Prostate Cancer Vaccine Research Articles

Forssman disaccharide antibodies predict positive response to ProstVac-VF prostate cancer vaccine

Forssman disaccharide antibodies predict positive response to ProstVac-VF prostate cancer vaccine

Herpes Simplex Viral Vectors: Late Bloomers with Big Potential

Human Gene TherapyVol. 25, No. 2 Pioneer PerspectiveHerpes Simplex Viral Vectors: Late Bloomers with Big PotentialJoseph C. GloriosoJoseph C. GloriosoSearch for more papers by this authorPublished Online:6 Feb 2014https://doi.org/10.1089/hum.2014.2501AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byViral vector-mediated gene therapy for opioid use disordersExperimental Neurology, Vol. 341Improvement of HSV-1 based amplicon vectors for a safe and long-lasting gene therapy in non-replicating cellsMolecular Therapy - Methods & Clinical Development, Vol. 21Vectors in gene therapy: Benefit for glioblastoma patientsViral Vectors for Gene Therapy28 June 2020Oncolytic Viruses and Their Potential as a Therapeutic Opportunity in Osteosarcoma8 August 2020Current Trends in Viral Gene Therapy for Human Orthopaedic Regenerative Medicine21 February 2019 | Tissue Engineering and Regenerative Medicine, Vol. 16, No. 4Gene Therapy: Use of Viruses as VectorsSustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV-1 vector19 November 2017 | The Journal of Gene Medicine, Vol. 19, No. 11Herpesviruses and Their Host Cells: A Successful LiaisonTrends in Microbiology, Vol. 25, No. 3Viral Vector Gene Delivery to the Brain for Treating Neurogenetic Diseases6 June 2017Supramolecular Gene Transfection AgentsEmerging Considerations in Virus-Based Gene Transfer Systems25 October 2016Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN DeficiencyMolecular Therapy, Vol. 24, No. 5Virotherapy: cancer gene therapy at last?30 August 2016 | F1000Research, Vol. 5DNA vaccination for prostate cancer: key concepts and considerations2 July 2015 | Cancer Nanotechnology, Vol. 6, No. 1Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in childrenMolecular Therapy - Oncolytics, Vol. 2 Volume 25Issue 2Feb 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Joseph C. Glorioso.Herpes Simplex Viral Vectors: Late Bloomers with Big Potential.Human Gene Therapy.Feb 2014.83-91.http://doi.org/10.1089/hum.2014.2501Published in Volume: 25 Issue 2: February 6, 2014PDF download

Immune impact induced by PSA-tricom, a therapeutic vaccine for prostate cancer.

245 Background: PSA-TRICOM is a vector-based therapeutic cancer vaccine designed to generate a targeted anti-tumor immune response against prostate-specific antigen (PSA)–expressing tumor cells. Early clinical trials have evaluated the immunologic impact of this vaccine and demonstrated promising clinical activity. PSA-TRICOM is being evaluated in a phase III trial in metastatic castration resistant prostate cancer (mCRPC). Methods: We recently conducted a broad overview of both published and new data which analyzed the immune responses to PSA-TRICOM. Immune responses included ELISPOT for antigen-specific immune response and flow-cytometry analysis of peripheral immune cells. Results: 104 patients (pts) with prostate cancer were tested for T-cell responses and 59 out of 104 (57%) demonstrated a greater than or equal to 2-fold increase in PSA-specific T cells 4 weeks after vaccine. The responders had a median 5-fold increase relative to pre-vaccine levels. For most pts PSA-specific immune responses (likely memory cells) seen 28 days following the most recent vaccine are quantitatively similar to levels of circulating influenza-specific T cells in the same pts. In addition, 19 out of 28 pts (68%) evaluated demonstrated immune responses to tumor-associated antigens not present in the vaccine (antigen spreading). Since PSA-TRICOM is designed to generate a cellular (TH1 immune response), it is not surprising that 2 out of 349 pts (<1.0%) demonstrated evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. Conclusions: PSA-TRICOM has demonstrated the ability to generate immune responses. Despite these findings, it is important to note that systemic immune response to PSA may underestimate the true therapeutic immune response since it does not measure cells that trafficked to tumor or antigen spreading. Furthermore, while the entire PSA gene is the vaccine, only one epitope of PSA is specifically evaluated in the T-cell responses. Further immune analysis continues in an ongoing phase III of PSA-TRICOM in mCRPC (NCT01322490), accruing worldwide, and two trials combining PSA-TRICOM with enzalutamide (biochemical recurrence/ NCT01875250 and mCRPC/ NCT01867333) currently accruing at NCI. Clinical trial information: multiple trials.

Peptide vaccines with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive castration resistant prostate cancer: A randomized phase II study.

3 Background: We previously developed MHC class I restricted peptide vaccines for prostate cancer and carried out a phase 1 trial for castration resistant prostate cancer (CRPC) patients to assess safety and immunological evaluation. In the present study, we conducted a randomized phase 2 trial to evaluate the efficacy of peptide vaccination therapy for chemotherapy-naive CRPC patients. Methods: Early-stage CRPC (PSA<10ng/ml) patients positive for HLA-A02 or A24 or A3 super family were randomized into two treatment groups; peptide vaccine with low dose (1mg/day) dexamethasone (Dx) versus low dose Dx alone. Patients were vaccinated subcutaneously with 3 mg of selected peptides (max. 4 kinds) 6 times at two weeks interval. Dx 1mg/day p.o. was started on the first day of peptide vaccination. Toxicity was assessed monthly, and immunological responses such as cytotoxic T lymphocyte activity and clinical responses were evaluated every 3 months. The primary endpoint of this study is progression-free survival including serum PSA. Secondary endpoints are overall survival and safety. Results: A total of 83 chemotherapy-naive CRPC patients were selected for this trial. Of these 10 patients were excluded due to HLA type mismatch and exclusion criteria. 73 patients were enrolled and randomized; 37 in the vaccine treatment group and 36 in the Dx group. One patient in the Dx group self-withdrew from the study immediate after the randomization. Median time to PSA failure in the vaccine group was significant longer than the Dx group; 602 days vs 210 days, p<0.001 (Table). Conclusions: These findings suggest that combination therapy of peptide vaccines and low dose dexamethasone may be a promising tool for chemotherapy-naive CRPC patients. Clinical trial information: UMIN000000959.[Table: see text]

Immunotherapy for prostate cancer: recent developments and future challenges

Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug development in this area has focused primarily on antigen-specific (i.e. cancer vaccines and antibody based therapies) or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved in advanced melanoma and two phase III trials evaluating ipilimumab in men with metastatic castrate-resistant prostate cancer are underway. A phase III trial evaluating ProstVac-VF, a poxvirus-based therapeutic prostate cancer vaccine, is also underway. While there has been reason for encouragement over the past few years, many questions regarding the use of immunotherapies remain. Namely, it is unclear what stage of disease is most likely to benefit from these approaches, how best to incorporate said treatments with each other and into our current treatment regimens and which therapy is most appropriate for which disease. Herein we review some of the recent advances in immunotherapy as related to the treatment of prostate cancer and outline some of the challenges that lie ahead.

Immunotherapy and therapeutic vaccines in prostate cancer: an update on current strategies and clinical implications

In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.

A randomized, double-blind, placebo-controlled, Phase I/II trial of RNActive®-vaccine cv9104 in patients with metastatic castrate-refractory prostate cancer (mcrpc): first results of the Phase I part

Meeting abstracts CV9104 is a novel mRNA-based therapeutic vaccine for prostate cancer encoding the prostate cancer-associated antigens PSA, PSMA, PSCA, STEAP, PAP and MUC1 by engineered mRNA molecules optimized for protein expression and immunostimulation (RNActive®). CV9103, an mRNA-based

Novel alphavirus-based vaccine induces strong immune responses against prostate-specific antigen (PSA) and mediates tumor cell elimination in a mouse model of prostate cancer

Prostate cancer is the second most frequently diagnosed cancer in men worldwide and sixth leading cancer-related cause of death in males. Treatments for recurrent prostate cancer are only rarely curative, and the majority of patients eventually demonstrate progressive disease. Animal and clinical studies suggested that immunological approaches can be useful for prostate cancer treatment and prevention. The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate-specific differentiation antigens is an attractive concept. Prostate specific antigen (PSA) is a serine protease of the glandular kallikrein gene family with highly restricted expression on prostate tumor cells and normal prostate. Previous attempts to develop PSA-based vaccines for prostate cancer primarily using poxvirus and adenovirus vectors resulted in promising clinical and immune responses. However, these approaches had limitations due to pre-existing antibody responses to viral vectors and insufficient safety. Previously we have constructed novel non-replicative alphavirus vector platform derived from live attenuated human TC-83 IND vaccine against Venezuelan equine encephalitis (VEE) virus infection. In earlier studies, vaccines based on alphaviruses demonstrated efficiency in targeted gene delivery to DC and induction of protective CTL immunity against several human viral pathogens and breast cancer in a rodent animal model. In this study we tested novel TC-83 based PSA-encoding alphavirus vaccine (vVLP-PSA) against prostate cancer using transgenic mouse model with established neonatal tolerance to human PSA. Preventive vaccination using vVLP-PSA demonstrated induction of strong PSA-specific CD8+ T-cell response as detected by IFNγ ELISPOT assay and intracellular cytokine staining. Potent expansion of PSA-specific CD8+ effector T-cells was found in peripheral blood and spleens of vaccinated mice using PSA peptide-loaded MHC I dextramers. vVLP-PSA vaccination also induced PSA-specific antibody production in immunized mice. Injection of TRAMP tumor cells expressing PSA into vaccinated mice resulted in elevated infiltration of tumor site with CD8+ T-cells and rapid elimination of PSA-expressing tumor cells during first several weeks after tumor challenge. Tumor survival analysis revealed tendency for delayed tumor growth in vVLP-PSA immunized mice. Altogether, our data demonstrate that TC83-based vaccine encoding PSA induces strong PSA-specific CTL response and mediates efficient elimination of antigen-expressing prostate tumor cells promptly after tumor challenge.

C164 AE37 peptide vaccination in prostate cancer induces long-lasting immunological memory and clinical efficacy

C164 AE37 peptide vaccination in prostate cancer induces long-lasting immunological memory and clinical efficacy

Monitoring luciferase-labeled human prostate stem cell antigen-expressing tumor growth in a mouse model

The aim of this study was to establish a tumor model in mice with the expression of luciferase (Luc) and human prostate stem cell antigen (PSCA), in order to evaluate the activities of anticancer drugs or vaccines for prostate cancer. RM-1 cells were stably transfected with pcDNA-Luc and pcDNA-PSCA plasmids. The Luc-expressing cells were examined using a luminometer and the PSCA-expressing cells were examined using a reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometric analysis. Male C57BL/6 mice were inoculated subcutaneously with the RM-PSCA/Luc cells, prior to the tumor growth and survival time of the mice being measured, respectively. In vivo bioluminescence imaging was used to detect Luc expression and immunohistochemical analysis was used to detect PSCA expression. Inoculation of the tumor cells into the C57BL/6 mice closely mimicked the tumor growth of prostate cancer. All of the inoculated mice exhibited a detectable tumor within two weeks. Tumor progression was able to be quantitatively monitored following the inoculation of 1×106 RM-PSCA/Luc cells. There was an excellent correlation (R2=0.9849) between the photon counts and tumor volume. The expression of PSCA in tumor tissues was confirmed using immunohistochemical analysis. The Luc and PSCA co-expression tumor model was successfully established in mice, which is likely to accelerate the understanding of the pathogenesis of prostate cancer and facilitate the development of novel antitumor drugs or vaccines for the disease.

Haptoglobin Proved a Prognostic Biomarker in Peripheral Blood of Patients with Personalized Peptide Vaccinations for Advanced Castration-Resistant Prostate Cancer

Haptoglobin (Hp) is a well-known acute-phase protein that possibly has influence on tumors through the immune response. This study was conducted to evaluate the correlation between Hp expression and the effect of treatment by cancer peptide vaccines in advanced castration-resistant prostate cancer (CRPC) patients. Hp expression was measured by RT-PCR using peripheral blood mononuclear cells (PBMCs) collected from advanced CRPC patients, who were divided into two groups: long-term survivors and short-term survivors. Before cancer peptide vaccination (pre-vaccination), Hp expression was almost same in the two groups, but after cancer peptide vaccination (post-vaccination), Hp expression was higher in short-term survivors, suggesting that Hp expression in the PBMCs increased in short-term survivors after treatment by cancer peptide vaccines. Our results suggest that Hp expression level in the PBMCs can serve as a prognostic biomarker in treatment by cancer peptide vaccine in advanced CRPC patients.

Abstract 1229: Pre-existing NY-ESO-1-specific T cell reactivity is associated with improved clinical outcome in castration resistant prostate cancer patients treated with Prostate GVAX and ipilimumab.

Abstract The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic castration resistant prostate cancer (van den Eertwegh et al, Lancet Oncology, 13: 509-17 2012). The GVAX and ipilimumab combination treatment led to PSA declines of more than 50% (Partial Response, PR) in 5 of 28 patients, PSA stabilizations (Stable Disease, SD) in 12 of 28 patients and disease progression (PD) in 11 of 28 patients. Regressing bone and lymph node metastases were observed in 2/5 PR patients. As an indication of tumor antigen-specific responsiveness we analyzed serologic and T cell responses against NY-ESO-1 before, during and after treatment. NY-ESO-1 seroreactivity (determined by ELISA) was observed in seven of 28 patients (25%). Five patients were seropositive at baseline and 2 became seropositive following treatment; no significant correlations were found with clinical benefit or survival. NY-ESO-1 T cell reactivity was determined in 19 patients by IFNγ ELISPOT after stimulation with a peptide pool of overlapping 20-mer peptides covering the immunodominant region aa121-180. NY-ESO-1-specific T cell responses were detected in 13 of 19 patients (68%) at any time before or during treatment. Increases in the frequency of NY-ESO-1 specific T cells following treatment were only observed in five of these (26%). A remarkably high number of nine out of 19 patients (47%) already exhibited NY-ESO-1-specific T cell reactivity before treatment. Interestingly, three of four (75%) PR patients displayed pre-existing frequencies of NY-ESO-1 T cells, whereas these cells were only detected in six of 15 SD/PD (40%) patients. Moreover, patients with pre-existing NY-ESO-1 T cell reactivity demonstrated a significantly prolonged overall survival (p=0.044, log-rank test). These data suggest that baseline NY-ESO-1 T cell reactivity may have predictive value for the clinical outcome of prostate GVAX and/or ipilimumab treatment. Citation Format: Anita GM Stam, Saskia JAM Santegoets, Alfons JM van den Eertwegh, Rik J. Scheper, Sinéad M. Lougheed, Helen Gall, Karin Jooss, Natalie Sacks, Thomas Harding, Kristen Hege, Israel Lowy, Sacha Gnjatic, Jedd D. Wolchok, Winald R. Gerritsen, Tanja D. de Gruijl. Pre-existing NY-ESO-1-specific T cell reactivity is associated with improved clinical outcome in castration resistant prostate cancer patients treated with Prostate GVAX and ipilimumab. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2013-1229

Abstract LB-344: Vascular normalization as an emerging strategy to enhance cancer immunotherapy.

Abstract The recent approval of a prostate cancer vaccine has renewed hope for anti-cancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they are often used at high doses in the clinic to prune tumor vessels and may paradoxically compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower “vascular normalizing” doses, but not high “anti-vascular/anti-angiogenic” doses of an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses at polarizing tumor-associated macrophages from immune inhibitory M2-like towards immune stimulatory M1-like phenotype, and in facilitating CD4+ and CD8+ T cell tumor infiltration. Based on this mechanism, scheduling lower dose anti-VEGFR2 therapy with T cell activation induced by a whole cancer cell vaccine therapy enhanced anti-cancer efficacy in a CD8+ T cell-dependent manner in both immune tolerant and immunogenic murine breast cancer models. These findings indicate that vascular normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a new strategy to more effectively use antiangiogenic agents in breast cancer with active immunotherapy and potentially other anti-cancer therapies. Citation Format: Yuhui Huang, Jianping Yuan, Elda Righi, Dan G. Duda, Dai Fukumura, Mark C. Poznanasky, Rakesh K. Jain. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-344. doi:10.1158/1538-7445.AM2013-LB-344 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Prostate cancer vaccines: an old yet novel target, the androgen receptor

Evaluation of: Olson BM, Johnson LE, McNeel DG. The androgen receptor: a biologically relevant vaccine target for the treatment of prostate cancer. Cancer Immunol. Immunother. doi:10.1007/s00262-012-1363-9 (2012) (Epub ahead of print).Cancer vaccines have been utilized as a therapeutic modality to treat prostate cancer in clinical studies for several decades. Recently with the approval of sipuleucel-T, vaccines have now been accepted as standard therapy for this disease. The androgen receptorhas long been recognized as a therapeutic target for the treatment of patients with locally advanced as well as metastatic disease. Recent preclinical studies described by Olson et al. have focused on the androgen receptor as a target for prostate cancer immunotherapy. They have developed and tested a DNA vaccine targeting the ligand-binding domain of the androgen receptor and have demonstrated in animal studies the ability to elicit T-cell responses towards the vaccine that have resulted in both antitumor activity as well as increased survival in the animal models described.

Prostate cancer vaccines

In 2010, the US FDA approved the first therapeutic cancer vaccine for the treatment of castration refractory prostate cancer – sipuleucel-T. Prostate cancer is an ideal model for cancer vaccine development based on the ready demonstration of humoral and cellular immunity to a range of cancer antigens as well as often slow progression which means that patients who are otherwise well may have a radiologically evaluable minor progression, after conventional treatment and can undergo vaccine therapy over sufficient periods of time, so as to allow the generation of a robust antitumor response. The association of prostate cancer with one of the few serum cancer biomarkers in general use has also allowed assessment of response and risk stratification of patients. In this review, we will examine key aspects of the evolution of prostate cancer vaccines, which provides an accurate prototype for other cancers, and the challenges we face.

Effect of PSA-tricom, a pox-viral vaccine in prostate cancer (PCa), on tumor growth rates within 80 days after initiation in nonmetastatic PCa.

57 Background: Our understanding of immunotherapies for prostate cancer (PSA-TRICOM, sipuleucel-T, ipilimumab) is incomplete in that such therapies have improved overall survival (OS) without changes in time to progression (TTP) in randomized trials. In an effort to better understand this discrepancy, we evaluated data from studies of PSA-TRICOM. A pox viral vaccine expressing PSA and 3 T-cell co-stimulatory molecules, PSA-TRICOM has demonstrated PSA-specific immune responses and evidence of clinical activity that supported initiation of a currently accruing Phase III trial. An analysis of NCI PCa trials (including a PSA-TRICOM trial) suggests that immune therapies may eventually slow the growth rate (GR) of tumors, leading to unaltered short term TTP, yet improved OS (Stein et al. Clin Can Res. 2011). Methods: PSA-TRICOM was administered to 50 hormone-naïve patients (pts.) with non-metastatic, castration naive PCa in a multi-center trial (ECOG 9802). Pts were treated every 4 weeks for 3 months, then every 12 weeks (preliminary data previously reported, DiPaola, RS et al. ASCO GU 2009). PSA values were used to calculate tumor GR within the first 100 days of treatment. (Pts were given no additional therapies during this time.) As previously described, a two-phase mathematical equation yielded concomitant PSA GR and regression rate constants.(Stein et. al., 2011) Results: See Table. Conclusions: These data suggest that PSA-TRICOM can alter GR significantly within 3 months. If confirmed in future trials, it could explain why vaccines have demonstrated improved OS without improved TTP. A slowing of the GR may not lead to substantial differences in short term TTP, but may enhance OS in the long term. This concept will be evaluated in an international Phase III trial of PSA-TRICOM in minimally symptomatic, metastatic castration-resistant PCa that is currently recruiting pts. Clinical trial information: NCT00108732. [Table: see text]

A phase II randomized clinical trial of samarium-153 EDTMP (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer (mCRPC) after docetaxel.

102 Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM demonstrated survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. This trial was intended to examine the safety and efficacy of the Sm-153 with PSA-TRICOM vs. Sm-153 alone. Methods: This phase 2 multi-center trial was designed to randomize 68 pts to Sm-153 with or without PSA-TRICOM. Eligibility included mCRPC, bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PSA-TRICOM was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint was comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. A Fisher’s exact test, assuming a one-tailed alpha = 0.10, was used to compare these fractions. 2° endpoints were OS, ORR, PSA changes, immunologic, and toxicity. Results: 44 pts were enrolled, 5 were not evaluable for the 1° endpoint due to withdrawal prior to 4 mos (4 on Arm A, 1 on Arm B). PFS and PSA findings are provided below. Hematologic toxicities were most common, and were well matched. Conclusions: This final analysis suggests the combination of PSA-TRICOM and Sm-153 has a similar toxicity profile to Sm-153 alone. Despite early closure of this trial due to poor accrual, which may be related to recent approval of multiple agents for mCRPC, this analysis appears to demonstrate improvement in PFS with the combination. This may indicate synergy between PSA-TRICOM and bone-seeking radiopharmaceuticals. Based on the data presented here, we are exploring the potential to combine PSA-TRICOM with alpharadin (radium-223), a next generation bone-seeking radiopharmaceutical. Clinical trial information: NCT00450619. [Table: see text]

Expression and purification of recombinant proteins based on human prostate stem cell antigen and heat shock protein-70

The aim of this study was to express and purify recombinant proteins based on human prostate stem cell antigen (PSCA) and heat shock protein-70 (HSP70). The PSCA gene and various structural domains of HSP70 were amplified by polymerase chain reaction (PCR) with the respective primers. Then, the PSCA was cloned into the prokaryotic expression vector pET21a(+) with the amino-terminus, carboxyl-terminus and overall length of HSP70, by enzyme digestion to construct the recombinant plasmids pET21-PSCA-HSPN, pET21-PSCA-HSPC and pET21-PSCA-HSP, respectively. After being expressed in Escherichia coli (E. coli) by isopropyl β-D-1-thiogalactopyranoside (IPTG) induction, recombinant fusion proteins were purified. Western blotting was performed to confirm the expression of the recombinant proteins. The results revealed that recombinant plasmids were successfully constructed. The PSCA-HSPC and PSCA-HSP expressed in E. coli existed in soluble form, as confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The purity of the recombinant proteins PSCA-HSPC and PSCA-HSP reached >95% following purification with the nickel-nitrilotriacetic acid (Ni-NTA) resin, Phenyl-Sepharose Fast Flow and Superdex 75, which lays a foundation for the development of vaccines for prostate cancer.

Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: Profile comparison

A dendritic cell-based cancer vaccine has recently received Food and Drug Administration approval in the USA based on its ability to prolong the survival of prostate cancer patients with advanced disease. However, tumor-mediated immunosuppressive mechanisms might represent an obstacle to optimal performance of this therapy. We have recently shown that monocytes from the blood of prostate cancer patients can fully mature to dendritic cells only after the tumor is removed. Here, we have tested the hypothesis that these tumor-driven monocytes correspond to the recently described subset of CD14(+) HLA-DR(low) immunosuppressor cells. Prostate cancer patients were studied before and 1 month after prostatectomy. Pre- and postsurgical patients with colorectal cancer were also included for comparison. Flow cytometric analysis was applied to define CD14(-) HLA-DR(low) CD33(+) CD11b(+) (myeloid) and CD14(+) HLA-DR(low) (monocytic) suppressor cells. Interferon-γ release was used to assess the immunocompetence of lymphocytes. In both prostate cancer and colorectal cancer patients, the percentage of CD14(+) HLA-DR(low) cells was several-fold higher compared with normal subjects. This was not the case for CD14(-) HLA-DR(low) CD33(+) CD11b(+) cells. Furthermore, postsurgical normalization of CD14(+) HLA-DR(low) cells only occurred in prostate cancer patients. In all patients, the interferon-γ response of T lymphocytes to phorbolmyristate acetate-ionomycin was higher compared with normal donors, but it was further increased after tumor ablation only in prostate cancer patients. The direct link between CD14(+) HLA-DR(low) increase and presence of primary tumor suggests a distinguishing immunosuppressive profile of prostate cancer. This observation supports the principle that the appropriate setting for prostate cancer vaccine therapy is a minimal disease status.

Proposed mechanisms of action for prostate cancer vaccines

Prostate cancer is responsible for the deaths of more than 33,000 American men every year. Once this disease has become metastatic, there is no curative treatment. Alternative therapies to chemotherapy and radical prostatectomy are being increasingly explored. Prostate cancer vaccines--which trigger a tumour-specific cytotoxic-T-lymphocyte-mediated immune attack by the patient's immune system--have been investigated in clinical trials with modest, yet encouraging, results. When developing and administering prostate cancer vaccines, it is critical to consider how vital parameters, such as the stage of disease progression and the nature of adjuvant therapies, could influence treatment outcome. Of particular interest are current and future strategies for diminishing the activity of regulatory T lymphocytes.