ex vivo from peripheral blood leukapheresis samples or buffy coats from CD34+ progenitor cells or CD14+ monocytes or can be isolated immediately from blood directly or following mobilisation with cytokines. After culturing with cytokines, DCs can be manipulated in vitro (eg, loaded with either tumour proteins or tumour peptides, transfected with tumour RNA) before administration to the patient. Various types of DCs have been used in clinical trials with major differences in batch preparation and quantity and quality of bona fide DCs. Immature and mature DC have been used, but immature DCs may have detrimental effects, as they may induce tolerance [4]. In vivo, DCs may acquire tumour antigens from free tumour antigens or apoptotic/dying tumour cells, and this may result in enhanced immune response against live tumour cells. 3.2.2.

Vaccines preferentially used with minimal tumour burden

Animal studies and human trials of various vaccine types indicate that active immunisation against a patient’s preexisting tumour is likely to be effective only when the tumour load is small. Patients who are at high risk of developing metastases but who still have minimal residual disease should be selected for vaccination strategies. 3.2.3.

Immunologic monitoring of vaccine strategies

Immunologic monitoring of cancer patients will be critical for understanding the nature of the immune responses to vaccination. Sophisticated monitoring of immune cells after administration to follow their migration in the body to lymph nodes and possibly to cancer sites has been limited up to now.

293

Traditional cytotoxic therapy can usually be understood in the context of pharmacokinetics of the drug, with tumour regression and response rates as surrogate markers for clinical outcome. This understanding led to the generally accepted concept that response rate is an acceptable end point in clinical trials and a valid alternative to OS. With the introduction of targeted agents in oncology, this concept has started to change, and TTP and OS have regained importance. Biological effects of vaccine approaches are not related to their pharmacokinetics, and immune response may require several repeated stimulations, whereas effectiveness may take months or years to become apparent. Effectiveness, as measured by tumour regression at traditional early time points, may fail to demonstrate any measurable potentially beneficial effect. Because immunotherapy may result in a transient increase of the tumour volume, OS is probably the best outcome measure. In addition, standardised immune monitoring assays are critically needed to adequately measure immune responses. Careful monitoring of the effect of the vaccination strategy on the tumour during and after treatment is important and requires the development of new, noninvasive diagnostic tests (eg, based on imaging or biomarkers). Currently, fine-needle biopsies are more frequently thought to precisely monitor changes induced by treatment at the site of the tumour deposits. 3.2.4.

The prostate is a favourable target for vaccination

The prostate is an attractive target for therapeutic cancer vaccines due to its slow growth [5], which could allow the stimulated immune system sufficient time for induction of an effective antitumour immune response to vaccination. Multiple prostate-specific proteins have already been identified to provide potential tumour antigen targets for antigen-specific vaccines [6,7]. Because the prostate is a nonessential organ, there is less concern about sparing normal prostate tissue following the production of tissuespecific immune responses targeting these antigens. PCa vaccines are potentially less toxic than traditional chemotherapy. 3.2.5.

Potential targets for vaccination strategies in prostate cancer:

tumour-associated antigens

Several potentially interesting tumour-associated antigens have been identified as immunologic targets for T cells and are described in a 2008 issue of European Urology [8]. In addition, other prostate antigens such as new gene expressed in prostate [9,10] and T cell receptor gamma alternate reading frame protein have been identified and are currently being investigated as potential targets of PCa vaccines [11,12]. PCa vaccines can be broadly classified as antigenspecific vaccines, viral vector-based vaccines, DNA vaccines, peptide-based vaccines, and antigen-nonspecific vaccines including whole cell–based vaccines. Randomised phase 2 and 3 clinical studies of PCa vaccines are presented in Table 1–4.

294

Table 1 – Randomised phase 3 clinical studies of prostate cancer vaccines PCa vaccine

Sipuleucel-T

Study design/patient characteristics Double-blind RCT (D9901) FU: 36 mo Asymptomatic, chemotherapy-naı¨ve mCRPC Sipuleucel-T arm, control arm

Survival/TTP

PSA response

127

Primary end point: TTP  Not met 11.7 vs 10 wk ( p = 0.06)  Gleason 7: 16.1 vs 9.1 wk ( p = 0.001) Secondary end point: Time to onset of disease-related pain; higher for APC8015 patients Median interim survival: Gleason 7: 30.7 vs 22.3 mo Gleason 8: no benefit

Not reported

Primary end point: TTP not met 11.7 vs 10 wk ( p = 0.052) Secondary end point: OS Median OS: 25.9 vs 21.4 mo (HR:1.70; 95% CI, 1.13–2.56; p = 0.01) OS advantage: 4.5 mo Extended 3-yr OS: 34% vs 11%

Not reported

Sipuleucel-T arms: PSA response rate: 4.8% 50% decrease in PSA: 3.4% 25% decrease in PSA: 1.4% Control arms: 25% decrease in PSA: 0/78 patients 50% decrease in PSA: 8/311 (2.6%) vs 2/153 (1.3%).

Immunologic response

Safety/QOL

Reference

Increased T cell response:  8-fold higher in APC8015 patients vs control-treated patients (16.9 vs 1.99, p = 0.0004)  7-fold higher in APC8015-treated patients when Gleason 7 compared with Gleason 8 (49.6 vs 7.26, p = 0.0065) Increased T-cell stimulation index: 8-fold higher in sipuleucel-T vs control-treated patients (16.91 vs 1.99, p < 0.001)

Well tolerated (grade 1–2) Most common AE: chills No withdrawals because of AE

Schelham-mer and Hershberg, 2005 [48]*

Small et al, 2006 [16]*

Not evaluated

Well tolerated: Rigors (59.8% vs 8.9%), pyrexia (29.3% vs 2.2%), tremor (9.8% vs 0%), feeling cold (8.5% vs 0%) Grade 1–2 AEs Grade 3–4: 24.4% vs 24.4% No withdrawals because of AE Most common AEs: chills, pyrexia, headache, asthenia, dyspnea, vomiting, tremor Grade 1–2 AEs (1–2 d) Grade 3–4, SAE: no significant difference Significantly different CVEs: 7.5% vs 2.6%

T-cell proliferation responses (stimulation index, >5) To PA2024: 73% vs 12.1% To PAP: 27.3% vs 8.0% Antibody titers (ELISA) >400 Against PA2024: 66.2% vs 2.9% Against PAP: 28.5% vs 1.4%

Within 1 d after infusion Grade 1–2: chills, fever, fatigue, nausea, and headache Grade 3: 6.8% vs 1.8% One grade 4: IV catheterassociated bacteraemia CVEs: 2.4% vs1.8%

Kantoff et al, 2010 [18]

Sipuleucel-T

Double-blind RCT (D9901 + D9902A) FU: 36 mo Integrated analysis Asymptomatic, chemotherapy-naı¨ve mCRPC Sipuleucel-T arms, control arms

225

Primary end point: TTP not met 11.1 vs 9.7 wk (P = 0.111) Secondary end point: OS Median OS: 23.2 vs 18.9 mo (HR: 1.50; 95% CI, 1.10–2.05; p = 0.011) OS advantage: 4.3 mo

Sipuleucel-T

Double-blind RCT (IMPACT, D9902B) Median FU: 34.1 mo Asymptomatic or minimally symptomatic chemotherapy-naı¨ve mCRPC Sipuleucel-T arm, control arm

512

Primary end point: OS Median OS: 25.8 vs 21.7 mo (HR: 0.78; 95% CI, 0.62–0.98; p = 0.032) OS advantage: 4.1 mo Extended 3-yr survival rate: 31.7% vs 23%

Prostate GVAX

Open-label randomised study (VITAL-1) Asymptomatic, chemotherapy-naı¨ve mCRPC GVAX arm, docetaxel/prednisone arm Open-label randomised study (VITAL-2) Symptomatic, chemotherapy-naı¨ve mCRPC GVAX + docetaxel arm, docetaxel/prednisone arm

626

Median OS: 20.7 vs 21.7 mo ( p = 0.78) Study closed based on futility analysis for efficacy

Higano et al, 2009 [33]

408

Median OS: 12.2 vs 14.1 mo ( p = 0.0076) Study closed due to imbalance in deaths (67 vs 47)

Small, 2009 [34]

Prostate GVAX

Higano et al, 2009 [17]

AE = adverse event; CI = confidence interval; CVE = cerebrovascular event; ELISA = enzyme-linked immunosorbent assay; FU = follow-up; HR = hazard ratio; IV = intravenous; mCRPC = metastatic castration resistant prostate cancer; OS = overall survival; PCa = prostate cancer; PSA = prostate-specific antigen; QOL = quality of life; RCT = randomised controlled trial; SAE = serious adverse event; TTP = time to progression. *Same study.

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No. of patients

Table 2 – Randomised phase 2 clinical studies of prostate cancer vaccines PCa vaccine

Prime/boost vaccine strategy using vaccinia virus and fowl pox virus expressing human PSA PROSTVAC-VF

MVA-MUC1-IL2 vaccine (TG4010)

Randomised ECOG study Median FU: 19.1 mo Patients with advanced PCa Group 1: 4 rF-PSA Group 2: 3 rF-PSA + 1 rV-PSA Group 3: 1 rV-PSA + 3 rF-PSA Double-blind RCT Median FU: 41.3 mo Minimally symptomatic mCRPC (Gleason score 7) PROSTVAC-VF arm, control arm

Randomised study Median FU: 44.6 mo Chemotherapy-naı¨ve mCRPC Four cohorts concerning immune adjuvants

Randomised study to test 2 dosing schedules (weekly for 6 wk + every 3 wk; every 3 wk) Duration: 9 mo Men with PSA progression with PSA DT <10 mo

No. of patients 64

125

32

40

Survival/TTP

PSA response

No objective PSA responses

Primary end point: PFS not met Estimated median PFS: 3.8 vs 3.7 mo (P = 0.6) Secondary end point: OS Median OS: 25.1 vs 16.6 mo (HR: 0.56; 95% CI, 0.37–0.85; p = 0.0061); OS advantage: 8.5 mo Extended 3-yr OS: 30% vs 17%

PSA responses were infrequent

Secondary end point: OS Median OS: 26.6 mo (predicted median OS by Halabi nomogram: 17.4 mo) Patients with Halabi-predicted survival:  <18 mo (median predicted 12.3 mo); actual median OS of 14.6 mo  18 mo (median predicted survival 20.9 mo); 37.3 mo, with 12/15 patients living longer than predicted ( p = 0.035) Trend ( p = 0.055) toward enhanced survival in patients with 6-fold increase in PSA-specific T-cell responses No difference in survival in patients receiving GM-CSF vs no GM-CSF

Decrease in PSA in 12/32 patients (37.5%) 30% decrease in PSA in 5 patients Decreases in index lesions in 2/12 patients

Median TTP: 148 d

Primary end point: 50% decrease in PSA: not met Secondary end point: PSA DT 2-fold prolongation of PSA DT in 13/40 patients (32.5%) PSA stabilisation for 8 mo in 10 patients

One PROSTVAC-treated patient had a PSA decline of >80%

Safety

Ref

Increase in PSA-specific T-cells in 14/30 (46%) patients (more in patients using rV-PSA but no difference between groups 2 and 3) No detectable antibody titers to PSA (ELISA) T-cell responses not evaluated

Injection site reaction and hyperglycemia Grade 1–2 AEs Two grade 3 hyperglycemia (not vaccine related) Grade 1–2: injection site reactions, fatigue, fevers, and nausea One grade 3: injection site cellulitis Two patients discontinued vaccine because of AEs SAEs in 1 patient associated with thrombotic thrombocytopenic purpura and myocardial infarction Not evaluated

Kaufman et al, 2004 [19]

No detectable antibody titers to PSA (ELISA) No correlation between antivector antibody responses with OS

Primary end point Immune response (ELISPOT assay) 2-fold increase in PSA-specific T-cell responses in 13/29 patients (44.8%) No difference in T-cell responses in patients receiving GM-CSF vs no GM-CSF Treg suppressive function: Decreased in 10/13 patients (77%) surviving longer than predicted Increased in 6/8 patients (75%) surviving less than predicted No detectable antibody titers to PSA (ELISA) No difference in antibody titers to fowl pox between patients with Halabi-predicted survival of 18 or <18 mo MUCI-specific ELISPOT response in 7 patients Arm A: 5 patients Arm B: 2 patients

Kantoff et al, 2010 [21]

Gulley et al, 2010 [22]

Well tolerated Dreicer et al, Grade 1–2 AEs 2009 [23] Local injection site reactions, fatigue and flulike syndrome One grade 3 hypertension, possibly vaccine related

295

PSA PFS in 26/64 (45.3%) patients Medium TTP: 13.6 mo Clinical PFS in 50/64 (78.1%) patients

Immunologic response

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PROSTVAC-VF

Study design/patient characteristics

296

AE = adverse event; CI = confidence interval; CRPC = castration-resistant prostate cancer; ECOG = Eastern Cooperative Oncology Group; ELISA = enzyme-linked immunosorbent assay; ELISPOT = enzyme-linked immunosorbent spot; FU = follow-up; GM-CSF = granulocyte-macrophage colony-stimulating factor; HR = hazard ratio; IgG = immunoglobulin G; mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; PCa = prostate cancer; PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time; PFS = progression-free survival; rF-PSA = prostate-specific antigen recombinant fowlpox vectors; rV-PSA = prostate-specific antigen vaccinia vectors; SAE = serious adverse event; Treg = regulatory T cell; TTP = time to progression.

Eaton et al, Well tolerated No withdrawals because of 2002 [35] AE Only flu-like symptoms Changing cytokine levels Increase in specific antibodies (IgG) T-cell proliferation to vaccinations in 19 patients (stimulation index) No sustained PSA decrease attributed solely to the vaccine Transient PSA response in the absence of cotreatment in 3 patients Not evaluated 60 Open phase 1/2 pilot study Patients with CRPC, 4 equal groups receiving different combination of four cell lines Allogeneic whole-cell vaccine

PCa vaccine

Table 2 (Continued )

Study design/patient characteristics

No. of patients

Survival/TTP

PSA response

Immunologic response

Safety

Ref

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3.3.

Antigen-specific vaccines

In antigen-specific vaccines, a tumour-associated antigen is directly targeted, either by loading that antigen onto APCs ex vivo or by incorporating the antigen into a vaccine vector at a protein or DNA level. 3.4.

Sipuleucel-T

Sipuleucel-T (APC8015, Provenge; Dendreon Corp., Seattle, WA, USA) is an autologous active cellular immunotherapy product designed to stimulate an immune response against human prostatic acid phosphatase (PAP), an antigen highly expressed in PCa tissue. Sipuleucel-T consists of peripheral blood mononuclear cells (PBMCs), including APCs, that have been loaded and activated in vitro with a recombinant fusion protein, PA2024, containing the target antigen PAP linked to granulocyte macrophage–colony-stimulating factor (GM-CSF). APCs should take up the recombinant target antigen PAPGM-CSF and process that into small peptides that are presented on the surface of the APC. PAP-GM-CSF–loaded APCs were considered the active component of sipuleucel-T and presumably bind in vivo T cells, which recognise the target antigen peptides on the APC surface, eliciting a response characterised by their proliferation. Activation of T cells could lead to improved recognition and destruction of PCa cells in vivo, but to date, the precise mechanism of action of sipuleucel-T is unknown. The contribution of DCs may be less important than a more general stimulation of the immune system by this PAP-GM-CSF–stimulated cell product because the initial leukapheresis products contain few DCs, and loading with PAP-GM-CSF protein may not suffice to generate a sufficient number of fully matured DCs [13]. Thus sipuleucel-T may be better classified as vaccine than as a DC product. Presumably, it stimulates the patient’s immune system via hitherto unknown mechanisms, resulting in a boost of antitumour immunity demonstrated by immunologic monitoring of patients’ immune cells prior to and following administration of the three autologous cell products. Product potency is measured in part by APC expression of CD54. Data have demonstrated that CD54 upregulation correlates with APC activation [14]. Each of the three doses of sipuleucel-T, administered at 2-wk intervals, contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF. Each dose is preceded by the leukapheresis procedure approximately 3 d prior to the scheduled treatment [15]. An advantage of this vaccine is its good tolerability and observed survival benefit. A disadvantage is that it is an individualised therapy; therefore, production can be time consuming and costly. No randomised phase 2 studies of sipuleucel-T have been identified. 3.4.1.

Randomised phase 3 studies

3.4.1.1. Methodology. Data to support the efficacy of sipuleucel-

T for the treatment of mCRPC were provided from three randomised, double-blind, controlled, multicentre phase 3 studies (D9901, D9902A, and D9902B) that enrolled a total of

Table 3 – Randomised phase 2 studies of poxviral vector–based vaccines combined with traditional therapies PCa vaccine

Recombinant vaccinia viruses containing the PSA and B7.1 costimulatory genes as prime vaccinations, and avipox-PSA as boosters

No. of patients

Survival/TTP

PSA response

Immunologic response

Randomised study comparing vaccine with nilutamide in men with nonmetastatic CRPC: crossover allowed Median duration: 15.9 mo

42

Median time to treatment failure: Vaccine arm: 9.9 mo HT arm: 7.6 mo HT + vaccine arm: 5.2 mo (after crossover in 8 patients) with median duration study entry of 15.5 mo Vaccine + HT arm: 13.9 mo (after crossover in 12 patients) with a median duration to study entry of 25.9 mo

Immune response (ELISPOT assay) HT arm: no induction of PSA-specific T-cells Vaccine arm: 2-fold increase in PSA-specific T cells after 3 monthly vaccinations in 4/8 patients No detectable antibody titers to PSA

Well tolerated Grade 1–2 AEs No patients discontinued study secondary to vaccine related toxicity

Arlen et al, 2005 [24]

30

Not evaluated

HT arm: Decrease in PSA that sustained 4.6 mo in 16/21 patients (76.2%) Vaccine arm: Decrease or stabilisation of PSA during first 6 mo and sustained 1 mo in >50% of patients Decrease in PSA between 25% and 50% in 5 patients, >75% in 1 pt Median PSA (ng/ml): At diagnosis, on study Vaccine + RT arm: 14.15–8.00 RT arm: 9.86–4.53

Well tolerated (grade2: injection-site reactions) with virtually all the toxicity related to IL-2

Gulley et al, 2005 [26]

28

Median TTP Vaccine alone arm: 1.8 mo (increasing serum PSA levels in 64.3% of patients) Docetaxel + vaccine arm: 3.2 mo (57.1% of patients progressed radiographically) Docetaxel (crossover from vaccine alone at time of progression) in 11 patients: 6.1 mo Docetaxel (historically): 3.7 mo

Serum PSA declines Vaccine alone arm: 3/14 patients (21.4%) None of these declines >50% Docetaxel + vaccine arm: 6/14 patients (42.9%) and 3 patients decline >75% Docetaxel alone, postvaccine: 9 /11 patients (81.8%) and 5 patients decline >50%, with 2 of these patients declining >75%

Immune response (ELISPOT assay) Vaccine + RT arm: 3-fold increases in PSA-specific T cells in 13/17 patients (76.5%) ( p < 0.0005) RT arm: no detectable increases No detectable antibody titers to PSA Denovo generation of T cells to welldescribed TAA not in the vaccine, providing indirect evidence of immune-mediated tumour killing Immune response (ELISPOT assay) Primary end point: effect of docetaxel on immune response Both arms: 3.33-fold increase in PSA-specific T-cell precursors following 3 mo of therapy (equal immune response) Immune response to other TAA not found in vaccine in 3 patients (epitope spreading and/or antigen cascade) No detectable antibody titers to PSA

Well tolerated with only grade 1–2 vaccine-related toxicity

Arlen et al, 2006 [25]

Increased OS: Vaccine vs HT: 5.1 vs 3.4 yrs ( p = 0.13) 3-yr survival: 81% vs 62% Vaccine + HT vs HT + vaccine 6.2 vs 3.7 yrs ( p = 0.045) in small cohort of patients (crossover) 3-yr survival: 100% vs 75% Longer survival with vaccine vs HT if at baseline patients had Gleason <7, PSA<20 ng/dl, and/or prior RT

Not evaluated

Immune response (ELISPOT assay)

Vaccine arm, nilutamide arm

Poxviral vaccine encoding PSA (rV-PSA + rV-B7.1 followed by monthly booster vaccines with recombinant fowl pox PSA)

Randomised study

Docetaxel (with dexamethasone) + vaccine vs vaccine alone (crossover allowed)

Randomised study

Vaccination regimen: rV-PSA admixed with rV-B7.1, and sequential booster vaccinations with rF-PSA + GM-CSF with each vaccination

Vaccine + weekly docetaxel arm, vaccine alone arm

Poxvirus-based PSA vaccine

Randomised study comparing vaccine with nilutamide in men with nonmetastatic CRPC (crossover allowed)

Clinically localised PCa Vaccine + RT arm, RT arm

Men with metastatic androgen-independent PCa

Median FU: 4.4 yr Vaccine arm, nilutamide arm

42

Safety

Docetaxel + vaccine arm: 2 patients with grade 3 lymphopenia, with 1 of them having arthralgias, hyperglycemia, and infection without neutropenia Dexamethasone comedication: responsible for lymphopenia and hyperglycemia and possibly contributed to the infection Not evaluated

Ref

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Study design/patient characteristics

Madan et al, 2008 [27]

Vaccine arm: 2-fold increase in PSA-specific T cells after 3 monthly vaccinations in 4/8 patients HT arm: no induction

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AE = adverse event; CRPC = castration-resistant prostate cancer; ELISPOT = enzyme-linked immunosorbent spot; FU = follow-up; HT = hormone therapy; IL-2 = interleukin 2; PCa = prostate cancer; PSA = prostate-specific antigen; OS = overall survival; RT = radiation therapy; TTP = time to progression.

298

PPV + low-dose EMP arm, standard-dose EMP arm

AE = adverse event; CRPC = castration-resistant prostate cancer; EMP = estramustine phosphate; FU = follow-up; IgG = immunoglobulin G; OS = overall survival; PCa = prostate cancer; PFS = progression-free survival; PSA = prostate specific antigen; TTP = time to progression.

Noguchi et al, 2010 [32] Well tolerated Grade 1–2 AEs (injection-site reactions) Grade 3 (21% vs 41%) PPV + low-dose EMP arm:  Increased levels of IgG and cytotoxic T-cell responses (in 52% and 29% of patients in first and second treatment)  No correlation between clinical outcome and immunologic responses 50% decrease in PSA 6/28 (21%) vs 6/29 (20%) <50% decreased or <25% increase in PSA (stable disease) 15/28 (54%) vs 8/29 (28%) Unlikely that vaccinated peptides have impact on measurement of PSA Randomised, open-label, crossover study Median FU: 11.7 mo HLA-A2 or A24-positive patients with CRPC Personalised peptide vaccine

57

Primary end point: PFS  First treatment: median PFS: 8.5 vs 2.8 mo (HR 0.28; 95% CI, 0.14–0.61; p = 0.0012)  Second treatment: after crossover, no significant difference in median PFS Median OS: Undefined, 16.1 mo (HR: 0.3; 95% CI, 0.1–0.91; p = 0.0328)

Ref Safety Immunologic response PSA response Survival/TTP No. of patients Study design/patient characteristics PCa vaccine

Table 4 – Randomised phase 2 studies of peptide-based vaccines combined with traditional therapies

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737 patients (Table 1). Controls were prepared by culturing APCs from one-third of the leukapheresis cells kept in medium for 36–44 h at 2–8 8C, without being pulsed with PA2024. Two studies (D9901 [16] and D9902A [17]) enrolled a combined total of 225 patients with asymptomatic mCRPC. One study, called Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT; D9902B), enrolled 512 patients with asymptomatic or minimally symptomatic chemotherapy-naı¨ve mCRPC [18]. The IMPACT trial is the study that led to FDA approval (April 2010). The age range of patients in these studies was 47–91 yr, with a median age of 69 yr. Follow-up time was up to 36 mo in two of the phase 3 studies (D9901 [16] and D9902A [17]). Median follow-up in the IMPACT study was 34.1 mo [18]. Most patients in these studies had Gleason score 7. In the integrated analysis of D9901 [16] and D9902A [17], 64.4% of the sipuleucel-T patients versus 53.8% in the control group had Gleason score 7. In the IMPACT study, the percentage was 75.4% in both groups. The percentage of patients with >10 bone metastases at baseline in the sipuleucel-T group versus the control group was 41.5% versus 26.7%, respectively, in the D9901 study; 50.8% versus 37.5%, respectively, in the D9902A study; and 40.2% versus 26.7%, respectively, in the IMPACT study. T-cell proliferation in these studies was assessed with the use of a stimulation index as a measure of CD4+ T-cell proliferative responses [16], and antibody titers were assessed by means of a standard enzyme-linked immunosorbent assay (ELISA). 3.4.1.2. Results. 3.4.1.2.1. Clinical efficacy. The D9901 study failed to show a statistically significant improvement in TTP, the primary end point [16]. However, sipuleucel-T provided a median survival benefit of 4.5 mo and extended 3-yr survival (34% vs 11% for control) [16]. An identical second phase 3 study (D9902A) was completed but has not yet been published. An integrated analysis of these two small studies (n = 225) demonstrated a median survival benefit of 4.3 mo. Patients randomised to sipuleucel-T demonstrated a 33% reduction in the risk of death [17]. The primary end point in IMPACT (D9902B), the largest phase 3 study, was OS. The median survival benefit was 4.1 mo for patients treated with sipuleucel-T compared to control. The 3-yr survival probability also improved significantly (31.7% vs 23.0% for control). A major concern regarding the observed improvement in OS was that the survival difference between the two groups might be attributable to differences in post-treatment use of docetaxel. However, the treatment effect remained consistent after adjustment for docetaxel use following vaccine therapy [18]. After censoring at the time of docetaxel initiation, a consistent treatment effect with sipuleucel-T was observed (hazard ratio [HR]: 0.65; 95% confidence interval [CI], 0.47–0.90; p = 0.009). HRs for the risk of death according to baseline characteristics of the patients in the sipuleucel-T group and the control group were performed, and subgroup analyses for 19 prespecified variables (including 1 variable, bone or soft-tissue disease, that was split into two analyses) were performed. In addition, three post hoc analyses

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(castration or combined androgen blockade, previous orchiectomy, and average pain score) were performed. 3.4.1.2.2. Prostate-specific antigen response rates. PSA response rates are summarised in Table 1. Small et al. mention that PSA response rate may be underestimated because PSA was collected only at baseline, at week 16, and then every 16 weeks thereafter until disease progression, and only 26% of patients had two or more PSA values at least 4 wk apart [17]. 3.4.1.2.3. Immune response. In the IMPACT study, a total of 237 patients treated with either sipuleucel-T (n = 160) or control (n = 77) were evaluated for some immune response. T-cell proliferation responses to the immunising antigen PA2024 (stimulation index: >5) were reported in the sipuleucel-T group and the control group (73% vs 12.1%). The same study reported T-cell proliferation responses to the antigen PAP (27.3% vs 8.0%). There was no association between T-cell proliferation responses and survival [18]. 3.4.1.2.4. Side effects and toxicity. The vaccine was well tolerated, and most adverse events (AEs) were mild or moderate in severity. AEs are summarised in Table 1. 3.5.

Recombinant viral vector-based vaccines containing DNA

encoding prostate-specific antigen or mucin 1

Another immunologic approach to CRPC involves the use of poxviral-based vectors. A small randomised phase 2 study conducted by the Eastern Cooperative Oncology Group (ECOG) demonstrated that use of vaccinia vectors followed by booster vaccinations with PSA recombinant fowlpox vectors was associated with a better immune response and improvement in PFS [19]. In an effort to further enhance the immune response, a triad of costimulatory molecules including intercellular adhesion molecule 1 (ICAM-1 or CD54, a cell surface adhesion molecule which plays a prominent role in regulating the migration and activation of both DCs and T lymphocytes in the immune system), B7-1, and leukocyte function-associated antigen 3 was added to the poxviral system [20]. PROSTVAC-VF is an off-the-shelf vaccine that does not require complex individualised therapy and can be manufactured and reproduced easily. No randomised phase 3 studies were identified. In the randomised, double-blind, phase 2 PROSTVAC-VF study, subcutaneously administered vaccinia-based vector was used for priming on day 1 followed by fowlpox-based vector boosts. Patients received GM-CSF subcutaneously near the vaccination site. Controls received empty vectors plus saline injections [21]. 3.5.1.

Randomised phase 2 studies

3.5.1.1. Methodology. In total, seven randomised phase 2

studies with poxvirus vector-based vaccines [19,21–27] (Table 2) were identified, of which three studies [24–27] examined these vaccines combined with another therapy (Table 3). In these studies, disease stage of the populations varied. These studies enrolled patients with a variety of Gleason scores, except the double-blind randomised controlled trial by Kantoff et al, which included only patients with Gleason score 7 [21]. In this study, 31.7% of patients in the PROSTVAC-VF group and 39% in the control

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group had >10 bone metastases at baseline. Most studies used enzyme-linked immunosorbent spot (ELISPOT) to monitor immune responses for PSA-specific T cells. Antibody titers against PSA were tested by an ELISA. 3.5.1.2. Results. 3.5.1.2.1. Clinical efficacy. PFS was evaluated in two of seven randomised phase 2 studies examining poxviral vectorbased vaccines [19,21]. The results of the ECOG study are summarised in Table 2. A recently published, randomised, controlled, double-blind, phase 2 study of PROSTVAC-VF including 125 patients with chemotherapy-naı¨ve minimally symptomatic mCRPC and Gleason score 7 shows promising results [21]. Like sipuleucel-T, PROSTVAC-VF did not show a significant effect on TTP, the primary end point of the study (3.8 vs 3.7 mo; p = 0.6). However, PROSTVAC-VF patients experienced a median survival benefit of 8.5 mo (25.1 mo vs 16.6 mo for control; HR: 0.56; 95% CI, 0.37–0.85; p = 0.0061) and extended 3-yr survival (30% vs 17%) [21]. Another recently published randomised phase 2 study including 32 chemotherapy-naı¨ve mCRPC patients and using the identical vaccine reported a median OS of 26.6 mo (predicted median OS by the Halabi nomogram was 17.4 mo). The Halabi nomogram was used to stratify mCRPC patients into those with predicted survival duration greater or less than the median at the time of enrolment [22]. The study suggests that patients with more indolent mCRPC (Halabi-predicted survival 18 mo) may have a more favourable response to vaccine therapy with PROSTVACVF, in that their observed survival was significantly longer than predicted. In total, 44% and 56% of patients had Gleason score 7 and 8–10, respectively. Patients with a 6-fold increase in PSA-specific T-cell responses showed a trend ( p = 0.055) towards enhanced survival [20]. A larger, randomised, multicentre, phase 3 confirmatory trial is planned, and studies combining PROSTVAC-VF with standard therapies are in development. Increased OS seen with poxviral-based PSA vaccine therapy in other studies should be interpreted cautiously because results are based on retrospectively determined small cohorts [24,27]. 3.5.1.2.2. Prostate-specific antigen response rates. PSA responses were infrequent in the double-blind study by Kantoff et al. [18] and were not reported in the study by Kaufman et al. [19]. The PSA response rates in other studies evaluating recombinant viral vector–based vaccines are presented in Table 2 and 3 [22–25]. 3.5.1.2.3. Immune response. No detectable antibody titers to PSA were seen in the poxviral vector–based vaccine studies. An increase in vaccine-specific T cells was reported in all studies, with the exception of the double-blind PROSTVACVF study [21], which did not evaluate PSA-specific T-cell responses. One study showed that docetaxel can be administered safely with immunotherapy without inhibiting vaccine-specific T-cell responses [25]. 3.5.1.2.4. Side effects and toxicity. Common AEs of PROSTVAC-VF observed in the double-blind study [21] were injection-site reactions, with only a subset of patients experiencing associated systemic AEs such as fatigue, fever, chills, and nausea. AEs were mainly mild or moderate in

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severity. Two patients discontinued because of treatmentrelated AEs, including one patient who developed serious AEs associated with thrombotic thrombocytopenic purpura and myocardial infarction reported as possibly related to the treatment [21]. Thrombotic thrombocytopenic purpura has not been reported in association with vaccinia immunisation [28]. AEs in the other poxviral vector–based studies are summarised in Table 2 and 3. 3.6.

DNA-based vaccines

No randomised studies using naked DNA or other forms of DNA vaccines could be identified [29]. A recent phase 1/2a study has demonstrated the safety and immunologic efficacy of a DNA vaccine encoding PAP in 22 patients with biochemically recurrent PCa [30]. 3.7.

Peptide-based vaccines

Because of the ubiquitous expression of prostate-specific membrane antigen (PSMA) and PSA in PCa, different peptides can be derived from these proteins. An advantage of peptide-based vaccines is the relatively low cost and simplicity of manufacturing. A disadvantage is the requirement of a specific human leukocyte antigen (HLA) allele to be recognised by patient T lymphocytes, thus restricting the number of patients that can be enrolled in a trial [31]. This issue can be circumvented by using overlapping peptides harbouring multiple class I (and potentially class II) binding CTL epitopes. 3.7.1.

Randomised phase 2 studies

3.7.1.1. Methodology. Only one randomised phase 2 peptide-

based vaccine study for PCa was identified (Table 4) [32]. This was an open-label, multicentre, crossover study that evaluated the antitumour effect and safety of a personalised peptide vaccine plus low-dose estramustine phosphate (EMP) versus standard-dose EMP in 57 HLA-A2–positive or HLA-A24–positive patients. The peptides in the vaccine were derived from tumour antigen targets, including PSA, PAP, PSMA, multidrug-resistance protein, and other epithelial tumour antigens. Patients needed to be immunoglobulin G reactive to at least one of the peptide candidates [32], and each patient was immunised with four peptides on the basis of the reactivity panel. 3.7.1.2. Results. Results are summarised in Table 4. 3.8.

Antigen-nonspecific vaccines

3.8.1.

Whole-tumour-cell vaccines

Prostate cell lines established in culture from various individuals (differing in MHC tissue type) and referred to as allogeneic may provide a source of whole-cell tumour vaccines. The advantage of this whole-cell-based approach is that it can be manufactured in large quantities, reducing cost and potentially increasing the number of patients that could be treated. Two large randomised phase 3 studies of prostate GVAX have been conducted [33,34]. One

randomised phase 1/2 pilot study using another allogeneic whole-cell vaccine in men with CRPC was identified [35]. 3.8.1.1. Randomised phase 2 studies. 3.8.1.1.1. Methodology. An allogeneic whole-cell PCa vaccine consisting of three cell lines (from a bank of four) was used in a randomised phase 1/2 pilot study in conjunction with an immunostimulant, with each of the four groups receiving a different combination of the four cell lines. T-cell proliferation was assessed with the use of the stimulation index. Antibody titers against PSA were tested with a standard ELISA [35] (Table 2). 3.8.1.1.2. Results. Results are summarised in Table 2. 3.8.1.2. Randomised phase 3 studies. 3.8.1.2.1. Methodology. Prostate GVAX is a mixture of two allogeneic PCa lines (LNCaP and PC3), genetically modified through adenoviral transfer to produce GM-CSF, an immune cell activator, and then irradiated to prevent further cell division [33]. Prostate GVAX is designed to be administered through intradermal injections on an outpatient basis. In the first open-label multicentre study (VITAL1), GVAX was compared with chemotherapy (docetaxel plus prednisone) in 626 patients with asymptomatic mCRPC [33]. The second open-label multicentre study (VITAL2) was designed to compare the combination GVAX plus chemotherapy (docetaxel) with chemotherapy alone (docetaxel plus prednisone) in 408 patients with more advanced (symptomatic) mCRPC [34]. The primary end point in both trials was improvement in survival. The objective was to test the hypothesis that combination of GVAX with chemotherapy would prolong survival in these patients. Although it has been shown in animal studies that GM-CSF– secreting tumour-cell vaccines are not inhibited by docetaxel administration, no phase 2 trials were performed to confirm the results in humans or to examine dose and treatment schedule [36]. 3.8.1.2.2. Results. The VITAL1 study was terminated prematurely because of an unplanned interim analysis indicating <30% chance of achieving the primary end point (OS benefit) [33]. A planned interim analysis of the VITAL2 study was also terminated prematurely because of an excess of deaths in the docetaxel/GVAX arm compared with the docetaxel/prednisone arm (67 vs 47 deaths). OS was shorter in the docetaxel/GVAX arm, with median survival of 12.2 mo versus 14.1 mo in the docetaxel/prednisone arm (HR: 1.70; p = 0.0076). No significant toxicities in the docetaxel/GVAX arm could explain the imbalance in deaths [34]. Because improved outcomes with GVAX could not be demonstrated, the future development of GVAX remains unclear. 3.9.

Discussion

Of the randomised studies discussed in this review, only four were double-blind controlled studies (three phase 3 [16–18] and one phase 2 [21]). These studies assessed OS and safety in vaccine-treated versus control-treated patients with mCRPC. The methodologies of all other phase

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2 studies included in this review are extremely variable with respect to disease stage and vaccine therapy, alone or combined with other traditional therapies, and make comparisons difficult. Most studies in this review were conducted in patients with mCRPC [16–18,21,22,25,37]. The studies also had varied end points, and not all reported on parameters such as biochemical or immune response and safety. Survival advantage for the vaccine group in the IMPACT trial [16–18] was 4.1 mo for sipuleucel-T and generally was considered clinically meaningful in metastatic cancer patients. The trial provides high-level evidence in favour of vaccination with the stimulated leukapheresis product and raises doubts about the appropriateness of a placebo arm in future trials with similar patients. Approximately one-fifth of patients in both groups (slight imbalance) received prior chemotherapy (docetaxel in most cases) prior to entry into the study. It seems unlikely that unfavourable effects in the control group might be responsible for the treatment arm’s 4-mo survival benefit. An unfavourable effect in the control group could result from the leukapheresis procedure itself; however, this procedure is unlikely to result in the treatment group’s survival advantage. Only a small number of total circulating cells are removed by leukapheresis; all (stimulated) cells are reinfused in the treatment group, and onethird of (unstimulated) cells are reinfused in the control group. At the time of second and third phereses, blood cell counts had returned to initial prepheresis levels, precluding significant depletion of blood cells by the leukapheresis procedure itself. For decades, similar procedures have been performed in healthy subjects and in cancer patients with no demonstrable harm caused by leukapheresis. Another theoretical possibility is that reinfusion of autologous cells after cold storage could exert a shortterm immunosuppressive effect; however, a resulting unfavourable effect in the control group that could account for an apparent OS benefit of 4 mo in the treatment group seems unlikely. The careful treatment of the control cells includes extensive washing procedures prior to reinfusion to prevent reinfusion of any cellular debris, and the number of dead cells is extremely low (<5%; this procedure is not different for patients who received stimulated cells). Interestingly, the survival curves already dissociate at 6 mo and support the addition of immunologic boosting with similar PAP-GM-CSF–stimulated cellular product in future sipuleucel-T trials. At the time of demonstrable disease progression, subjects in the control arm [17,18] were unblinded and could choose to receive other anticancer interventions. Alternatively, they could enrol in an open-label, nonrandomised study (PB-01) and receive APC8015F, a stimulated autologous cell product prepared from the frozen PBMC product collected at the time of preparation for the control arm. After thawing, PBMCs were pulsed with PAP-GM-CSF and prepared in a manner similar to sipuleucel-T. APC8015F production did not involve fresh PBMCs, as in sipuleucel-T, but rather frozen and thawed cells. Of the 171 control patients, 109 received salvage treatment with PAP-GM-CSF–stimulated autologous cells,

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and these patients had slightly better survival that those control patients who did not receive the salvage treatment. Median survival time was 25.8 mo for subjects in the sipuleucel-T arm, 23.8 mo for subjects in the control arm who subsequently received APC8015F, and 11.6 mo for subjects in the control arm who did not receive APC8015F. These results might suggest a beneficial effect of salvage treatment with frozen and thawed cells and, subsequently, with PAP-GMCSF stimulated cells; however, because this analysis is based on nonrandomised groups that were likely subject to selection bias, this post hoc analysis is insufficient to support any firm conclusions. Because docetaxel therapy has a proven survival benefit in metastatic hormone-refractory PCa, the improvement in OS in favour of sipuleucel-T might be related to the use of docetaxel therapy. To test this hypothesis, a post hoc exploratory analysis of OS was performed to evaluate the interaction of subsequent docetaxel therapy with the treatment effect of sipuleucel-T. The data suggest no treatment effect of sipuleucel-T compared with placebo in the subgroup that received docetaxel therapy and appear to suggest a treatment effect of sipuleucel-T compared with placebo in the subgroup that did not receive subsequent docetaxel therapy. Considering that this analysis is based on nonrandomised subgroups that were likely subject to selection bias, no statistically meaningful conclusions can be drawn. There are questions about the benefit of sipuleucel-T in patients aged <65 yr. The FDA statistical review included a subgroup analysis by age in pooled studies D9901, D9002A, and IMPACT. For patients aged 65 yr, the median OS in the sipuleucel-T group was 23.4 mo versus 17.3 mo in the control group (HR: 0.66; 95% CI, 0.538–0.813). For patients aged <65 yr, the median OS in the sipuleucel-T group was 29.0 mo versus 28.2 mo in the control group (HR: 0.91; 95% CI, 0.618–1.366). The improvement in OS in the older patients (65 yr) was statistically significant; however, the numerical improvement in OS in patients aged <65 yr was minimal [13]. Based on the FDA statistical reviewer’s analysis of survival, no evidence shows adverse outcome in patients <65 yr of age [38]. In the PROSTVAC-VF study by Kantoff et al. [21], some authors refer to the imbalance in the percentage of lymph node–only patients (a group with favourable prognosis) that favoured the PROSTVAC-VF arm (9.8% vs 0%) and that possibly could have influenced the outcome. Interestingly, 8.5-mo longer survival was observed in the PROSTVAC-VFtreated group, although survival data from phase 2 studies should be seen as supporting but certainly not confirming a hypothesis [39]. The PSA response reported in these studies varied significantly. Where reported, the proportion of men showing a PSA response following vaccine therapy was generally low. Only a few studies reported a decrease in PSA 50% in a small number of patients (see Table 1 and 4) [17,18,32]. The lack of PSA response with vaccine-based therapies makes quantifying the clinical benefit of cancer vaccines especially difficult. There is concern that results could have been influenced by an unmeasured prognostic

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variable that was accidentally imbalanced in the assignment of study groups. The lack of PSA decline indicates that the observed survival advantage, if considered a true effect of the vaccine strategy, must result from disease stabilisation in the absence of marked tumour cell destruction or from improved efficacy of subsequent treatment following vaccination. The time of separation of the two curves may argue against this latter assumption. None of the included studies identified a clear relationship between immune responses and clinical outcome. In the IMPACT study, sipuleucel-T–treated patients showed an increased T-cell immune response to PA2024 (73%) versus control-treated patients (12.1%) (stimulation index: >5). T-cell immune responses were not evaluated in the large double-blind PROSTVAC-VF study [21] but rather in a smaller study [22] showing a 2-fold increase in PSA-specific T-cell response detected by ELISPOT in 13 of 29 patients (44.8%). No patients mounted an anti-PSA antibody response detectable by ELISA in the poxviral vector–based vaccine studies. Gulley et al. reported a trend ( p = 0.055) towards enhanced survival in patients, with a 6-fold increase in PSA-specific T-cell responses following PROSTVAC-VF therapy [22]. No optimal standard method currently exists for measuring immune response, and the difficulty in demonstrating a clear relationship between the induction of antigen-specific immune responses and clinical outcome has raised scepticism regarding immunotherapies. A major issue may be the detection of tumour-specific T cells in tissues. For other tumour types, it is often difficult to relate clinical responses to immune responses. In melanoma, it has been reported that, in particular, T cells migrating into skin containing the vaccine (delayed-type hypersensitivity [DTH]) correlated extremely well with clinical outcome. T cells that were isolated from biopsies of these DTH sites after 48 h and that showed reactivity against the tumourassociated antigens correlated well with clinical outcome [40,41]. It would be extremely interesting to perform similar tests in PCa patients who receive vaccines. Very little is known about the kinetics and trafficking of reinfused cells in sipuleucel-treated patients. It would be informative to study whether these cells reach lymph nodes and are capable of activating T cells. Imaging techniques such as magnetic resonance imaging and scintigraphy have already proven valuable in following labelled cells in vivo in patients [42]. The kinetics and the magnitude of an immune response depend on the antigen but also on whether a response is initiated in a naı¨ve environment or is a recall response of existing immune memory. To mount a sustained immune response over time, repeated stimulations will be required. Positron emission tomography/CT using metabolic biomarkers now allows determination of the proliferative capacity of cells in vivo. This capability is of interest in measuring effects on the tumour as well as, for instance, measuring proliferative capacity of the immune cells in lymph nodes after vaccination. In general, vaccines included in these studies showed a good safety profile, with AEs that were mostly low grade and transient. In controlled clinical trials, 72.9% of patients (438 of 601) in the sipuleucel-T group were 65 yr of age

[15]. The package insert of sipuleucel-T indicates no apparent differences in the safety of sipuleucel-T for patients aged 65 yr and for younger patients. Although reported in previous studies [17], no significant increase in the incidence of cardiovascular events (CVEs) after sipuleucel-T treatment versus control was observed in the IMPACT study [18]. Safety results of four controlled clinical trials of sipuleucel-T showed CVEs including hemorrhagic and ischemic strokes in 3.5% of patients in the sipuleucel-T group compared with 2.6% of patients in the control group. Whether there is a causal relationship between CVEs and sipuleucel-T remains unclear [13]. The FDA has required a postmarketing study to assess the risk of CVEs in 1500 patients with PCa who receive sipuleucel-T. Severe side effects are not likely to occur, but monitoring of patients remains important. Questions remain about whether the cost of sipuleucel-T treatment is justified by the real benefit that might be achieved. Patients are not cured by the current vaccination approach, yet the benefit of the therapy includes improved survival with few side effects and delay in time to first nonhormonal treatment in these CRPC patients. Data from randomised studies on peptide-based vaccine therapies and whole-tumour-cell–based vaccine therapies are limited [32–35]. DNA vaccines have not been evaluated yet in randomised studies. Currently, a large number of pharmaceutical companies have various vaccines under development for prostate and other types of cancer, and the results are eagerly awaited. Other cancer vaccines that have been evaluated in recent phase 3 clinical studies are PANVAC-VF for treatment of a pancreatic tumour, Oncophage (vitespen) for treatment of melanoma or renal cancer, gp100:209-217 (210 M) for melanoma, Oncovax for colon cancer, and Reniale for renal cancer. Stimuvax has been evaluated in a phase 2b study in lung cancer patients. The encouraging results are discussed in a recent review paper by Vergati et al. [43]. Other immunotherapeutic approaches are not vaccination strategies and fall outside the scope of this review, for instance, adoptive cellular immunotherapy administering activated effector T cells infused in or breaking tolerance to antigens by targeting specific immune checkpoint inhibitors such as the use of anti-CTLA4 monoclonal antibodies. In addition, treatment with monoclonal antibodies targeting expressed or overexpressed membrane antigens such as Her-2/neu on cancer cells are not included in this review on vaccination strategies in PCa. Certainly, tumour-induced immune tolerance and antitumour effects of checkpoint blockade may influence the development of combination strategies in the future. 3.10.

Future studies

To properly evaluate PCa vaccines in future studies, certain principles of study design need to be applied. The definition of immune response in phase 1 studies is vital to determining the optimal dose for later phases. To avoid the biases that can be introduced in the conduct of the

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study and in the analyses of the study results, novel therapeutic cancer vaccine studies should have an appropriate control arm, using either an active comparator or placebo control. The selection of an appropriate patient population is important for the design of future cancer vaccine studies. Currently, no known markers can be used as an identifier of likely responders to vaccine-based therapy. Theoretically, patients most likely to benefit from vaccine therapy are those with slow-growing and/or low-volume disease and minimal prior exposure to chemotherapy. Several studies tested vaccines in chemotherapy-naı¨ve metastatic CRPC. Due to the time required for generating an immune response to vaccination, studies showed that PCa vaccines might be more efficacious for asymptomatic or minimally symptomatic patients with indolent metastatic or nonmetastatic disease and lower disease volume and/or with prior radiotherapy [27] or for patients with mCRPC and Halabi-predicted survival 18 mo [22]. It might be advisable to vaccinate these patients before they become highly immune suppressed because of chemotherapy or larger tumour volume (increased number of regulatory T cells that can decrease the effect of the vaccine). The Halabi or Armstrong nomograms may provide a potential method of stratifying patients who are entering future vaccine therapy studies [44,45]. Although future research should focus on vaccine therapies in patient populations at earlier PCa stages, the long timeline required for such studies is daunting for companies developing such therapies. An alternative approach is to select patients who have a high performance status following initial docetaxelbased chemotherapy. Sipuleucel-T is currently being tested in an open-label phase 2 study as a neoadjuvant treatment (prior to radical prostatectomy) in men with localised PCa (Clinicaltrials.gov identifier: NCT00715104). Ideally, patients with minimal tumour burden should be eligible for vaccination approaches. These include high-risk patients after surgical and/or radiotherapeutic and/or hormonal treatment for the primary tumour or those with early metastatic disease that is preferably measurable by sophisticated molecular markers enabling identification of metastatic disease in a very early stage at the time of minimal tumour burden. A similar approach is being explored for haematologic malignancies in which molecularly defined relapse in the bone marrow can be assessed very early. The selection of an appropriate primary end point is as important as the selection of the appropriate patient population. In contrast to traditional anticancer drugs, the survival advantage of sipuleucel-T [18] and PROSTVACVF [21] was not associated with prolongation of PFS. Clinical trial design in the era of vaccine strategies, if more trials are to be successful, will require reconsideration of relevant end points including clinical benefit, preferably OS (with the disadvantage of a long time period between the start of trials and the assessment of primary outcome OS), possibly PFS (ie, TTP), and quality of life. Secondary end points are measurable immunologic effects. Surrogate end points and biomarkers other than PSA that could appropriately predict clinical efficacy should be explored in future studies.

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Moreover, careful standardisation of tests is critical for comparison of immune monitoring of different vaccines in different trials. Another important factor to consider in a successful study design is the combination of the vaccine therapy with another traditional or novel therapy. It is likely that a vaccine induces an immune response that can persist and may work in combination with another therapy to enhance clinical outcome. Therapeutic cancer vaccines lack the immediate cytotoxicity and tumour shrinkage seen with chemotherapy and radiotherapy. Combinations of PROSTVAC-VF with radiotherapy [26,46], androgen ablation [24,27], and chemotherapy [25] have been tested. Examining how these combinations affect the immune responses and clinical outcomes may help guide the design of future studies. Data from phase 2 studies [27,47] suggest that the timing of androgen ablation and vaccination can be crucial. Challenging studies investigating combinations of PCa vaccines with immune checkpoint inhibitors such as anti-CTLA4 monoclonal antibodies (ipilimumab, also known as MDX-010) and PD-1 monoclonal antibodies (MDX-1106) are under way. An example is the study testing PSA-based vaccine and GM-CSF plus MDX-010 in patients with metastatic androgen-independent PCa (Clinicaltrials.gov identifier: NCT00124670). The potentially fatal toxicity of ipilimumab may be a limiting factor in such studies. If confirmed in larger studies, PD-1 blockade might become an ideal candidate for future combination immunotherapy studies. There is room for improvement of the vaccines themselves. More insight into the migratory capacity of injected cells and their in vivo immune stimulating activity is desirable. Ultimately, targeting DCs in vivo may be a more cost-effective treatment, as this approach would omit the tailor-made ex vivo culturing. Patients with CRPC frequently use corticosteroids, which may modulate the immune system and, in a dosedependent fashion, antagonise the effects of vaccination strategies. In the pivotal sipuleucel-T trial, systemic glucocorticoids were not permitted for 28 d prior to enrolment in IMPACT, and immune-monitoring indicated that vigorous immune responses were evoked by the administration of the PAP-GM-CSF–stimulated autologous blood cells. Omitting corticosteroid use prior to and during vaccination strategies is advised and will positively affect bone integrity. 4.

Conclusions

The recent FDA approval of sipuleucel-T in chemotherapynaı¨ve patients with mCRPC and the encouraging results of PROSTVAC-VF create new opportunities for the design of clinical trials in earlier stages of PCa as well as in combination with traditional or novel treatment modalities. Sipuleucel-T is unique in that it is being manufactured for individual patients. In contrast, most of the vaccines under development are off-the-shelf products. The limited number and the magnitude of side effects are advantageous

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in comparison to those of chemotherapy. The PROSTVAC-VF results need to be confirmed in larger, well-designed, prospective phase 3 studies. Based on the current evidence derived from three phase 3 trials and circumstantial evidence and extrapolation from phase 2 trials, it is likely that vaccination approaches will become part of the armamentarium of urologists and medical oncologists who care for PCa patients. Careful selection of patients and stratification into risk categories is crucial, and detailed assessment of crossover and secondary treatments will be most important for a solid introduction of vaccine approaches in uro-oncology. PCa remains one of the best targets for vaccination approaches based on the wealth of antigens commonly shared by different patients’ PCa cells. In addition, when expressed at normal prostate cells, an immune attack of these cells will not result in major harm for the patient. A critical analysis of future trials is needed and is timely now that we seem to be on the verge of a new era in the treatment of PCa patients. Author contributions: Steven Joniau had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Osanto, Van Poppel, Joniau. Acquisition of data: Osanto, Van Poppel, Joniau. Analysis and interpretation of data: Osanto, Van Poppel, Joniau. Drafting of the manuscript: Osanto, Van Poppel, Joniau. Critical revision of the manuscript for important intellectual content: Joniau, Abrahamsson, Bellmunt, Figdor, Hamdy, Verhagen, Vogelzang, Wirth,

Administrative, technical, or material support: None. Supervision: Osanto, Van Poppel, Joniau. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.

Appendix A. Data acquisition A literature search was conducted for articles on vaccination strategies for prostate cancer published between January 1995 and October 2010. The following databases were searched: PubMed, Embase (OVID version), and Cochrane Library. The search strategy consisted of the AND combination of the two main concepts: (1) prostate cancer and (2) cancer vaccines. For these concepts, all relevant keyword variations were used, not only in the controlled vocabularies of the various databases but also in free text word variations. The search strategy was optimised for all consulted databases, taking into account the differences of the various controlled vocabularies as well as the differences of database-specific technical variations (eg, use of quotation marks). See Appendix 2 for literature search details. Only articles publishing data on humans were considered.

Van Poppel, Osanto. Statistical analysis: None. Obtaining funding: None.

Database PubMed

Appendix B. Literature search details

Strategies (((‘‘Vaccination Strategies’’ OR ‘‘Vaccination Strategy’’ OR ‘‘sipuleucel-T’’[Substance Name] OR ‘‘sipuleucelT’’[tw] OR ‘‘cancer vaccines’’[MeSH Terms] OR ‘‘cancer vaccines’’[tw] OR ‘‘cancer vaccine’’[tw] OR ‘‘cancer vaccination’’[tw] OR ‘‘provenge’’[tw] OR GVAX[tw] OR DVAC[tw] OR ‘‘poxvirus vector vaccine’’[tw] OR ‘‘poxvirus vector vaccines’’ OR ‘‘immune-based therapy’’ OR ‘‘immune-based therapies’’ OR ‘‘immune-based strategy’’ OR ‘‘immune-based strategies’’ OR ((immunotherapy OR immunotherap* OR immunization OR immunisation OR immunosuppression OR radioimmunotherapy) AND (moab OR moabs OR monoclonal OR antibody OR monoclonals OR antibodies))) AND (‘‘prostate cancer’’[ti] OR ‘‘prostatic cancer’’[ti] OR ‘‘prostate carcinoma’’[ti] OR ‘‘prostatic carcinoma’’[ti] OR ‘‘prostate carcinomas’’[ti] OR ‘‘prostatic carcinomas’’[ti] OR ‘‘Prostatic Neoplasms’’[mesh]) NOT medline[sb]) OR ((‘‘Vaccination Strategies’’ OR ‘‘Vaccination Strategy’’ OR ‘‘sipuleucel-T’’[Substance Name] OR ‘‘sipuleucel-T’’[tw] OR ‘‘cancer vaccines’’[MeSH Terms] OR ‘‘cancer vaccines’’[tw] OR ‘‘cancer vaccine’’[tw] OR ‘‘cancer vaccination’’[tw] OR ‘‘provenge’’[tw] OR GVAX[tw] OR DVAC[tw] OR ‘‘poxvirus vector vaccine’’[tw] OR ‘‘poxvirus vector vaccines’’ OR ‘‘immune-based therapy’’ OR ‘‘immune-based therapies’’ OR ‘‘immune-based strategy’’ OR ‘‘immune-based strategies’’ OR ((immunotherapy OR immunotherap* OR immunization OR immunisation OR immunosuppression OR radioimmunotherapy) AND (moab OR moabs OR antibody OR monoclonal OR monoclonals OR antibodies))) AND (‘‘prostate cancer’’[ti] OR ‘‘prostatic cancer’’[ti] OR ‘‘prostate carcinoma’’[ti] OR ‘‘prostatic carcinoma’’[ti] OR ‘‘prostate carcinomas’’[ti] OR ‘‘prostatic carcinomas’’[ti] OR ‘‘Prostatic Neoplasms’’[mesh]) AND human)) AND (‘‘1995’’[PDAT]: ‘‘3000’’[PDAT]) AND (‘‘Randomized Controlled Trial’’[Publication Type] OR ‘‘Randomized Controlled Trials as Topic’’[mesh] OR RCT OR RCTS OR randomised OR randomized OR random* OR ‘‘Clinical Trial, Phase II’’[Publication Type] OR ‘‘Clinical Trial, Phase III’’[Publication Type] OR ‘‘Clinical Trial, Phase IV’’[Publication Type] OR ‘‘Clinical Trials, Phase II as Topic’’[mesh] OR ‘‘Clinical Trials, Phase III as Topic’’[mesh] OR ‘‘Clinical Trials, Phase IV as Topic’’[mesh] OR ‘‘phase 4’’ OR ‘‘phase IV’’ OR ‘‘phase four’’ OR ‘‘phase 3’’ OR ‘‘phase III’’ OR ‘‘phase three’’ OR ‘‘phase 2’’ OR ‘‘phase II’’ OR ‘‘phase two’’ OR ‘‘Clinical Trial, Phase I’’[Publication Type] OR ‘‘phase 1’’ OR ‘‘phase I’’ OR ‘‘phase one’’)

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Appendix B (Continued) Database

Strategies

Embase (OVID-version

(‘‘Vaccination Strategies’’.ti OR ‘‘Vaccination Strategy’’.ti OR provenge/ OR sipuleucel.ti OR cancer vaccine/ OR cancer vaccin*.ti OR provenge.mp OR active immunization/ OR GVAX.mp OR DVAC.mp OR poxvirus vector vaccine*.mp OR immune-based therap*.mp OR immune-based strateg*.mp OR ((immunotherap* OR immunization OR immunisation OR immunosuppression OR radioimmunotherap*) AND (moab OR moabs OR monoclonal OR antibody OR monoclonals OR antibodies)).mp OR (exp Immunotherapy/ AND exp Antibody/)) AND (exp *prostate tumor/ OR exp *prostate cancer/ OR (prostate cancer OR prostatic cancer OR prostate carcinoma* OR prostatic carcinoma*).ti) AND (exp randomized controlled trial/ OR phase 1 clinical trial/ OR phase 2 clinical trial/ OR phase 3 clinical trial/ OR phase 4 clinical trial/ OR RCT.mp OR RCTS.mp OR random*.mp OR (clinical trial AND (‘‘phase 3’’ OR ‘‘phase III’’ OR ‘‘phase three’’ OR ‘‘phase 2’’ OR ‘‘phase II’’ OR ‘‘phase two’’ OR ‘‘phase 4’’ OR ‘‘phase IV’’ OR ‘‘phase four’’ OR ‘‘phase 1’’ OR ‘‘phase I’’ OR ‘‘phase one’’)).mp) limit to 1995-current

Cochrane Library

(‘‘Vaccination Strategies’’ OR ‘‘Vaccination Strategy’’ OR sipuleucel OR cancer vaccin* OR provenge OR GVAX OR DVAC OR ‘‘poxvirus vector vaccine’’ OR ‘‘poxvirus vector vaccines’’ OR ‘‘immune-based therapy’’ OR ‘‘immune-based therapies’’ OR ‘‘immune-based strategy’’ OR ‘‘immune-based strategies’’ OR ((immunotherapy OR immunotherap* OR immunization OR immunisation OR immunosuppression OR radioimmunotherapy) AND (moab OR moabs OR monoclonal OR antibody OR monoclonals OR antibodies))) AND (‘‘prostate cancer’’ OR ‘‘prostatic cancer’’ OR ‘‘prostate carcinoma’’ OR ‘‘prostatic carcinoma’’ OR ‘‘prostate carcinomas’’ OR ‘‘prostatic carcinomas’’ OR (Prostat* AND (cancer OR carcinoma*)))

Web of Science

TI=(‘‘Vaccination Strategies’’ OR ‘‘Vaccination Strategy’’ OR sipuleucel OR cancer vaccin* OR provenge OR GVAX OR DVAC OR ‘‘poxvirus vector vaccine’’ OR ‘‘poxvirus vector vaccines’’ OR ‘‘immune-based therapy’’ OR ‘‘immune-based therapies’’ OR ‘‘immune-based strategy’’ OR ‘‘immune-based strategies’’ OR ((immunotherapy OR immunotherap* OR immunization OR immunisation OR immunosuppression OR radioimmunotherapy) AND (moab OR moabs OR monoclonal OR antibody OR monoclonals OR antibodies))) AND TI=(‘‘prostate cancer’’ OR ‘‘prostatic cancer’’ OR ‘‘prostate carcinoma’’ OR ‘‘prostatic carcinoma’’ OR ‘‘prostate carcinomas’’ OR ‘‘prostatic carcinomas’’ OR (Prostat* AND (cancer OR carcinoma*))) AND TS=(Random* OR RCT OR RCTS OR ‘‘phase 4’’ OR ‘‘phase IV’’ OR ‘‘phase four’’ OR ‘‘phase 3’’ OR ‘‘phase III’’ OR ‘‘phase three’’ OR ‘‘phase 2’’ OR ‘‘phase II’’ OR ‘‘phase two’’ OR ‘‘phase 1’’ OR ‘‘phase I’’ OR ‘‘phase one’’)

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