Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate adenocarcinoma, treated with localized tumor hyperthermia (LTH), can potentially serve as a source of tumor antigen, where dying apoptotic/necrotic cells release tumor peptides slowly over time. In addition, LTH-treated cells can release heat shock proteins that can chaperone antigenic peptides to antigen-presenting cells, such as dendritic cells. We attempted to discern whether sequential LTH and intratumoral dendritic cell and/or systemic granulocyte macrophage colony-stimulating factor (GM-CSF) would activate antitumor immune response in a syngeneic murine model of prostate cancer (RM-1). Palpable RM-1 tumors, grown in the distal appendage of C57BL/6 male mice, were subjected to LTH (43.7 degrees C for 1 h) x 2, separated by 5 days. Following the second LTH treatment, animals received either PBS or dendritic cells (2 x 10(6)) intratumorally (every 3 days for three injections). Separate cohorts also received i.v. injection of recombinant adenovirus-expressing murine GM-CSF (AdGMCSF), 1 day after LTH. Control animals received AdenoLacZ or AdenoGFP. Intratumoral dendritic cell injection induced tumor-specific T-helper cell activity (IFNgamma ELISPOTS) and CTL activity, which was further augmented by AdGMCSF, indicating amplification of tumor-specific TH1 immunity. The combination of LTH, AdGMCSF, and intratumoral dendritic cell injection resulted in significant tumor growth delays when compared with animal cohorts that received LTH alone. These results support an in situ autovaccination strategy where systemic administration of GM-CSF and/or intratumoral injection of autologous dendritic cells, when combined with LTH, could be an effective treatment for local and systemic recurrence of prostate cancer.
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PMID:Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity. 1769 85

The nitroreductase (NR)/CB1954 enzyme prodrug system has given promising results in pre-clinical studies and is currently being assessed in phase I and II clinical trials in prostate cancer. Enhanced cell killing by apparent immune-mediated mechanisms has been shown in pancreatic and colorectal cancer models, by co-expressing murine granulocyte macrophage colony-stimulating factor (GM-CSF) with NR in a single replication deficient adenoviral vector. This consists of the CMV immediate early promotor driving expression of NR, with an internal ribosome entry site (IRES) and the gene for murine GM-CSF (mGM-CSF). To examine if similar enhancement of tumour cell killing could be produced in prostate cancer, the TRAMP model was chosen. Results illustrate that the combination of suicide gene therapy using NR and CB1954, with cytokine stimulation with mGM-CSF gives an improved response compared with either modality alone. The mechanism of this improved response is however likely to be non-immune based as it lacks a memory effect.
Prostate Cancer Prostatic Dis 2008
PMID:Combining gene and immunotherapy for prostate cancer. 1772 52

GM-CSF stimulates the differentiation of hematopoietic progenitors to monocytes and neutrophils, and reduces the risk for febrile neutropenia in cancer patients. GM-CSF also has been shown to induce the differentiation of myeloid dendritic cells (DCs) that promote the development of T-helper type 1 (cellular) immune responses in cognate T cells. This review summarizes some of the immunological effects of GM-CSF relevant to antitumor immunity in cancer patients. GM-CSF has been used to augment the activity of rituximab in patients with follicular lymphoma and to induce autologous antitumor immunity in patients with hormone-refractory prostate cancer. GM-CSF causes upregulation of costimulatory molecule expression on leukemia blasts in vitro, enhancing their ability to present antigen to allogeneic T cells, and, in combination with interferon-alpha, can induce antitumor immune responses in patients whose acute leukemia has relapsed following allogeneic hematopoietic progenitor cell transplant. Tumor cells engineered to secrete GM-CSF are particularly effective as antitumor vaccines, and the addition of GM-CSF to standard vaccines may increase their effectiveness by recruiting DCs to the site of vaccination. However, a significant limitation in the use of GM-CSF as an immunostimulatory agent is that objective antitumor responses are infrequent, and are often not durable. Effective and durable antitumor immunity will likely require novel methods to eliminate counterregulatory immune responses that limit activation and expansion of cytotoxic T cells with antitumor activity.
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PMID:The role of sargramostim (rhGM-CSF) as immunotherapy. 1803 36

Interleukin-6 (IL-6) can stimulate a variety of tumors including prostatic carcinoma. Research has recently shown that IL-6 may act to stimulate the progression of prostatic cancer. To date, little research has been performed to better understand the nature of granulocyte macrophage colony-stimulating factor (GM-CSF) and the expression of IL-6. The aim of this study was to evaluate the effects of GM-CSF on the expression of IL-6 in prostate cancer-3 (PC-3) cells. The bone-derived PC-3 cell line was used in this study. Reverse transcription polymerase chain reaction (RT-PCR) and real- time PCR were performed to detect IL-6 mRNA expression. The IL-6 protein was measured by enzyme-linked immunosorbent assay (ELISA) after treatment with hGM-CSF. Our data indicated that IL-6 mRNA expression did not increase after treatment with hGM-CSF in comparison to the control group. However, the expression of IL-6 protein was increased compared to the control group. GM-CSF may modulate the post-transcription pathway of IL-6 expression in prostate carcinoma cells. Our data suggest that GM-CSF may have a role in IL-6-mediated development of prostate cancer.
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PMID:Granulocyte macrophage colony-stimulating factor may modulate the post-transcription pathway of interleukin-6 expression in prostate carcinoma cells. 1830 6

Hematopoietic cytokines have been used primarily as supportive care for patients undergoing cytotoxic chemotherapy or hematopoietic progenitor mobilization. Although the commonly used agents, granulocyte colony-stimulating factor and granulocytemacrophage colony-stimulating factor (GM-CSF), have been used interchangeably, it is clear that they have different effects on immune function and immune priming. GM-CSF has been used for some time as a vaccine adjuvant agent because of its activity on monocytes and dendritic cells. In order to capitalize on the immune activation effects of GM-CSF, numerous groups have transduced the GM-CSF gene into tumor cells in an effort to recruit local inflammatory cells and cytokines to the site of vaccination. Additionally, GM-CSF alone has been demonstrated to have activity for patients with high-risk melanoma and hormone-refractory prostate cancer. This article discusses some of the immune enhancing and suppressive activities of the hematopoietic cytokines, with particular focus on the immunomodulatory effects of GM-CSF, both in the context of single-agent therapy for solid tumors as well as in the context of dendritic cell modulation during therapy for hematopoietic malignancies.
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PMID:Immunomodulation: the role of hematopoietic cytokines. 1862 84

A panel of cytokine-secreting RM-9 prostate cancer cells were tested as whole cell vaccines to determine their capacity to evoke an anti-prostate cancer immune response. In our model, vaccines secreting mGM-CSF or mIL-7 resulted in the highest increase in circulating T lymphocytes after vaccination, prolonged survival and, in a proportion of animals, tumor-free survival. Anti-tumor effects were more evident after a subcutaneous RM-9 challenge than after an intraprostatic challenge. However, when the RM-9/mGM-CSF cell line was used as intraprostatic tumor challenge, protection after RM-9/mIL-7 vaccination was restored.
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PMID:A prostate cancer vaccine comprising whole cells secreting IL-7, effective against subcutaneous challenge, requires local GM-CSF for intra-prostatic efficacy. 1864 82

CTL-associated antigen 4 (CTLA4) is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment antitumor immunity in animal models and is being developed as a treatment for cancer patients. As has been seen in preclinical models, combining CTLA4 blockade and granulocyte macrophage colony-stimulating factor (GM-CSF)-based immunotherapies can enhance the antitumor efficacy of this approach. We therefore examined whether CTLA4 blockade could be combined with GM-CSF administration. We treated 24 patients with metastatic, castration-resistant prostate cancer in a phase I trial where sequential cohorts were treated with increasing doses of ipilimumab, a fully human anti-CTLA4 antibody. Study subjects also received s.c. injections of GM-CSF at a fixed dose. Of the six patients treated at the highest dose level, three had confirmed PSA declines of >50%, including one patient that had a partial response in visceral metastases. Expansion of activated, circulating CD25(+) CD69(+) CD8(+) T cells occurred more frequently at higher doses of treatment and was greater in magnitude than was seen in patients who received the same doses of either ipilimumab or GM-CSF alone. By screening sera with protein arrays, we showed that our treatment can induce antibody responses to NY-ESO-1. These results show that this combination immunotherapy can induce the expansion not only of activated effector CD8 T cells in vivo but also of T cells that are specific for known tumor-associated antigens from the endogenous immune repertoire.
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PMID:Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. 1914 75

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.
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PMID:Immunotherapeutics in development for prostate cancer. 1934 74

Whole-cell immunotherapies and other cellular therapies have shown promising results in clinical trials. Due to the complex nature of the whole cell product and of the sometimes limited correlation of clinical potency with the proposed mechanism of action, these cellular immunotherapy products are generally not considered well characterized. Therefore, one major challenge in the product development of whole cell therapies is the ability to demonstrate comparability of product after changes in the manufacturing process. Such changes are nearly inevitable with increase in manufacturing experience leading to improved and robust processes that may have higher commercial feasibility. In order to comprehensively assess the impact of the process changes on the final product, and thus establish comparability, a matrix of characterization assays (in addition to lot release assays) assessing the various aspects of the cellular product are required. In this study, we assessed the capability of DNA-microarray-based, gene-expression analysis as a characterization tool using GVAX cancer immunotherapy cells manufactured by Cell Genesys, Inc. The GVAX immunotherapy product consists two prostate cancer cell lines (CG1940 and CG8711) engineered to secrete human GM-CSF. To demonstrate the capability of the assay, we assessed the transcriptional changes in the product when produced in the presence or absence of fetal bovine serum, and under normal and hypoxic conditions, both changes intended to stress the cell lines. We then assessed the impact of an approximately 10-fold process scale-up on the final product at the transcriptional level. These data were used to develop comparisons and statistical analyses suitable for characterizing culture reproducibility and cellular product similarity. Use of gene-expression data for process characterization proved to be a reproducible and sensitive method for detecting differences due to small or large changes in culture conditions as might be encountered in process scale-up or unanticipated bioprocess failures. Gene expression analysis demonstrated that cell products of representative lots under the same production process and at the same production scale were statistically identical. Large process changes that resulted from the artificial stress conditions used (absence of FBS and induction of hypoxia) displayed profoundly different gene expression patterns. We propose the use of simple t-test analysis in combination with the herein introduced expression ratio with mean intensity (ERMI) analysis as useful tools for process characterization by global gene expression analysis.
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PMID:Microarray-based gene expression analysis as a process characterization tool to establish comparability of complex biological products: scale-up of a whole-cell immunotherapy product. 1959 Nov 86

A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). The study reported here employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of <18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of > or =18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival > or =18 months) may best benefit from vaccine therapy.
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PMID:Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. 2063 24


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