Prostate Cancer Immunotherapy Research Articles

A primer on tumour immunology and prostate cancer immunotherapy.

No abstract

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance.

Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation. Unlike afore said immune check point inhibitors, both cell-based (by the use of prostate specific antigen carriers autologous dendritic cells or even whole cancer cells) and recombinant viral vector vaccines are able to induce immune-mediated focused killing of specific antigen-presenting prostate cancer cells. Such vaccines, either used alone or concurrently/sequentially combined with above-mentioned conventional therapies, led to generally reach, in the field of various clinical trials, reasonable results particularly as regards the patient's overall survival. Adoptive trasferred T-cells, as adoptive T-cell passive immunotherapy, and monoclonal antibodies against specific antigen-endowed prostate cancer cells can improve immune micro-environmental conditions. On the basis of a preliminary survey about various immunotherapy strategies, are here also outlined their effects when combined with androgen deprivation therapy or radiation. What's more, as regard the immune-based treatment effectiveness, it has to be pointed out that suitable personalized epigenetic/gene profile-achieved pharmacogenomic approaches to target identified gene aberrations, may lead to overcome - as well as for conventional therapies - possible prostate cancer resistance to immunotherapy.

Role of the Immune System and Possibilities of Immunotherapy in Prostate Cancer

In recent years, thanks to new advances in tumor immunology, immunotherapy became a part of intensive research as a novel strategy in cancer treatment. Sipuleucel T is the first and only medicinal product approved by the regulatory agencies in the USA and Europe for the treatment of asymptomatic or minimal symptomatic castrate re-fractory prostate cancer. It represents the first product of autologous cell therapy. This article gives a brief overview of new approaches in cancer immunotherapy in clinical development.

Immunotherapy in Prostate Cancer: Challenges and Opportunities

Although treatment options for castration-resistant prostate cancer (CRPC) have increased over the last decade, there remains a need for strategies that can provide durable disease control and long-term benefit. Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of CRPC. To date, there are multiple strategies to target the immune system, and several approaches including therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in clinical trials. With regard to this, we report the results of the most recent clinical trials investigating immunotherapy in CRPC and discuss the future development of immunotherapy for CRPC, as well as the potential importance of biomarkers in the future progress of this field.

Combining radiotherapy and immunotherapy for prostate cancer: two decades of research from preclinical to clinical trials

The combination of radiation therapy and immunotherapy is a novel therapeutic approach for prostate cancer. Preclinical evidence has shown that ionizing radiation can have immunostimulatory effects. Ionizing radiation can also affect the tumor microenvironment, enhance infiltration of activated T cells, and trigger an inflammatory process. Together, the combined radio-immunotherapy can enhance cancer cell kill and stimulate the host immune system, providing improved local and systemic control as well as prolongation of survival. The goal of combining radiation therapy with immunotherapy is also to improve cancer cure without an increase in treatment-related toxicity. The combined approach offers a new paradigm, whereby two local therapies, i.e., radiotherapy and in situ immunotherapy, are combined to elicit both local and systemic effects. Herein, we review the rationale for combining radiation and different immunotherapies, the interactions between tumors and the immune system, as well as immunological and abscopal effects of ionizing radiation. The preclinical and clinical trials of combined radiation therapy and immunotherapy for prostate cancer are reviewed. This combined approach holds promise in the management of prostate cancer.

Effects of oxygen on the antigenic landscape of prostate cancer cells

BackgroundUse of allogeneic cancer cells-based immunotherapy for treatment of established prostate cancer (PCa) has only been marginally effective. One reason for failure could stem from the mismatch of antigenic signatures of vaccine cells and cancer in situ. Hence, it is possible that vaccine cells expressed antigens differently than tumor cells in situ. We hypothesized that cells grown in vitro at low oxygen tension (pO2) provide a better antigen match to tumors in situ and could reveal a more relevant antigenic landscape than cells grown in atmospheric pO2.MethodsWe tested this hypothesis by comparing PCa cells propagated at pO2 = 2 kPa and 20 kPa. To identify potential tumor-associated antigens (TAAs), we prepared PCa cell lysates, resolved them by two-dimensional electrophoresis and immunoblotting using spontaneous antibodies from plasma derived from PCa patients and control subjects. Antibody-labeled spots were analyzed by MALDI-TOF mass spectrometry and validated by ELISA. We selected hypoxia-regulated HSP70 and hnRNP L and hypoxia-independent HSP60 and determined the frequency of plasma samples reacting with these molecules.ResultsFrequency of HSP60-reactive plasma was low in healthy controls [1.3 % (1/76)], while it was elevated in PCa patients [13.0 % (7/54); p < 0.05]. These data suggest a humoral immune response to HSP60 in PCa. Levels of autoantibodies to HSP70 did not differ from healthy controls [3.7 % (2/54)] in PCa patients [5.3 % (2/38)]. Similarly, hnRNP L autoantibodies did no differ between healthy controls [6.1 % (3/49)] and PCa patients [5.3 % (2/38)].ConclusionsOverall our results suggest the value of hypoxia as a modifier of the cellular and antigenic landscape of PCa cells. By modifying the immune reactivity of PCa cells in culture, manipulation of pO2 can be proposed as a new avenue for improving diagnosis, prognosis and immunotherapy for PCa.

Prostate Cancer Immunotherapy with Sipuleucel-T: Current Standards and Future Directions

The management of advanced prostate cancer, specifically metastatic castrate-resistant prostate cancer (mCRPC), remains a therapeutic challenge. Sipuleucel-T (Provenge; APC8015) was approved by the FDA in 2010 for the treatment of asymptomatic or minimally symptomatic mCRPC patients, and it remains the only FDA-approved immunotherapy for prostate cancer of any indication to date. Given the continued need to improve therapeutics in patients with advanced prostate cancer, as well as recent enthusiasm for cancer immunotherapy, there is a wide range of ongoing trials evaluating combinations of sipuleucel-T with other therapeutics. Additional trials are aiming to expand the application of sipuleucel-T to prostate cancer patients beyond the mCRPC setting. Ongoing challenges include understanding the full mechanism of action of sipuleucel-T, optimizing the sequence of sipuleucel-T in relation to other therapies for mCRPC in clinical practice, and the identification of surrogate markers to predict survival benefit in clinical trials.

Abstract B13: Prostate cancer immunotherapy development using tumor-specific CAR design

Abstract Prostate cancer that has progressed to metastatic disease remains largely untreatable. One of the most promising modalities for treatment of advanced cancer is immunotherapy based on adoptive transfer of T lymphocytes. It was demonstrated that T lymphocytes expressing tumor-specific chimeric artificial receptor (CAR) exert potent anti-tumor activity upon adoptive transfer into tumor-bearing host. Recent studies identified Prostate-specific membrane antigen (PSMA) and ligands for NK cell –activating receptors (e.g. NKG2D ligands) as the targets primarily expressed on tumor cells but absent on most normal tissues. We generated two sets of chimeric DNA constructs: CAR-PSMA and CAR-NKG2D, that can be used for transduction of human T cells. Both of them consist of an antigen-recognizing domain bound to the transmembrane and intracellular domains of various signal-transducing and/or cell-activating molecules and a signaling molecule. Extracellular antigen-recognizing domain of CAR-PSMA consists of single chain anti-PSMA antibody (scFv) while in another construct set it is human NKG2D receptor. Intracellular CD3 ξ-chain functions as a signaling molecule triggering T-cell activation. Co-stimulatory proteins CD28, CD40L or OX40L which can compensate for the lack of co-stimulation from the target tumor cell are either fused to CD3 ξ-chain as intracellular domains or are expressed on cell surface from bi-cistronic constructs. Upon transduction of human T cells with these constructs, transduced cells presented surface expression of the chimeric scFv anti-PSMA or NKG2D, respectively. In vitro experiments demonstrated specific binding activity and cytotoxicity of human T lymphocytes expressing anti-PSMA or NKG2D CARs against prostate cancer cells which creates the basis for a viable prostate cancer immunotherapy development. *VP and SK contributed equally to the project. Citation Format: Victor Prima, Sergei Kusmartsev, Johannes Vieweg. Prostate cancer immunotherapy development using tumor-specific CAR design. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B13.

Anti-tumor effect of the alphavirus-based virus-like particle vector expressing prostate-specific antigen in a HLA–DR transgenic mouse model of prostate cancer

The goal of this study was to determine if an alphavirus-based vaccine encoding human Prostate-Specific Antigen (PSA) could generate an effective anti-tumor immune response in a stringent mouse model of prostate cancer. DR2bxPSA F1 male mice expressing human PSA and HLA-DRB1*1501 transgenes were vaccinated with virus-like particle vector encoding PSA (VLPV–PSA) followed by the challenge with Transgenic Adenocarcinoma of Mouse Prostate cells engineered to express PSA (TRAMP–PSA). PSA-specific cellular and humoral immune responses were measured before and after tumor challenge. PSA and CD8 reactivity in the tumors was detected by immunohistochemistry. Tumor growth was compared in vaccinated and control groups. We found that VLPV–PSA could infect mouse dendritic cells in vitro and induce a robust PSA-specific immune response in vivo. A substantial proportion of splenic CD8 T cells (19.6±7.4%) produced IFNγ in response to the immunodominant peptide PSA65–73. In the blood of vaccinated mice, 18.4±4.1% of CD8 T cells were PSA-specific as determined by the staining with H-2Db/PSA65–73 dextramers. VLPV–PSA vaccination also strongly stimulated production of IgG2a/b anti-PSA antibodies. Tumors in vaccinated mice showed low levels of PSA expression and significant CD8+ T cell infiltration. Tumor growth in VLPV–PSA vaccinated mice was significantly delayed at early time points (p=0.002, Gehan–Breslow test). Our data suggest that TC-83-based VLPV–PSA vaccine can efficiently overcome immune tolerance to PSA, mediate rapid clearance of PSA-expressing tumor cells and delay tumor growth. The VLPV–PSA vaccine will undergo further testing for the immunotherapy of prostate cancer.

Integrating Immunotherapies in Prostate Cancer.

In recent years, immunotherapy has emerged as a viable and promising treatment for prostate cancer. Beyond sipulecuel-T, phase III trials are evaluating multiple vaccine and immune-based therapies in men with this disease. Evidence suggests that many of these therapies are effective at augmenting immune responses and slowing tumor growth rates. Yet prospective data evaluating these responses as surrogates for survival are still needed. In the absence of validated intermediate markers of response, growing data suggests that patients with more indolent disease are more likely to benefit from immunotherapies. In order to further optimize immunotherapy use, ongoing trials are evaluating its combination with traditional as well as other immune-based treatments. Preliminary data from these trials are promising and are shedding new light on this area.

Highlights of This Issue

In this prospective, population-based epidemiological cohort study of 1,026 patients with primary invasive breast cancer, a significantly differential prognostic role of the androgen receptor (AR) tumor expression in patients with estrogen receptor alpha (ER)-positive and ER-negative tumors was demonstrated. Furthermore, AR-negativity was predictive of early treatment failure to aromatase inhibitors, but not to tamoxifen, among chemonaïve patients aged 50 or older with ER-positive tumors. The results warrant confirmation in an independent study, preferably in a randomized trial. In conclusion, AR tumor assessment may be useful in the clinical setting for improved tailoring of breast cancer treatment.Antigen spread, an adaptive immune response to nontargeted tumor antigens following treatment with an antigen-specific immunotherapy may indicate tumor cell destruction and subsequent recognition of additional antigens. Using samples from a phase 3 clinical trial, GuhaThakurta and colleagues showed that antigen spread occurs within weeks of administration of sipuleucel-T, a cellular immunotherapy for prostate cancer directed against prostatic acid phosphatase. Most significantly, antigen spread was found to correlate with overall survival. These results suggest that antigen spread may serve as a posttreatment biomarker for the efficacy of immunotherapy, a finding with broad implications for the field of tumor immunology.Filatenkov and colleagues found that the high-dose radiation transformed the immunosuppressive tumor microenvironment by inducing an intense CD8+ T cell tumor infiltrate, and a loss of myeloid derived suppressor cells (MDSCs). The change was dependent on antigen cross-presenting CD8+ dendritic cells, secretion of IFN-γ, and CD4+T cells expressing CD40L. Antitumor CD8+ T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated durable remissions in an IFN-γ dependent manner. Interestingly, extended fractionated radiation regimen did not result in robust CD8+ T-cell infiltration.Prostate cancers develop immunosuppressive microenvironment resisting current treatments and the emerging immunotherapies. Hossain and colleagues identified a population of Lin−CD15HICD33LO granulocytic MDSCs (G-MDSCs) accumulating in patients during prostate cancer progression. The G-MDSCs secreted large amounts of Arginase 1, thereby suppressing T cells' proliferation and activity. The MDSC functions were under control of the STAT3 transcription factor and a central immune checkpoint regulator. To functionally eliminate prostate cancer-associated G-MDSC, the authors successfully employed an siRNA-based approach to silence STAT3 specifically in TLR9-expressing G-MDSCs. These findings underscore the potential of oligonucleotide-based therapeutics to alleviate immunosuppressive signaling in advanced prostate cancers.

Development of PROSTVAC immunotherapy in prostate cancer.

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.

Abstract 268: Cytotopically modified antibodies to checkpoint proteins can actively reconstitute immune checkpoint blockade and inhibit tumor growth in a prostate cancer mouse model

Abstract Introduction &amp; Objectives: Prostate cancer progression can arise by tolerance to, and evasion of tumour cells from immune effector cells such as CD8 T cells and NK cells due to the immunosuppressive tumour microenvironment. Immunotherapeutic drugs can eliminate tumours by breaking this tolerance, and such drugs that can be localized to the prostate will have greater efficacy and less systemic toxicity than drugs administered systemically. It has also been shown that a localized stimulation of the immune system can boost immunity all over the body to clear distant metastases. However, in the highly immunosuppressive prostate cancer microenvironment, most activated effector immune cells are rendered anergic or even regulatory. We have shown that IL-15 in a localizable form retains its ability to activate NK and CD8 T cells in the presence and absence of prostate cancer cells. We have now used a similar approach to modify two antibodies (patent pending) which have been shown previously to be potent in inhibiting checkpoint blockade of the immune response in clinical trials. Material &amp; Methods: The antibodies were modified to enable their conjugation to a cytotopic “tail” molecule. The “tail” consists of three regions - a thiol reactive region which interacts with free cysteines on the protein of interest, a cationic region, which binds to the negatively charged cell membrane surface, and a hydrophobic region that enters the cell membrane. The cytotopic antibodies can then adhere to cell membranes and can thus localize to any lesion where it is potentially injected. The tailed agents were then compared to non-tailed ones in in-vitro assays of T cell inhibition to measure their neutralizing ability and an in-vivo prostate tumour challenge model in C57/BL6 mice. Results: We have shown that the modified antibodies can attach to cell membranes through their cytotopic tails. The two cytotopically modified antibodies were both active in reconstituting T cell activation as shown by IL-2 secretion assays in Jurkats and EL4 by upto 50% (p&amp;lt;0.05 n = 5) which was equivalent to that seen with the non-modified antibodies Furthermore we have also demonstrated in vivo in a TRAMP-C2 tumour challenge model using C57/BL6 wild type mice model that a cocktail of tailed antibodies and cytotopically modified IL-15 can completely clear animals of tumour by day 73 whereas tumour size is only reduced by 50% with the non-tailed cocktail. Conclusion: We have identified that a cocktail of a modified cytokine, IL-15, together with two antibodies directed to immune checkpoint proteins can break tolerance to immunity in the prostate cancer microenvironment and cause disease regression. A tailed form of these molecules, has equivalent or greater activity in in vivo model and makes it therefore a promising new agent for immunotherapy of prostate cancer. Citation Format: Dorota Smolarek, Christina A. Sakellariou, Prokar Dasgupta, Richard A. G. Smith, Christine Galustian. Cytotopically modified antibodies to checkpoint proteins can actively reconstitute immune checkpoint blockade and inhibit tumor growth in a prostate cancer mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 268. doi:10.1158/1538-7445.AM2015-268

Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer.

Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer.

210. Complete Control of Tumor Growth In Vivo By a Synthetic Consensus Multi-Antigen DNA Immune Therapy for Prostate Cancer

Prostate cancer (PCa) is one of the leading causes of cancer deaths among men with limited treatment options. Accordingly, new approaches, such as immunotherapy, may represent important approaches for PCa treatment. Electroporation (EP) delivered DNA vaccines has recently shown promising results for therapeutic treatment of HPV early disease in humans. Application of this technology for PCa immunotherapy strategies has been limited to single antigen and epitope targets with limited success. We hypothesized that a broader collection of antigens adjuvanted by plasmid encoded IL-12 would bypass immune tolerance and improve the breadth and effectiveness of a PCa immunotherapy approach. We tested this hypothesis in NHP for immune tolerance effects as well as in the highly relevant TRAMP-C2 challenge model. We developed highly optimized DNA vectors encoding consensus antigens for important PCa targets prostate-specific antigen (SynCon PSA), prostate-specific membrane antigen (SynCon PSMA), and human six-transmembrane epithelial antigen of the prostate (STEAP). In mice the vaccines demonstrated potent IFNγ production by ELISpot (2740 SFU) and robust immune responses in the CD4+ (0.53%) and CD8+ (3.0%) T cell compartments. Further, sera from immunized mice reacted in ELISA with relevant targets and specifically stained LNCaP cells, a human PCa cell line, as well as human PCa tumor sections, supporting that the vaccine antigens induced relevant antibody responses. Vaccination of Rhesus Macaques, which share greater than 98% identity with humans, showed robust anti-PSA, PSMA and STEAP IFNγ production (612 SFU), potential for cytotoxic T cell function, and antigen specific seroconversion supporting the ability of these constructs to break tolerance. The therapeutic potential of PSMA, STEAP, and the combination of PSMA and STEAP, alone or with the molecular adjuvant IL-12, was evaluated in mice in the TRAMP-C2 tumor model. Alone, PSMA, STEAP or PSMA+STEAP demonstrated prolonged survival and a modest impact on tumor growth. However, the combination of synthetic vaccine antigens with IL-12 resulted in 100% efficacy in treatment and clearance of tumors resulting in 100% survival. These data support further study of this novel immune therapy of PCa.

Immunotherapy in prostate cancer.

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.

The focus and prospect of prostate cancer research

The incidence and mortality of prostate cancer in China are increasing year by year. The review is focused on current hot prospects of prostate cancer. The value of serum prostate specific antigen (PSA) screening is still controversial, and PSA screening in high-risk groups is recommended for early diagnosis of prostate cancer. Prostate biopsy including transrectal approach and perineal approach, and two methods have both advantages and disadvantages. There is significant correlation between testosterone levels and the prognosis of prostate cancer, and the monitoring of testosterone level contributes to the treatment. The main complications of radical resection of prostate cancer is urinary incontinence and erectile dysfunction, three-dimensional laparoscopic and robot assisted laparoscopic techniques have obvious advantages in radical operation. Brachytherapy is another option for radical treatment, with relaxed age limit, low incidence of erectile dysfunction, urinary incontinence and reliable curative effect. The diagnosis and treatment of new technologies include such as MRI dynamic enhancement scan, ¹⁸F-fluoroethyl PET/CT, ultrasound contrast technology, prostate cancer immunotherapy, et al.

Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer.

172 Background: Results of recent clinical trials have intensified interest in immunotherapy in oncology. A number of cancer immunotherapies have been approved recently, while others are in late stage clinical development. The poxvirus-based active immunotherapy, PROSTVAC is generally well tolerated and is currently being evaluated in a global Phase 3 randomized, placebo-controlled trial. Ipilimumab, an approved immune checkpoint inhibitor in melanoma, is also being evaluated in a Phase 3 trial in chemo-naïve mCRPC. Methods: Results of two Phase 2 trials in men with mCRPC who were treated with PROSTVAC alone were compared with results from a Phase 1 combination study in mCRPC patients treated with PROSTVAC plus escalating doses of ipilimumab. Patients were enrolled in the Phase 1 combination study when docetaxel was the only FDA-approved mCRPC treatment that improved overall survival (OS). Results: In a multicenter Phase 2 trial, 125 men were randomized 2:1 to receive PROSTVAC or placebo. Patients treated with PROSTVAC had improved OS compared to placebo (25.1 vs 16.6 months; HR 0.56; 95% CI 0.37-0.85).Similar data was seen in a second phase 2 trial of PROSTVAC, where 32 patients with mCRPC had a median OS of 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months. Conclusions: The comparison of data from three independent trials of PROSTVAC active immunotherapy in three similar patient populations provides hypothesis-generating data that the addition of an immune checkpoint inhibitor may have a positive effect on overall survival through a potential synergy in mechanism of action. The updated long term survival data is further evidence of improved OS with PROSTVAC. Future randomized trials are being planned to prospectively evaluate this hypothesis. Clinical trial information: NCT00113984.

Expression of the leukocyte chemoattractant chemerin in human prostate tumors.

81 Background: The infiltration of immune cells into the tumor microenvironment can regulate growth and survival of neoplastic cells. Several studies have shown a correlation between increases in the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including prostate. The field of prostate cancer immunotherapy continues to grow, with sipuleucel-T already approved and a recombinant vaccinia-PSA (Prostvac) currently in a Phase III clinical trial. Recent studies have shown immune cell infiltration into prostate tumors after systemic administration of sipuleucel-T, suggesting infiltration of these cells may be a key step in the mechanism of action. Methods: Here, in a survey of public whole genome expression datasets we found that the gene for chemerin (RARRES2), a widely expressed endogenous chemoattractant protein for immune cells, is downregulated in prostate cancer. In mouse models, we have previously shown that forced re-expression of chemerin at sites of tumor results in an increase in immune cell infiltration (e.g. NK and T cells), as well as significantly reduced tumor growth (Pachynski JEM 2012). Results: In addition to this published analysis, using RT-qPCR we have gone on to confirm that human prostate tumors have significantly less chemerin (RARRES2) compared to normal prostate tissue. Preliminary immunohistochemistry results in human tumors using an anti-human chemerin antibody, are consistent with our qPCR results, suggesting human prostate tumors downregulate chemerin during their malignant transformation. Conclusions: We have shown, for the first time, that human prostate tumors downregulate chemerin compared to normal prostate tissue. We hypothesize that this is one mechanism of “immune escape.” Therapeutic forced re-expression of chemerin in human tumors may restore anti-tumor immunity within the tumor microenvironment resulting in slowed growth and regression of established tumors. Additionally, chemerin’s ability to recruit NK and T cells into the tumor microenvironment may make it an ideal therapy to combine with other treatments aimed at boosting the immune response, such as sipuleucel-T or checkpoint inhibition (e.g. anti-CTLA4, anti-PD1/PDL1).

XAGE-1b Cancer/Testis Antigen Is a Potential Target for Immunotherapy in Prostate Cancer

Introduction: Gene-modified cell vaccines are now considered to be the best way to achieve immunotherapy for a variety of cancers including prostate cancer (PCa). XAGE-1b is a member of the cancer/testis antigen family which has demonstrated strong immunogenicity. We investigated whether XAGE-1b is an ideal target for PCa immunotherapy. Materials and Methods: The recombinant eukaryotic expression vector pDisplay-XAGE-1b was constructed. Then the recombinant vector was transfected into Myc-CaP cells and its immunogenicity in vitro was studied. After transfection, the Myc-CaP-XAGE-1b cells were injected into FVB mice subcutaneously. Tumor growth was periodically observed and the anti-tumor effect and mechanism in vivo were further studied. Results: The recombinant vector was correctly constructed by DNA sequencing and restriction endonuclease digestion. Myc-CaP cells were successfully transfected with XAGE-1b gene by immunofluorescence staining and Western blot. The transfected cells exhibited increased IFN-γ secretion, decreased IL-6 secretion and enhanced killing activity. Tumor grew slower in XAGE-1b-modified FVB mice than in wild-type FVB mice. High dendritic cell expression and low myeloid-derived suppressor cell expression were observed in tumor tissues expressed with XAGE-1b. Conclusions: XAGE-1b gene transfection could significantly enhance the immunogenicity of Myc-CaP cells. Therefore, XAGE-1b may be an attractive target for antigen-specific immunotherapy in PCa.