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BackgroundProstate cancer (PC) is the most common non-cutaneous diagnosed cancer among men in USA.1 Although clinical outcomes are favorable for patients with localized disease, 20–30% of patients will develop metastatic prostate cancer (mPC) and have poor prognosis. Immunotherapy, as a single agent, provides benefit to a small subset of PC patients, which is thought to be partially due to its known cold tumor immune microenvironment (TIME). Combination studies are needed to enhance benefit.2 Prostvac is a therapeutic cancer vaccine engineered to activate an immune response against prostate-specific Antigen (PSA).3 Prostvac alone could induce systemic immune response by increasing immune-cell infiltrates in and around the tumor.4 In this study, we are exploring the effect of Prostvac in combination with nivolumab in TIME in prostate cancer.MethodsWe treated locally advanced prostate cancer patients (n=6) undergoing radical prostatectomy (RP) with neoadjuvant Prostvac in combination with nivolumab, an immune checkpoint PD-1 inhibitor. Dynamic changes in TIME before and after treatment were studied using multiplex immunofluorescence (Opal Method). Formalin fixed paraffin-embedded sections from matched pre-treated prostate biopsies and post-treated RP samples were stained with a validated T cell panel (DAPI, CD4, CD8, FOXP3, Ki67, Pan CK and PD-L1). To analyze the data, TIME was segmented into 3 compartments: intratumoral, invasive margin and benign.ResultsCombination immunotherapy significantly increased CD4+ T cell density in the invasive margin (mean 211.5 cells/mm2 vs 592.2 cells/mm2, pConclusionsThe combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patients. A broader examination of the TIME and the role immune cells undertake to control tumor growth is on-going.Trial RegistrationNCT02933255ReferencesSiegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin (Internet) 2020;70:7–3Zhao SG, Lehrer J, Chang SL, et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst 2018;111:301–10.Madan RA, Arlen PM, Mohebtash M, et al. Prostvac-VF: a vectorbased vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009;18:1001–11Abdul Sater H, Marté JL, Donahue RN, et al. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J Immunother Cancer 2020;8(1):655–64Ethics ApprovalThis study was performed in compliance with ethical standard and was approved by the NIH IRB, 17C-0007. All patients participating in this study gave an informed consent before taking part.

Introduction Therapeutic cancer vaccines have been recognized as a promising treatment option in clinical oncology for nearly three decades. However, despite many efforts, only one cancer vaccine – sipuleucel-T, activating the anti-PAP (prostatic acid phosphatase) immune response, has obtained Food and Drug Administration (FDA) approval. Material and methods This review describes the most advanced research on the use of therapeutic cancer vaccines in the treatment of prostate cancer. Results In addition to sipuleucel-T, which was approved in urologic oncology in 2010, four cancer vaccines were and have been tested in phase III clinical trials in patients with metastatic castration resistant prostate cancer (mCRPC): GVAX (prostate cancer variant) containing irradiated prostate cancer cell, PPV peptide vaccine, PCVAC/PCa dendritic cell-based vaccine and PROSTVAC anti PSA (prostate-specific antigen) vaccine. This review compares the most promising and best-studied cancer vaccines: sipuleucel-T and PROSTVAC. Currently, both vaccines have been tested in combination with other therapeutic approaches, including check point inhibitors. Conclusions It seems possible that the efficacy of sipuleucel-T and PROSTVAC could be increased in combination therapy with other medications.

BackgroundClinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site.MethodsAn open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1.ResultsOf 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm² vs 152/mm²; IQR 136–317/mm² vs 69–284/mm²; p=0.0249; median ratio 1.20; IQR 0.64–2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm² vs 151/mm²; IQR 123–500/mm² vs 85–256/mm²; p=0.042; median ratio 1.44; IQR 0.59–4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm² vs 105/mm²; IQR 91–175/mm² vs 83–163/mm²; p=0.036; median ratio 1.25; IQR 0.88–2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated.ConclusionNeoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response.Trial registration numberNCT02153918.

Immunotherapy has historic and contemporary presence in prostate, urothelial (UC), and renal cell (RCC) carcinomas. However, robust data on utility and generalizability of these treatments in older patients are lacking.To systematically evaluate evidence regarding the efficacy and safety of immunotherapy in elderly patients with prostate cancer, UC, or RCC.PubMed/Medline, Embase, Web of Knowledge, and Cochrane Library databases were searched up to October 2017 and according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A narrative review of studies was performed.Twenty-one reports were included regarding prostate cancer (four studies), UC (eight), and RCC (nine). In prostate cancer, sipuleucel-T improves survival (median age70 yr) and similar results were seen in the PROSTVAC phase 2 trial. Ipilimumab has not improved survival independent of age; data for programmed cell death 1 inhibition is evolving. In metastatic UC, ≥50% of patients enrolled in pivotal checkpoint inhibitor studies were aged ≥65 yr. Three studies reported similar objective response rates (ORRs) in patients aged65 versus ≥65 yr, whereas one study reported comparable ORRs in patients80 versus ≥80 yr. In metastatic RCC, cytokine studies showed no efficacy difference by age; one study reported more ≥grade 3 toxicity in patients aged ≥65 yr. One vaccine-based study suggests that older age was associated with shorter survival. The benefit of nivolumab in second-line therapy was more apparent for patients aged 65-75 yr than for those aged ≥75 yr. Across tumor subtypes, immunotherapy was well tolerated with minimal data stratifying toxicity by age.Contemporary immunotherapy has informed practice in genitourinary malignancies independent of patient age. Trial reporting of outcomes by age will be important to understand the generalizability of ongoing investigations for elderly patients.With the growing use of immunotherapy in genitourinary malignancies, benefits appear to apply independent of age. As the field advances, detailed reporting on outcomes and toxicities by age will be informative for both patients and physicians when discussing treatment options.

Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for a decade. However, neither of the two clinically most developed prostate cancer vaccines, Sipuleucel-T and ProstVac, induce strong T cell immunity. In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early stage prostate cancer and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate specific antigen (PSA) change and assessment of phenotype and functionality of antigen-specific T cells. The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMCs). Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumour infiltrating lymphocytes (TILs) were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ. The potent T cell responses elicited support the evaluation of these vectored vaccine in efficacy trials.

Background Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. Patients and methods Human kidney tissues were stained for AR and 11β-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. Results Concurrent AR and 11β-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. Conclusion Enzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

To date, prostate cancer has been poorly responsive to immunotherapy. In the current review, we summarize and discuss the current literature on the use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T currently remains the only FDA-approved immunotherapeutic agent for prostate cancer. Single-agent phase 3 vaccine trials with GVAX and PROSTVAC have failed to demonstrate survival benefit to date. Clinical trials using combination approaches, including combination PROSTVAC along with a neoantigen vaccine and checkpoint inhibitor immunotherapy, are ongoing. Checkpoint inhibitor monotherapy clinical trials have demonstrated limited efficacy in advanced prostate cancer, and combination approaches and molecular patient selection are currently under investigation. The optimal use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer remains to be determined. Ongoing clinical trials will continue to inform future clinical practice.

Purpose of review In recent clinical trials, immunotherapeutic agents have demonstrated promising results for the treatment of prostate cancer. This review discusses emerging immunotherapies for prostate cancer and their evolving role in sequencing and combination therapy. Recent findings Therapeutic vaccines including PROSTVAC and DCVAC/PCa have completed promising phase 2 trials for the treatment of prostate cancer and phase 3 trials are underway. Recent evidence supports a synergistic relationship between immunotherapy agents themselves, antiandrogens and with cytotoxic chemotherapy. Prostate cancer patients with good prognostic factors, such as minimal disease burden, appear to achieve the optimal benefit from immunotherapy. Summary Therapeutic cancer vaccines and immunomodulating agents have demonstrated activity in the treatment of prostate cancer. Immunotherapies may alter the prostate tumor microenvironment and ongoing studies aim to provide guidance on effective sequencing and combination strategies.

BackgroundThe standard treatment for non-metastatic castration sensitive prostate cancer (nmCSPC) is androgen deprivation therapy (ADT) or surveillance. This study evaluated the potential synergy of immunotherapy and enzalutamide (without ADT) in nmCSPC. In addition, the immunologic impact of enzalutamide was also evaluated in men with normal testosterone.MethodsPatients with rising prostate-specific antigen (PSA) after definitive therapy, normal testosterone and no radiographic metastasis were randomized to enzalutamide for 3 months with/without PROSTVAC for 6 months. Thereafter, patients could be retreated with another 3 month course of enzalutamide when PSA returned to baseline. Immune profiles were evaluated in these patients.ResultsThirty-eight patients were randomized with a median PSA=4.38 ng/dL and PSA doubling time=4.1 months. No difference was observed between the two groups for PSA growth kinetics, but PSA responses to enzalutamide were noteworthy regardless of PROSTVAC. The median PSA decline after short-course enzalutamide without ADT/testosterone lowering therapy was 99% in both courses. The median time to PSA recovery to baseline after each 84-day course of enzalutamide was also noteworthy because of the duration of response after enzalutamide was discontinued. After the first and second 3 month cycle of enzalutamide, PSA recovery to baseline took a median 224 (range 84–1246) and 189 days (78–400), respectively. The most common adverse events related to the enzalutamide were grade 1 fatigue (71%) and grade 1 breast pain/nipple tenderness (81%). The only grade 3 toxicity was aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation in two patients. Enzalutamide was independently associated with immune changes, increasing natural killer cells, naïve-T cells, and decreasing myeloid-derived suppressor cells.ConclusionsThree months of enzalutamide without ADT induced substantial PSA control beyond the treatment period and was repeatable, perhaps representing an alternative to intermittent ADT in nmCSPC. In addition, enzalutamide was associated with immune changes that could be relevant as future immune combinations are developed.Trail registration numberclinicaltrials.gov (NCT01875250).

TPS192 Background: Despite robust advances in the use of immune checkpoint blockade (ICB) across multiple cancer types, responses in prostate cancer remain suboptimal. Overall response rates for single-agent ICB in prostate cancer are low, but recent modest gains have been made with ipilimumab and nivolumab combination therapy in metastatic castrate-resistant prostate cancer. Prostvac-VF Tricom is a therapeutic vaccine that incorporates DNA for the shared self-antigen PSA into the vaccinia (or fowlpox) virus strain. A large randomized phase III clinical trial recently showed no improvement in overall survival (OS) with Prostvac compared with placebo, suggesting that a combinatorial approach is warranted. Personalized neoantigen vaccines based on specific mutated epitopes may have the ability to overcome immunoresistance seen with self antigens. Even in low mutational burden tumors like prostate cancer, T cell responses against neoantigens are observed in patients with favorable clinical outcomes, supporting neoantigen vaccination as a promising therapeutic strategy. Improvements in computational genomics and predictive algorithms have allowed the incorporation of MHC class II neoepitopes and those from gene fusion events relevant in prostate cancer. We thus hypothesized that a strategy utilizing both shared antigen (Prostvac) and personalized MHC-I and MHC-II neoantigen vaccines combined with dual ICB would induce robust immune responses and improve clinical outcomes. To maximize tumor burden reduction and minimize tumor-mediated immunoresistence, we are evaluating this novel strategy in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who have completed frontline docetaxel chemotherapy. Methods: This ongoing trial (NCT03532217) began accrual in September 2018. Eighteen of 20 planned patients have been enrolled to date. Eligible patients have histologically confirmed high risk/volume mHSPC defined as 4 or more sites of metastatic disease or visceral involvement. Patients receive continuous androgen deprivation therapy (ADT) and have completed upfront docetaxel chemotherapy. Patients begin treatment with Prostvac-VF in combination with ipilimumab (1 mg/kg every 3 weeks for 2 doses), and nivolumab (3 mg/kg every 3 weeks for 6 doses) within 60 days of the last dose of docetaxel. Subsequently, patients receive nivolumab 480 mg IV every 4 weeks in conjunction with a personalized neoantigen DNA vaccine administered monthly via intramuscular electroporation. The primary objective of this exploratory study is to assess the feasibility, safety/tolerability, and immune responses of this combination strategy. Key secondary objectives include failure-free survival and milestone survival at 2 years, PSA response, and radiographic progression-free survival. Clinical trial information: NCT03532217.

Càncer de pròstata; Metàstasi neoplàsica; Immunoteràpia Cáncer de próstata; Metástasis neoplásica; Inmunoterapia Prostate cancer; Metastatic neoplasm; Immunotherapy PURPOSE PROSTVAC, a viral vector–based immunotherapy, prolonged median overall survival (OS) by 8.5 months versus placebo in metastatic castration-resistant prostate cancer in a phase II study. This phase III study further investigated those findings. PATIENTS AND METHODS Patients were randomly assigned to PROSTVAC (Arm V; n = 432), PROSTVAC plus granulocyte-macrophage colony-stimulating factor (Arm VG; n = 432), or placebo (Arm P; n = 433), stratified by prostate-specific antigen (less than 50 ng/mL v 50 ng/mL or more) and lactate dehydrogenase (less than 200 v 200 U/L or more). Primary end point was OS. Secondary end points were patients alive without events (AWE)—namely, radiographic progression, pain progression, chemotherapy initiation, or death—at 6 months and safety. The study design was a superiority trial of PROSTVAC (Arm V or Arm VG) versus Arm P. Three interim analyses were planned. RESULTS At the third interim analysis, criteria for futility were met and the trial was stopped early. Neither active treatment had an effect on median OS (Arm V, 34.4 months; hazard ratio, 1.01; 95% CI, 0.84 to 1.20; P = .47; Arm VG, 33.2 months; hazard ratio, 1.02; 95% CI, 0.86 to 1.22; P = .59; Arm P, 34.3 months). Likewise, AWE at 6 months was similar (Arm V, 29.4%; odds ratio, 0.96; 95% CI, 0.71 to 1.29; Arm VG, 28.0%; odds ratio, 0.89; 95% CI, 0.66 to 1.20; placebo, 30.3%). Adverse events were similar for the treatment and placebo groups, with the most common being injection site reactions (62% to 72%) and fatigue (21% to 24%). Arrhythmias were the most common cardiac-related events (1.4% to 3.5%). There were no reports of either myocarditis or pericarditis. Serious treatment-related events occurred in less than 1% of all patients. CONCLUSION Whereas PROSTVAC was safe and well tolerated, it had no effect on OS or AWE in metastatic castration-resistant prostate cancer. Combination therapy is currently being explored in clinical trials. Supported by Bavarian Nordic, the National Institute for Health Research Biomedical Research Centre at the Royal Marsden National Health Service Foundation Trust, and the Institute of Cancer Research. Funded in part by National Cancer Institute Cancer Center Support Grant No. P30-CA008748 and the Center for Cancer Research, National Cancer Institute. P30 CA008748/CA/NCI NIH HHS/United States DH_/Department of Health/United Kingdom

Background Immune checkpoint inhibitors have revolutionized treatment and improved survival in many cancers. However, since immune-related adverse events (irAEs) are potentially fatal, early recognition and prompt treatment are warranted. One of the rarest but most dramatic irAE is myocarditis, which has significant morbidity and mortality if not recognized and treated early. Objective To report the first case of myocarditis in a patient with metastatic castration-resistant prostate cancer (mCRPC) treated with a combination of nivolumab, an anti-programmed cell death protein 1 antibody, and PROSTVAC, a vector-based therapeutic prostate cancer vaccine. Case Report A 79-year-old man with mCRPC metastatic to bone and lymph nodes and a history of atrial fibrillation presented with blurred vision and pain and stiffness in the upper back after 8 weeks on a clinical trial with nivolumab (1 mg/kg) and PROSTVAC, both given every 2 weeks. Eye exam was within normal limits, while musculoskeletal exam revealed tenderness in trapezius muscles and decreased motor strength in arms (III/V) and neck (IV/V). The rest of the physical exam was within normal limits, with the exception of an irregular heart rhythm. Laboratory tests were as follows: creatinine kinase (CK) 3200 U/L (normal: 39–308 U/L), CK-MB 65.7 mcg/L (normal: 0–7.6 mcg/L), troponin I 0.209 ng/mL (normal: 0–0.056 ng/mL). Electrocardiogram (ECG) revealed atrial fibrillation with QT prolongation (QTc 514 msec) and left anterior fascicular block, unchanged from baseline. 2D-echocardiogram showed a left ventricular ejection fraction of 65% with an enlarged left atrium, dilated right ventricle, and increased pulmonary artery pressure (45 mmHg). ProBNP was elevated at 1463 pg/mL and peaked at 3066 pg/mL one day after hydration. With a presumed diagnosis of autoimmune myositis and possible myocarditis, the patient was admitted and started on methylprednisolone 1 mg/kg/day. Cardiac MRI showed elevated native myocardial T1 values consistent with myocarditis (Fig. 1). The patient was discharged on a prednisone taper after normalization of cardiac enzymes on day 4. Treatment with PROSTVAC continued for three more months; nivolumab was discontinued. Six months later, patient is doing well, with no residual cardiac damage. Discussion Cardiovascular irAEs are relatively rare (< 1%) and have a variety of clinical presentations. Myocarditis is potentially life-threatening and can range from subclinical to fulminant. Therefore, clinical suspicion, early detection, and prompt treatment are imperative (1). The initial diagnostic workup should include cardiac enzymes, ECG, and 2D-echocardiogram. The most commonly observed ECG changes are generalized repolarization abnormalities, prolonged QT interval, and conduction abnormalities (2). An elevated troponin I in the absence of overt coronary artery disease is suggestive of myocarditis and should be evaluated further. Myocardial biopsy is the standard diagnostic procedure; however, a cardiac MRI can achieve a diagnosis when biopsy is not feasible (3). Advancements in parametric mapping techniques have allowed the use of native myocardial T1 in the detection of myocarditis, as it has superior diagnostic performance and higher sensitivity than older parameters (3). Our patient had been treated with an immune checkpoint inhibitor and a therapeutic cancer vaccine to induce effective antitumor activity through immunogenic intensification and presented with muscle stiffness and elevated CK. Although he had no new cardiovascular symptoms, cardiac enzymes were tested to rule out myocardial involvement. MRI with gadolinium confirmed the diagnosis of myocarditis. To date, none of the 1360 patients treated with PROSTVAC as a single agent have developed myocarditis, while myocarditis has been rarely reported in patients treated with nivolumab (< 1%) (1). Whether the combination of PROSTVAC and nivolumab presents an additional risk of myocarditis is unclear. To our knowledge, this is the first case of myocarditis in a patient with mCRPC receiving simultaneous treatment with an immune checkpoint inhibitor and a prostate cancer vaccine. Our experience highlights the importance of suspicion and early intervention in patients who present with cardiac abnormalities after receiving cancer immunotherapy. We propose following protocol: baseline troponin, ECG, and 2D-echocardiogram prior to treatment, then repeated troponin at 2, 4, and 12 weeks post-treatment, then monthly. If troponin becomes positive without alternative explanation, myocarditis should be ruled out with cardiac MRI or myocardial biopsy, and patient should be admitted for treatment with high-dose steroids as early intervention may minimize myocardial injury.

The Immunotherapy to Prevent Progression on Active Surveillance Study is the first trial of immunotherapy for localized prostate cancer. We randomized active surveillance patients to PSA-TRICOM (PROSTVAC) or placebo for 5mo. Final results will be available in 2019.

Background Autoantibodies (AAB) targeting self-antigens can be found in two clinically and immunologically opposing diseases, autoimmune diseases and cancer. While in autoimmune diseases, the immune system is hyperactivated against self-antigens, many tumours suppress the anti-tumour immune response. The therapeutic cancer vaccines PSA-Tricom (Prostvac) is designed to generate an antigen-specific tumour response in metastatic castration-resistant prostate cancer (mCRPC), which is in phase 3 testing. To further augment the immune response, combination therapies of Prostvac with ipilimumab are currently tested in clinical studies. Ipilimumab is an antibody that blocks the immune checkpoint molecule cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). However, treatment with ipilimumab is associated with immune-related adverse events (irAEs).1 Objectives Since there are no biomarkers for predicting irAEs, we aimed to investigate AAB profiles as biomarkers associated with irAE in mCRPC patients treated with prostvac and ipilumumab combination therapy. Methods Serum samples from 24 mCRPC patients treated with prostvac and ipiliumab therapy were tested for the presence of serum autoantibodies against 842 preselected antigens. Candidate antigens comprise immune-related and cancer signalling pathway proteins, autoimmune disease antigens, and tumor-associated antigens (TAA). Samples were collected prior to treatment (T0 samples), at 3 and 6 month. IrAEs included rash, elevated aminotransferases, neutropenia, diarrhoea, colitis and endocrine irAEs. Overall survival was also captured and correlated with AABs. Autoantibody levels were measured by Luminex FlexMap3D bead based multiplex protein arrays2 and data were analysed by significance analysis of microarrays (SAM), Partial least squares regression (PLS) and Pearson’s correlation. Results In total, 87 AABs were found that were significantly different in patients with irAEs and those without irAEs (SAM |d|>2.5; Pearson’s correlation |3|>0.35). PLS analysis revealed that AABs associated with irAEs were also associated with overall survival. Gene ontology analysis of pathways, molecular function and cellular localization revealed that AABs predicting irAEs target cancer, cell cycle, cell adhesion and apoptotic pathways. We also found elevated levels of AABs in patients who do not experience irAEs. Interestingly, these 40 AABs target proteins that are involved in inflammatory, adaptive and cellular immune response pathways or are autoimmune disease antigens. Conclusions AABs that target antigens involved in cancer signalling pathways are associated with irAEs following prostvac plus checkpoint inhibitor combination therapy. In contrast, AABs targeting immune response pathways were found in patients who do not develop iRAEs and may counteract the action of inflammatory molecules. Similarly, anti-cytokine AABs have been found in autoimmune diseases, were they appear to counteract the pathological effects of cytokines.3 Further studies in larger sample sets are needed to confirm these findings. References [1] Madan RA, et al. Lancet Oncol2012;13(5):501–8. [2] Budde P, et al. Lupus. 2016;25:812–22. [3] Cappellano G, et al. Am J Clin Exp Immunol. 2012;1(2):136–46. Disclosure of Interest P. Budde Employee of: Protagen, J. Marte: None declared, H.-D. Zucht Employee of: Protagen, S. Bhandari Employee of: Protagen, M. Tuschen Employee of: Protagen, P. Schulz-Knappe Shareholder of: Protagen, R. Madan: None declared, J. Gulley: None declared, J. Schlom: None declared

PROSTVAC immunotherapy is a heterologous prime-boost regimen of two different recombinant pox-virus vectors; vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against prostate-specific antigen. Both vectors contain transgenes for prostate-specific antigen and a triad of T-cell costimulatory molecules (TRICOM). In a placebo-controlled Phase II trial of men with minimally symptomatic, chemotherapy-naive metastatic castration-resistant prostate cancer, PROSTVAC was well tolerated and associated with a 44% reduction in death. With a novel mechanism of action, and excellent tolerability, PROSTVAC has the potential to dramatically alter the treatment landscape of prostate cancer, not only as a monotherapy, but also in combination with other novel agents, such as immune check point inhibitors and novel androgen receptor blockers. A Phase III trial recently completed accrual.

Purpose Autoantibodies (AAB) targeting self-antigens can be found in two clinically and immunologically opposing diseases, autoimmune diseases and cancer. While in autoimmune diseases, the immune system is hyperactivated against self-antigens, many tumours suppress the anti-tumour immune response. The therapeutic cancer vaccines PSA-Tricom (Prostvac) is designed to generate an antigen-specific tumour response in metastatic castration-resistant prostate cancer (mCRPC), which is in phase 3 testing. To further augment the immune response, combination therapies of Prostvac with ipilimumab are currently tested in clinical studies. Ipilimumab is an antibody that blocks the immune checkpoint molecule cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). However, treatment with ipilimumab is associated with immune-related adverse events (irAEs). 1 Since there are no biomarkers for predicting irAEs, we investigated AAB profiles as biomarkers associated with irAE in mCRPC patients treated with prostvac and ipilumumab combination therapy. Methods Serum samples from 24 mCRPC patients treated with prostvac and ipiliumab therapy were tested for the presence of serum autoantibodies against 842 preselected antigens. Candidate antigens comprise immune-related and cancer signalling pathway proteins, autoimmune disease antigens, and tumor-associated antigens (TAA). Samples were collected prior to treatment (T0 samples), at 3 and 6 month. IrAEs included rash, elevated aminotransferases, neutropenia, diarrhoea, colitis and endocrine irAEs. Overall survival was also captured and correlated with AABs. Autoantibody levels were measured by Luminex FlexMap3D bead based multiplex protein arrays 2 and data were analysed by significance analysis of microarrays (SAM), Partial least squares regression (PLS) and Pearson’s correlation. Results In total, 87 AABs were found that were significantly different in patients with irAEs and those without irAEs (SAM |d|>2.5; Pearson’s correlation |3|>0.35). PLS analysis revealed that AABs associated with irAEs were also associated with overall survival. Gene ontology analysis of pathways, molecular function and cellular localization revealed that AABs predicting irAEs target cancer, cell cycle, cell adhesion and apoptotic pathways. We also found elevated levels of AABs in patients who do not experience irAEs. Interestingly, these 40 AABs target proteins that are involved in inflammatory, adaptive and cellular immune response pathways or are autoimmune disease antigens. Conclusions AABs that target antigens involved in cancer signalling pathways are associated with irAEs following prostvac plus checkpoint inhibitor combination therapy. In contrast, AABs targeting immune response pathways were found in patients who do not develop iRAEs and may counteract the action of inflammatory molecules. Similarly, anti-cytokine AABs have been found in autoimmune diseases, were they appear to counteract the pathological effects of cytokines. 3 Further studies in larger sample sets are needed to confirm these findings. References . Madan RA, et al. Lancet Oncol2012;13(5):501–8. . Budde P, et al. Lupus2016;25:812–22. . Cappellano G, et al. Am J Clin Exp Immunol2012;1(2):136–46.

Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel- T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen-targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway. Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction.

Treatment of cancer patients involves a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Traditionally, patients with metastatic disease are treated with combination chemotherapies or targeted agents. These cytotoxic agents have good response rates and achieve palliation; however, complete responses are rarely seen. The field of cancer immunology has made rapid advances in the past 20 years. Recently, a number of agents and vaccines, which modulate the immune system to allow it to detect and target cancer cells, are being developed. The benefit of these agents is twofold, it enhances the ability the body’s own immune system to fight cancer, thus has a lower incidence of side effects compared to conventional cytotoxic chemotherapy. Secondly, a small but substantial number of patients with metastatic disease are cured by immunotherapy or achieve durable responses lasting for a number of years. In this article, we review the FDA-approved immunotherapy agents in the field of genitourinary malignancies. We also summarize new immunotherapy agents being evaluated in clinical studies either as single agents or as a combination.

Immunotherapy represents an emerging modality of treatment utilized in patients with prostate cancer, among various other malignancies.Sipuleucel-T is an autologous active cellular immunotherapy that has demonstrated improved survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The IMPACT trial led to the FDA approval of sipuleucel-T as first-line treatment for men with asymptomatic or minimally symptomatic mCRPC. Additional immunotherapies in cancer have shown promising results in clinical studies. These include ProstVac, which is a poxvirus vaccine targeting prostate-specific antigen, and cell cycle checkpoint inhibitors of cytotoxic T lymphocyte antigen-4 and programmed death-1 (PD-1) and its ligand (PD-L1). The combination of sipuleucel-T with both androgen deprivation therapy and androgen signaling agents has demonstrated robust and augmented immune responses. The responses to immunotherapy are often seen via different parameters compared with other therapies, including increased T-cell activation and antibody response.The role of immunotherapy in cancer continues to grow and encompass agents with different mechanisms, and ongoing efforts to identify appropriate timing of therapy and patients for use is integral to the management of prostate cancer.

Abstract: Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

Preclinical studies have demonstrated that the combination of systemic subcutaneous (s.c.) vaccination with intratumoral (i.t.) vaccination was superior in the induction of antitumor activity vs. vaccination with either route alone. A subsequent phase I study employing i.t.-s.c. vaccination was carried out in men with locally recurrent or progressive prostate cancer. rF-PSA-TRICOM (PROSTVAC) vaccine was administered intraprostatically and rV-PSA-TRICOM followed by rF-PSA-TRICOM vaccine was administered systemically. In that study no dose limiting toxicities were observed, 19/21 patients had stable or improved prostate-specific antigen (PSA) values and tumor-infiltrating lymphocytes (TILs) increased in post- vs. pre-treatment tumor biopsies, analyzed employing conventional immunohistochemistry (IHC). In the studies reported here, 31 phenotypes of peripheral blood mononuclear cells (PBMCs) were analyzed prevaccination and postvaccination as well as the functions of PBMC regulatory T cells (Tregs) and natural killer cells. A trend was observed in decreases in serum PSA with the reduction of circulating Tregs postvaccination. Digital IHC was employed prevaccination and postvaccination to measure CD4 and CD8 TILs, as well as Treg TILs by conventional IHC. Few correlations were observed with CD4, CD8 or Treg in TILs vs. PBMCs. However, patients with lower levels of CD4 TILs prevaccination showed the greatest increases in CD4 TILs postvaccine, while Treg TILs decreased postvaccine. There was also a strong correlation between decreases in serum PSA and increases in CD8 TILs postvaccine. These studies provide additional rationale for the use of i.t.-s.c. vaccinations and demonstrate a noncoordinate expression of specific immune subsets in PBMCs vs. tumor.

The primary end point of this study was to determine the safety and feasibility of intraprostatic administration of PSA-TRICOM vaccine [encoding transgenes for prostate-specific antigen (PSA) and 3 costimulatory molecules] in patients with locally recurrent or progressive prostate cancer. This trial was a standard 3 + 3 dose escalation with 6 patients each in cohorts 4 and 5 to gather more immunologic data. Nineteen of 21 patients enrolled had locally recurrent prostate cancer after definitive radiation therapy, and 2 had no local therapy. All cohorts received initial subcutaneous vaccination with recombinant vaccinia (rV)-PSA-TRICOM and intraprostatic booster vaccinations with recombinant fowlpox (rF)-PSA-TRICOM. Cohorts 3–5 also received intraprostatic rF-GM-CSF. Cohort 5 received additional subcutaneous boosters with rF-PSA-TRICOM and rF-GM-CSF. Patients had pre- and post-treatment prostate biopsies, and analyses of peripheral and intraprostatic immune cells were performed. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. The most common grade 2 adverse events were fever (38 %) and subcutaneous injection site reactions (33 %); the single grade 3 toxicity was transient fever. Overall, 19 of 21 patients on trial had stable (10) or improved (9) PSA values. There was a marked increase in CD4+ (p = 0.0002) and CD8+ (p = 0.0002) tumor infiltrates in post- versus pre-treatment tumor biopsies. Four of 9 patients evaluated had peripheral immune responses to PSA or NGEP. Intraprostatic administration of PSA-TRICOM is safe and feasible and can generate a significant immunologic response. Improved serum PSA kinetics and intense post-vaccination inflammatory infiltrates were seen in the majority of patients. Clinical trials examining clinical end points are warranted.

Until recently, the only therapy shown to improve survival in men with metastatic castration-resistant prostate cancer (mCRPC) had been chemotherapy, usually reserved for symptomatic patients. However, sipuleucel-T, a cellular product directed toward a specific antigen, prostatic acid phosphatase, was Food and Drug Administration (FDA) approved in 2010 in the United States, based on phase 3 data showing improved overall survival in men with minimal or no symptoms due to mCRPC compared with placebo. Subsequently, several other promising immunotherapeutic approaches have advanced to study in the phase 3 setting, including ipilimumab and PROSTVAC. The demonstration of efficacy of immunotherapy in prostate cancer provides a new treatment option for men with no or few symptoms early in the course of mCRPC. Since sipuleucel-T was approved, several drugs that favorably impact survival have also been approved or are close to approval in the United States. These agents include cabazitaxel, abiraterone, radium-223, and MDV3100. There are many unresolved issues about sipuleucel-T, such as best timing in the course of mCRPC, the role for booster therapy, and the role of combinations with other active drugs, including other immune-modulating approaches. There are also many questions regarding sequencing of these new agents and, given the number of other promising agents in phase 3 trials, these questions will become more complicated, underscoring the need for better predictors of benefit for the individual patient.

Castrate-resistant prostate cancer (CRPC) occurs when disease progresses in the presence of castrate levels of androgens and remains sensitive to further hormonal manipulation. For many years the treatment of CRPC was limited to the use of docetaxel for metastatic disease. However, this has recently changed with the approval of several new agents. Sipuleucel-T, an immunotherapeutic vaccine, is now available in the US for patients with non-metastatic CRPC and abiraterone, an oral enzyme inhibitor of androgen biosynthesis, as well as cabazitaxel, a cytotoxic chemotherapeutic, have been approved for the treatment of metastatic CRPC. Also, denosumab, a subcutaneous antibody, is now an option for the treatment of patients with CRPC with bone metastases, in addition to zoledronic acid, an intravenous bisphosphonate. Further treatment advances for metastatic CRPC therapeutics are in late stage phase III development. These include therapies affecting the androgen receptor (MDV3100) as well as additional immune-based therapeutics, PROSTVAC and ipilimumab. A broad range of agents is also emerging under the term targeted therapies. The endothelin-A receptor antagonist zibotentan, the tyrosine kinase inhibitors dasatinib, sorafenib and cabozantinib, the anti-angiogenic agent aflibercept, and the clusterin inhibitor custirsen, are all currently being tested for efficacy in metastatic CRPC. The mechanism of action of these and other promising agents are discussed alongside current therapeutic options and their potential place in the treatment landscape for CRPC is considered.

Summary Background Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. Methods We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×10 8 plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×10 9 plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984. Findings We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. Interpretation The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. Funding US National Institutes of Health.

Prostate cancer is the second leading cause of death from cancer for men in the United States, claiming over 32,000 lives each year.1 Patients who present with bone metastasis have a 5-year survival rate of 3%.2 Metastatic prostate cancer is initially treated with either hormonal therapy or orchiectomy to deprive prostate cancer cells of testosterone, which binds to the androgen receptor and induces cellular proliferation. Although these treatments may initially limit tumor growth, the cancer cells will ultimately proliferate in spite of decreased levels of testosterone, a state known as castration resistance,3 increasing the potential for metastasis. Conventional treatment for metastatic castration-resistant prostate cancer (mCRPC) employs additional agents, such as androgen receptor antagonists (ARAs) and cytotoxic chemotherapy (i.e., docetaxel and cabazitaxel), which has been shown to prolong survival and palliate symptoms in patients with mCRPC.4 The recent approval by the U.S. Food and Drug Administration (FDA) of sipuleucel-T for mCRPC and ipilimumab for metastatic melanoma have generated significant momentum in the field of cancer immunotherapy. PSA-TRICOM (PROSTVAC®) is an investigational, off-the-shelf, vector-based therapeutic cancer vaccine genetically engineered with transgenes for prostate-specific antigen (PSA) and 3 human T-cell costimulatory molecules.5 A phase II randomized, placebo-controlled trial in 125 patients with mCRPC demonstrated a survival benefit of 8.5 months for patients treated with PSA-TRICOM compared to patients treated with placebo (25.1 vs. 16.6 months; P = 0.0061).6 In a separate single-arm study in 32 patients with mCRPC, the median overall survival was 26.6 months, and enhanced PSA-specific T-cell responses were associated with improved survival.7 The most common adverse event in these trials was a mild, local injection-site reaction, with only a subset of patients experiencing systemic flu-like symptoms. One patient had grade 3 injection-site cellulitis.6 Here we present a case report of a patient who, despite multiple negative prognostic factors, demonstrated prolonged survival with minimal toxicity after receiving treatment with PSA-TRICOM. Furthermore, the patient had a prolonged stable disease course while on PSA-TRICOM in spite of fluctuations in his PSA.

BACKGROUND Most prostate cancer-related deaths occur in patients with castration-resistant prostate cancer (CRPC). Recent preclinical and clinical studies have identified intracellular signaling pathways and changes in the tumor and bone microenvironment as potential key drivers of CRPC. This increased understanding of mechanisms associated with CRPC has driven the development of numerous new agents, many of which are poised to alter the current CRPC treatment landscape. METHODS A review of literature was conducted to identify ongoing and planned phase III studies of novel agents to treat CRPC. RESULTS Multiple studies were identified, including novel androgen biosynthesis inhibitors (abiraterone, TAK-700), androgen-receptor inhibitors (MDV3100), angiogenesis inhibitors (aflibercept, tasquinimod), endothelin antagonists (zibotentan, atrasentan), a Src tyrosine kinase inhibitor (dasatinib), a novel radiotherapy (radium-223), and new immunotherapies (ipilimumab and ProstVac). In addition, both sipuleucel-T (an immunotherapy) and cabazitaxel (third-generation taxane) and the RANK-L inhibitor, denosumab, have recently been approved by the US Food and Drug Administration. CONCLUSIONS Various combinations of these agents could theoretically be used to treat future patients with CRPC by targeting multiple signaling pathways as well as aspects of the tumor and bone microenvironments. Additional research will be needed to understand how to best use these agents and individualize care to optimize CRPC patient outcomes. Prostate 72:338–349, 2012. © 2011 Wiley Periodicals, Inc.

Recent phase III trial results have demonstrated the effectiveness of sipuleucel-T, a therapeutic cancer vaccine, in the treatment of metastatic prostate cancer. Yet, despite the survival benefit of sipuleucel-T, questions remain about how immunologic agents can be used in the treatment of metastatic prostate cancer. The primary issue confounding researchers and practitioners about the benefits of sipuleucel-T is the lack of effect on time to progression. It may be helpful to note that recent phase II data from a different therapeutic prostate cancer vaccine (Prostvac), as well as phase III data from an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking agent in metastatic melanoma, also show improved survival without short-term changes in disease progression. Furthermore, mathematical tumor growth models provide some insight into the fact that immunologic therapies do allow for continued tumor growth, but at a slower rate, thus prolonging survival. This understanding can help to clarify the role of the newly approved sipuleucel-T in the treatment of metastatic prostate cancer. It is also possible that appropriate sequencing of therapies could further improve the clinical course for such patients. Additional clinical trials will further our understanding of the role of therapeutic cancer vaccines and add new agents to the armamentarium of therapy for patients with prostate cancer.

TO THE EDITOR: In the March 1, 2010, issue of Journal of Clinical Oncology, Kantoff et al reported the results of a phase II randomized trial of a poxviral-based prostate-specific antigen vaccine (PROSTVAC) in metastatic castration-resistant prostate cancer. Eighty-two patients received PROSTVAC and 40 received control vectors. The primary end point was progression-free survival, which was similar in both groups (hazard ratio, 0.884; 95% CI, 0.568 to 1.375; P .6), but overall survival (OS) favored PROSTVAC arm (25.1 v 16.6 months). The authors conclude that PROSTVAC immunotherapy is associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS. Although these data merit further exploration, we have concerns about whether both study arms are comparable. First, the difference in median age (71.6 v 79 years), percentage of lymph node involvement only (9.8% v 0%), and median survival estimated by Halabi nomogram may favor the PROSTVAC arm. Second, as Kantoff et al point out, the lack of treatment data after initial progression limits the interpretation of the survival result. PROSTVAC plus subsequent treatment improved in 3 months the survival predicted by Halabi. In the control arm, OS is reduced by 4 months as estimated by the Halabi nomogram. Half of the patients in the control arm received PROSTVAC as second-line treatment. An interesting question is whether a higher percentage of patients in the PROSTVAC arm received second-line docetaxel, obtaining a benefit in survival. Third, Kantoff et al mentioned that only docetaxel has been shown to affect survival in metastatic prostate cancer, by approximately 3 months. In the TAX 327 study, an OS of 19.2 months was reported in the every-3-weeks docetaxel arm. Nevertheless, patients included in the TAX 327 had an disfavorable prognosis when compared with the PROSTVAC study. Patients in TAX 327 were more symptomatic with a higher median prostate-specific antigen, Eastern Cooperative Oncology Group performance status of 2 was permitted, and 30% of patients had a Gleason score of 8 to 10. In a retrospective subanalysis of 110 minimally symptomatic patients, Berthold et al reported an OS of 28.4, 25.9, and 22 months for docetaxel every 3 weeks, docetaxel every week, or mitoxantrone, respectively. These differences did not reach statistical significance as a result of the small number of patients, and the results should be interpreted with caution. These data suggest than docetaxel should offer similar results to PROSTVAC in this population and should be the control arm in a phase III study. We agree with Kantoff et al that their findings are regarded as hypothesis generating, but OS data should be interpreted with caution in the absence of treatment information after progression to PROSTVAC or placebo.

Background Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. Methods In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. Results In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P = 0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P = 0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P = 0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. Conclusions The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

5083Background: PSA-TRICOM (Prostvac) is a vector-based vaccine designed to generate a robust immune response (IR) against PSA–expressing tumor cells. To date, studies of Prostvac in patients with ...

BACKGROUND In recent years, there has been an increasing interest in targeting human prostate tumor-associated antigens (TAAs) for prostate cancer immunotherapy as an alternative to other therapeutic modalities. However, immunologic tolerance to TAA poses a significant obstacle to effective, TAA-targeted immunotherapy. We sought to investigate whether androgen deprivation would result in circumventing immune tolerance to prostate TAA by impacting CD8 cell responses. METHODS To this end, we generated a transgenic mouse that expresses the human prostate-specific antigen (PSA) specifically in the prostate, and crossed it to the HLA-A2.1 transgenic mouse to evaluate how androgen deprivation affects human HLA A2.1-resticted T cell responses following immunization of PSA-expressing mice by vaccinia-PSA (PROSTVAC). RESULTS Our PSA transgenic mouse showed restricted expression of PSA in the prostate and detectable circulating PSA levels. Additionally, PSA expression was androgen-dependent with reduced PSA expression in the prostate within 1 week of castration, and undetectable PSA by day 42 after castration as evaluated by ELISA. Castration of the PSA/A2.1 hybrid mouse prior to immunization with a PSA-expressing recombinant vaccinia virus resulted in a significant augmentation of PSA-specific cytotoxic lymphocytes. CONCLUSIONS This humanized hybrid mouse model provides a well-defined system to gain additional insight into the mechanisms of immune tolerance to PSA and to test novel strategies aiming at circumventing immune tolerance to PSA and other TAA for targeted prostate cancer immunotherapy. Prostate © 2010 Wiley-Liss, Inc.

Prostvac is a prostate cancer vaccine regimen consisting of a recombinant vaccinia vector as a primary vaccination, followed by multiple booster vaccinations employing a recombinant fowlpox vector. Both vectors contain the transgenes for prostate-specific antigen (PSA) and multiple T-cell costimulatory molecules (TRICOM). The PSA-TRICOM vaccines infect antigen-presenting cells (APCs) and generate proteins that are expressed on the surface of the APCs in an immune context. The interaction of these APCs with T cells initiates a targeted immune response and T cell-mediated tumor cell destruction. Preliminary clinical trials have indicated negligible toxicity and determined the optimal dosing schedule. In addition, these trials indicate that Prostvac may hold promise in the treatment of prostate cancer. Phase II trials have shown a survival benefit after treatment with Prostvac, especially in patients with indolent disease characteristics. Preclinical and clinical data indicate that radiation, hormonal therapy, and chemotherapy may be combined with Prostvac to enhance the vaccine’s efficacy. Additional strategies are in development to further enhance the clinical benefits of Prostvac, and a phase III trial is being planned in metastatic castration-resistant prostate cancer.

Whereas chemotherapy is the standard of care for metastatic castration-resistant prostate cancer and is associated with a survival benefit, there remains a need for alternative approaches. Extensive work has been done evaluating multiple immunotherapies for the treatment of prostate cancer. This review discusses clinical results for the most promising developments. These include cytokine-based therapy with GM-CSF; vaccines; antibody-based immunotherapies, including anti–cytotoxic T lymphocyte associated antigen 4 therapy and antibodies against additional targets; and dendritic cell-based immunotherapy.

Sipuleucel-T, approved in 2010 for treatment of minimally symptomatic or asymptomatic metastatic castrationrefractory prostate cancer (mCRPC), was the first immunotherapy vaccine approved for any type of advanced solid malignancy [1]. Treatment with sipuleucel-T is associated with amodest overall survival (OS) benefit of approximately 4mo, and no improvement in prostate-specific antigen (PSA) response or radiographic progression-free survival (PFS). Given these attributes, its current use is limited to a small number of patients with mCRPC, notably men with good performance status and limited disease burden, assuming the treating physician has easy access to an apheresis center. On the contrary, significant strides have beenmade in the development of immunotherapies in other advanced malignancies (mostly with immune checkpoint blockers) and mCRPC has lagged behind, with several novel immunotherapeutic agents failing to improve survival outcomes (Table 1). A phase 3 trial evaluating ipilimumab for men with mCRPC who had already received docetaxel did not demonstrate improved OS, although there was a suggestion of benefit in those with lower tumor burden (Table 1). Disappointingly, the much awaited pre-docetaxel phase 3 trial of ipilimumab has also reported negative results (press release by BristolMyers Squibb, July 23, 2015). Furthermore, tasquinimod, an oral immunotherapy with effects on the tumor microenvironment, failed to improve OS in a randomized, placebocontrolled, phase 3 study in chemotherapy-naive men with mCRPC [2]. Among the immunotherapeutic agents currently in development in the mCRPC setting, Prostvac is one of the mostpromising.However, evenProstvacwasassociatedwith

Several therapies for patients with castrate resistant prostate cancer (CRPC) have been approved within the last 5 years that have shown safety, tolerability and survival benefits that have far exceeded the expectations of oncologists. The treatment algorithms have sufficiently changed from approving drugs in the post docetaxel and cabazitaxel treatment space, to applying the same drugs much earlier in the prechemotherapy window. This may permit for earlier more effective control of the disease and may allow patients to avoid more toxic therapies later in the treatment arena. While prostate cancer was the first solid tumor malignancy to have an approved immunotherapy Sipuleucel-T™, nevertheless, prostate cancer still falls behind melanoma, renal cell, bladder, and non small cell lung cancers in its response to a novel class of agents, i.e., the checkpoint inhibitors. The rationale for studying immunotherapy in prostate cancer, the current immunologic modalities under development, and how to develop novel immune strategies either alone or in combination with other agents remains a challenge that may yet to be solved as more biologic agents become available for testing. Understanding why prostate cancer remains resistant to certain immune approaches, ie, checkpoint inhibition or may be suboptimally responsive to other vaccine strategies is an important goal in successfully using immunologic agents. This chapter brings to the forefront how to best deal with these issues and how prostate can be viewed as a target for rational immunotherapeutic approaches.

Immunotherapy for the treatment of malignant neoplasms has made significant progress over the last 20 years. Multiple molecular targets and clinical agents have been developed recently, particularly in the field of metastatic adenocarcinoma of the prostate. Sipuleucel-T is currently the only FDA approved immunotherapy for prostate cancer. PSA-TRICOM (Prostvac) currently has a phase III randomized trial underway after a phase II trial showed an improvement in overall survival. Interestingly, both these agents showed improvement in overall survival with no measurable change in disease state, leading to significant controversy as the utility of these agents in prostate cancer. Ipilimumab revealed a benefit for a sub-cohort of men in a post-docetaxel group and is currently undergoing investigation in a pre-docetaxel group. There are a number of other targets such as PD-1 which have shown effectiveness in other neoplasms that will likely be investigated in the future for use in prostate cancer.

PURPOSE: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. EXPERIMENTAL DESIGN: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells. RESULTS: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. CONCLUSION: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.

Purpose There is no current standard treatment for patients with prostate cancer who have received hormonal therapy but have an increasing prostate specific antigen (PSA) without radiographic evidence of metastasis. This trial was designed to analyze toxicity, immunogenicity and time to treatment failure using vaccine, antiandrogen therapy or their sequential use. Materials and Methods A total of 42 patients were randomized to receive vaccine vs antiandrogen therapy with nilutamide. The vaccine consisted of recombinant vaccinia viruses containing the PSA and B7.1 costimulatory genes as prime vaccinations, and avipox-PSA as boosters. After 6 months patients with an increasing PSA and no metastasis may receive a combination of both treatments. Results Three patients on nilutamide were removed from study secondary to grade 3 toxicities but no grade 3 toxicities were attributed to vaccine. In the vaccine arm median time to treatment failure was 9.9 months with 13 of 21 decreases in PSA velocity vs 7.6 months with 16 of 21 decreases in PSA velocity in the nilutamide arm (p =0.28). Of the patients in the nilutamide arm 8 had vaccine added at the time of PSA progression. Median time to treatment failure with combined therapy was 5.2 months, with a median duration from study entry of 15.9 months. Of the patients in the vaccine arm 12 had nilutamide added at the time of PSA progression. Median time to treatment failure with combined therapy was 13.9 months and a median of 25.9 months from initiation of therapy. Conclusions Further studies are merited to investigate the role of combining vaccine with antiandrogen therapy or vaccine followed by vaccine plus antiandrogen therapy in this patient population.

Purpose: Many patients with clinically localized prostate cancer develop biochemical failure despite excellent local therapy perhaps due to occult metastatic disease. One potential solution is the utilization of a well-tolerated systemic therapy (e.g., vaccine) in concert with local therapy. Experimental Design: We present a randomized phase II clinical trial designed to determine if a poxviral vaccine encoding prostate-specific antigen (PSA) can induce a PSA-specific T-cell response when combined with radiotherapy in patients with clinically localized prostate cancer. Thirty patients were randomized in a 2:1 ratio into vaccine plus radiotherapy or radiotherapy-only arms. Those patients in the combination arm received a “priming” vaccine with recombinant vaccinia (rV) PSA plus r V containing the T-cell costimulatory molecule B7.1 (rV-B7.1) followed by monthly booster vaccines with recombinant fowlpox PSA. The vaccines were given with local granulocyte-macrophage colony-stimulating factor and low-dose systemic interleukin-2. Standard external beam radiation therapy was given between the fourth and the sixth vaccinations. Results: Seventeen of 19 patients in the combination arm completed all eight vaccinations and 13 of these 17 patients had increases in PSA-specific T cells of at least 3-fold versus no detectable increases in the radiotherapy-only arm (P < 0.0005). There was also evidence of de novo generation of T cells to well-described prostate-associated antigens not found in the vaccine, providing indirect evidence of immune-mediated tumor killing. The vaccine was well tolerated. Conclusion: This vaccine regimen can be safely given in patients undergoing radiation therapy for localized prostate cancer, with the majority of patients generating a PSA-specific cellular immune response to vaccine.

Purpose: To develop and validate a model that can be used to predict the overall survival probability among metastatic hormone-refractory prostate cancer patients (HRPC). Patients and Methods: Data from six Cancer and Leukemia Group B protocols that enrolled 1,101 patients with metastatic hormone-refractory adenocarcinoma of the prostate during the study period from 1991 to 2001 were pooled. The proportional hazards model was used to develop a multivariable model on the basis of pretreatment factors and to construct a prognostic model. The area under the receiver operating characteristic curve (ROC) was calculated as a measure of predictive discrimination. Calibration of the model predictions was assessed by comparing the predicted probability with the actual survival probability. An independent data set was used to validate the fitted model. Results: The final model included the following factors: lactate dehydrogenase, prostate-specific antigen, alkaline phosphatase, Gleason sum, Eastern Cooperative Oncology Group performance status, hemoglobin, and the presence of visceral disease. The area under the ROC curve was 0.68. Patients were classified into one of four risk groups. We observed a good agreement between the observed and predicted survival probabilities for the four risk groups. The observed median survival durations were 7.5 (95% confidence interval [CI], 6.2 to 10.9), 13.4 (95% CI, 9.7 to 26.3), 18.9 (95% CI, 16.2 to 26.3), and 27.2 (95% CI, 21.9 to 42.8) months for the first, second, third, and fourth risk groups, respectively. The corresponding median predicted survival times were 8.8, 13.4, 17.4, and 22.80 for the four risk groups. Conclusion: This model could be used to predict individual survival probabilities and to stratify metastatic HRPC patients in randomized phase III trials.

215 Background: Annually about 30-50,000 men are diagnosed with biochemically recurrent prostate cancer (BCRpc), defined by a rising PSA after radical prostatectomy (RP) or definitive radiation therapy (RT) with negative conventional imaging (CT and bone scan). Standard treatments include salvage therapies, androgen deprivation or surveillance. The role of immunotherapy in BCRpc is undefined. Methods: This study evaluates PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA, in BCRpc. Key eligibility criteria include PSA > 0.8 after RP or > 2.0 after RT with a maximum PSA of 30, PSA doubling time (DT): 5-15 months; testosterone > 100, negative CT and bone scan. Patients (pts) are randomized to vaccine for 6 months or 6 months surveillance followed by 6 months of vaccine. In a post hoc analysis delayed PSA declines were characterized as a confirmed PSA decline after an intra-study apex PSA (ISAP) defined by a peak PSA affirmed by a contiguous PSA within 10% (to exclude lab variations). 80 pts will be enrolled at NCI, Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Results: Of the 26 pts enrolled thus far, 22 have been followed for > 9 months after vaccine and are evaluable. On-study median values were age 66.8 years (54-78), PSA 2.67 ng/ml (0.83-28.5), PSA DT 7.5 months (5.1-14.9). 8 pts (38%) had delayed PSA declines after ISAP (-12% to -99%). Of 13 pts on surveillance for 6 months, only one pt had a similar decline lasting only 56 days. Conclusions: Preliminary data from this study suggests that PROSTVAC may be associated with delayed, but sustained PSA declines in BCRpc which are rarely seen in surveillance alone. Additional data will be acquired from this study, but this provides rationale to develop immunotherapy combinations in BCRpc. Clinical trial information: NCT02649439. [Table: see text]

BACKGROUND A Phase I trial of recombinant vaccinia prostate specific antigen (rV-PSA) in patients with advanced metastatic prostate cancer was conducted. This report describes 42 patients who were treated with up to three monthly vaccinations. METHODS All patients were entered on a dose-escalation phase I study of recombinant vaccinia containing the gene for PSA (rV-PSA). The primary objective of this study was to determine the safety of this vaccine in metastatic androgen-independent prostate cancer patients. A secondary objective was to assess evidence of anti-tumor activity by PSA measurements, radiologic findings, and immunologic methods. RESULTS There was no significant treatment-related toxicity apart from erythema, tenderness, and vesicle formation that lasted several days at the site of injection in some patients. There were immunologic responses, in selected patients, as evidenced by an increase in the proportion of PSA-specific T cells after vaccination. Furthermore, we show that these patients' T cells can lyse PSA-expressing tumor cells in vitro. CONCLUSION Given the low toxicity profile and the evidence of immunologic activity, we believe future study is warranted with PSA-based vaccines in prostate cancer. New PSA-based vaccines and vaccine strategies are currently being evaluated. Prostate 53: 109–117, 2002. © 2002 Wiley-Liss, Inc.

Manipulations capable of breaking host tolerance to induce tissue-specific T cell-mediated inflammation are of central importance to tumor immunotherapy and our understanding of autoimmunity. We demonstrate that androgen ablative therapy induces profuse T cell infiltration of benign glands and tumors in human prostates. T cell infiltration is readily apparent after 7–28 days of therapy and is comprised predominantly of a response by CD4+ T cells and comparatively fewer CD8+ T cells. Also, T cells within the treated prostate exhibit restricted TCR Vβ gene usage, consistent with a local oligoclonal response. Recruitment/activation of antigen-presenting cells in treated prostate tissues may contribute to local T cell activation. The induction of T cell infiltration in prostate tissues treated with androgen ablation may have implications for the immunotherapeutic treatment of prostate cancer as well as other hormone-sensitive malignancies, including breast carcinoma.

Although significant progress has been made in the immunotherapy of prostate cancer, the challenges involved in the successful development of immunotherapy for prostate cancer are many. First, from an immunologic perspective, prostate cancer is almost certainly not one disease, and the progression from one disease state to another and development of castration-resistant prostate cancer (CRPC) are likely associated with antigenic drift. Thus, the development of seemingly efficacious therapy in patients with advanced metastatic CRPC may or may not be relevant to the treatment of patients with earlier stage or androgen deprivation–responsive (hormone-sensitive) prostate cancer. Second, under the best of circumstances, defining clinical responses is challenging in prostate cancer, with considerable debate and confusion over how to use prostate-specific antigen (PSA) kinetics and, in the case of immunotherapy, the apparent disconnect between the intermediate outcomes such as response proportion and time to progression (TTP) traditionally used in oncology and survival. Third, the difficulty in demonstrating a clear relationship between the induction of antigen-specific immune responses and clinical outcome has fueled skepticism regarding immunotherapies. Finally, there is inherent tension between the imperative to have a rapid and realistic drug development timeline (hence the instinct to test new agents in patients with high disease burden and a shorter time to events such as progression or death) and the selection of patients with a lower likelihood of immunosuppressive mechanisms (hence the instinct to test new agents in patients with minimal disease burden, but in whom time to clinically meaningful events such as progression or death can be prohibitively long). In this issue of Journal of Clinical Oncology, Kantoff et al report the results of a randomized phase II trial of a poxviral-based vaccine approach targeting PSA in men with metastatic CRPC. One hundred forty-two men were randomly assigned in a ratio of two to one to receive either PROSTVAC or control vectors. The primary end point, progression-free survival, was not met. However, and somewhat unexpectedly, an overall survival advantage favoring the investigational agent was observed. This report in many ways highlights some of the challenges that confront investigators in seeking to develop immunotherapy in prostate cancer. Prostate cancer is not one disease. Like most immunotherapeutic studies undertaken to date, the present study clearly defined the target population, an important element of any clinical investigation, but in so doing, it also limited the ability to generalize these results. In particular, the group of patients with CRPC was intentionally limited to patients believed to have favorable risk features. Thus, patients with visceral metastases or pain requiring opioid analgesics were excluded, and only patients with Eastern Cooperative Oncology Group performance status of 0 or 1 and Gleason score (GS) of less than or equal to 7 were included. These are reasonable eligibility criteria, because each one of these features is associated with worse survival in a multivariable predictive model developed by Halabi et al on the basis of 1,100 patient with CRPC. Furthermore, an earlier study of sipuleucel-T (Dendreon, Seattle, WA) suggested that only patients with low GSs benefited from such therapy, although this preliminary observation subsequently was shown to be incorrect, with all GS subsets benefiting. However, the use of these eligibility criteria raises important questions. For example, should the development of PROSTVAC proceed only in patients with GSs of 7 or less? Is there biologic plausibility to segmenting the CRPC population in this fashion? With regard to patient selection and balance between the two treatment groups, the survival predicted by Halabi et al in such patients was 22.5 months for those treated with PROSTVAC and 20.4 months for controls. Although the difference in median survival predicted by Halabi et al was not statistically significant, this difference nevertheless favored the experimental treatment group. Furthermore, although the small sample size precludes definitive conclusions, there was also an imbalance in the percentage of lymph node–only patients (a group with favorable prognosis) that favored the PROSTVAC arm (9.8% v 0%) and that conceivably could have had an impact on outcome. PSA kinetics and the apparent disconnect between response proportion or TTP and survival. Kantoff et al indicate that PSA responses were infrequent, although they describe a single case of a patient with a drop in PSA and prostatic acid phosphatase of more than 80%. It is not clear if this was the only case of a PSA decline in the 84 patients assigned to receive PROSTVAC, but the lack of PSA declines has previously been described in immunotherapy trials with some agents (eg, sipuleucel-T, GVAX). In an academic community that has grown accustomed to screening for anti–prostate cancer activity with PSA declines, it will take a concerted effort to move away from PSA end points to define activity. The fact that some apparently active immunotherapeutic agents, such as ipilimumab, do have significant PSA-lowering effects makes this adjustment all the more difficult. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 28 NUMBER 7 MARCH 1 2010

Objectives. Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo. Methods. A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction. Results. Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline. Conclusions. Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization.

Prostate cancer is a suitable target of innovative immunotherapeutic treatment approaches [1,2]. It has been hypothesized that such therapies could be most efficient when used earlier in the course of the disease [1]. In their phase 2 study, reported in this month’s issue of European Urology, DiPaola and coworkers administered prostatespecific antigen (PSA) pox virus vaccine (PROSTVAC-VF) to 40 patients with nonmetastatic PSA recurrence after local treatment for histopathologically confirmed prostate cancerwithout current hormonal therapy [3]. Of the 50 patients initially enrolled, 10 were excluded because of various violations of predefined study entry criteria. Treatment consisted of two types of fowlpox virus–based vaccine directed against the PSA molecule (a single dose of PROSTVAC-V followed by PROSTVAC-F boosts). Toxicity was mild to moderate with mainly immune response– related side effects. Within 18 mo, most patients experienced disease biochemical or clinical progression. With too few events, survival analysis was not possible. A slower PSA velocity after vaccination treatmentwas themain finding of this study [3]; however, without a control group available, it is impossible to estimate the size of this effect. Vaccination including PROSTVAC-VF, as used in the study by DiPaola et al [3], represents a promising new approach to treat advanced or recurrent prostate cancer [4,5]. It was found to be associated with improved survival outcome in patientswithmetastatic castration-resistantprostate cancer, although it was not associated with a measurable impact on diseaseprogression [5].MajorPSAresponseswere infrequent [6]. Taking these observations [5] into consideration, it is difficult to evaluate the clinical significance of slowing down of the PSA velocity, particularly at this early stage of disease

We recently reported the clinical results of a Phase I trial combining ipilimumab with a vaccine containing transgenes for prostate-specific antigen (PSA) and for a triad of costimulatory molecules (PROSTVAC) in patients with metastatic castration-resistant prostate cancer. Thirty patients were treated with escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naïve patients, 58 % had a PSA decline. Combination therapy did not exacerbate the immune-related adverse events associated with ipilimumab. Here, we present updated survival data and an evaluation of 36 immune cell subsets pre- and post-therapy. Peripheral blood mononuclear cells were collected before therapy, at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow cytometry for the subsets of T cells, regulatory T cells, natural killer cells, and myeloid-derived suppressor cells. Associations between overall survival (OS) and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63 years (1.77-3.45). There were trends toward associations for longer OS and certain immune cell subsets before immunotherapy: lower PD-1(+)Tim-3(NEG)CD4EM (P = 0.005, adjusted P = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P = 0.004), and a higher number of CTLA-4(NEG) Tregs (P = 0.005, adjusted P = 0.010). We also found that an increase in Tim-3(+) natural killer cells post- versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P = 0.015). These results should be considered as hypothesis generating and should be further evaluated in larger immunotherapy trials.

PSA-TRICOM (PROSTVAC) is a novel vector-based vaccine designed to generate a robust immune response against prostate-specific antigen (PSA)-expressing tumor cells. The purpose of this report is to present an overview of both published studies and new data in the evaluation of immune responses to the PSA-TRICOM vaccine platform, currently in phase III testing. Of 104 patients tested for T-cell responses, 57% (59/104) demonstrated a ≥2-fold increase in PSA-specific T cells 4 weeks after vaccine (median 5-fold increase) compared with pre-vaccine, and 68% (19/28) of patients tested mounted post-vaccine immune responses to tumor-associated antigens not present in the vaccine (antigen spreading). The PSA-specific immune responses observed 28 days after vaccine (i.e., likely memory cells) are quantitatively similar to the levels of circulating T cells specific for influenza seen in the same patients. Measurements of systemic immune response to PSA may underestimate the true therapeutic immune response (as this does not account for cells that have trafficked to the tumor) and does not include antigen spreading. Furthermore, although the entire PSA gene is the vaccine, only one epitope of PSA is evaluated in the T-cell responses. Because this therapeutic vaccine is directed at generating a cellular/Th1 immune response (T-cell costimulatory molecules and use of a viral vector), it is not surprising that less than 0.6% of patients (2/349) tested have evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. An ongoing phase III study will evaluate the systemic immune responses and correlation with clinical outcomes. Cancer Immunol Res; 2(2); 133–41. ©2013 AACR.