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Vaccination of Urological Cancer Patients With WT1 Peptide-Pulsed Dendritic Cells in Combination With Molecular Targeted Therapy or Conventional Chemotherapy Induces Immunological and Clinical Responses.
Juni 2018 | Ogasawara, Masahiro; Miyashita, Mamiko; Ota, Shuichi
The prognosis of metastatic or relapsed renal cell carcinoma (RCC) or bladder cancer (BC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with WT1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with molecular targeted therapy or conventional chemotherapy. Five eligible patients with metastatic or relapsed RCC and five eligible patients with BC were enrolled. No severe adverse events related to a vaccination were observed. Seven patients with RCC or non-muscle invasive BC had durable stable disease and three other patients had disease progression after DC vaccination. DC vaccination augmented WT1 specific immunity and the reduction of regulatory T cells which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a molecular targeted therapy or a conventional chemotherapy is safe and feasible for patients in advanced stage of RCC or BC. PMID 29851270

Current status of clinical trials assessing oncolytic virus therapy for urological cancers.
März 2017 | Taguchi, Satoru; Fukuhara, Hiroshi; Homma, Yukio; Todo, Tomoki
Oncolytic virus therapy has recently been recognized as a promising new option for cancer treatment. Oncolytic viruses replicate selectively in cancer cells, thus killing them without harming normal cells. Notably, T-VEC (talimogene laherparepvec, formerly called OncoVEX(GM)(-)(CSF) ), an oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in October 2015, and was subsequently approved in Europe and Australia in 2016. The efficacies of many types of oncolytic viruses against urological cancers have been investigated in preclinical studies during the past decade, and some have already been tested in clinical trials. For example, a phase I trial of the third-generation oncolytic Herpes simplex virus type 1, G47Δ, in patients with prostate cancer was completed in 2016. We summarize the current status of clinical trials of oncolytic virus therapy in patients with the three major urological cancers: prostate, bladder and renal cell cancers. In addition to Herpes simplex virus type 1, adenoviruses, reoviruses, vaccinia virus, Sendai virus and Newcastle disease virus have also been used as parental viruses in these trials. We believe that oncolytic virus therapy is likely to become an important and major treatment option for urological cancers in the near future. PMID 28326624

Recent advances in immuno-oncology and its application to urological cancers.
Sep. 2016 | Mataraza, Jennifer M; Gotwals, Philip
Recent advances in immuno-oncology have the potential to transform the practice of medical oncology. Antibodies directed against negative regulators of T-cell function (checkpoint inhibitors), engineered cell therapies and innate immune stimulators, such as oncolytic viruses, are effective in a wide range of cancers. Immune'based therapies have had a clinically meaningful impact on the treatment of advanced melanoma, and the lessons regarding use of single agents and combinations in melanoma may be applicable to the treatment of urological cancers. Checkpoint inhibitors, cytokine therapy and therapeutic vaccines are already showing promise in urothelial bladder cancer, renal cell carcinoma and prostate cancer. Critical areas of future immuno-oncology research include the prospective identification of patients who will respond to current immune-based cancer therapies and the identification of new therapeutic agents that promote immune priming in tumours, and increase the rate of durable clinical responses. PMID 27123757

Dendritic cell vaccine modified by Ag85A gene enhances anti-tumor immunity against bladder cancer.
Okt. 2012 | Zhang, Pei; Wang, Jinyan; Wang, Danan; Wang, Huan; Shan, Fengping; Chen, Liudan; Hou, Ying; Wang, Enhua; Lu, Chang-Long
The ability of dendritic cells to provide all the signals required for T-cell activation makes them an ideal cancer vaccine platform. With the use of established DC2.4 cell line, originated from C57BL/6 mice and developed by superinfecting GM-CSF transduced bone marrow cells with myc and raf oncogenes, we investigated whether the DC 2.4 cell line transfected with Ag85A gene could enhance immunity against bladder cancer. Both phenotypic and functional analyses of Ag85A-DCs were done with use of FCM and T cell proliferation test. The cytotoxicity of Ag85A-DCs loaded with tumor cell lysate was verified by LDH. Finally, the production of interferon gamma was assayed by both ELISA and FCM. The immunotherapeutic effect of DC vaccine on murine bladder cancer was assessed pharmacologically and pathologically. Our results showed that Ag85A gene transfected DCs expressed high levels of key surface markers such as CD80, CD86 and MHC-II. The CTL primed with MB49 lysate-pulsed Ag85A-DCs elicits higher activity against MB49 tumor cells and upregulated level of IFN-γ production. Furthermore, the significant inhibitive effect on tumor growth in mice was found in the group of Ag85A-DC vaccine. The infiltration of CD4(+) or CD8(+) T cell within established tumor treated by Ag85A-DC vaccine significantly increased as compared with control groups. It is therefore concluded that DCs engineered by Ag85A gene exerts enhanced anti-tumor immunity against bladder cancer and this study might provide a meaningful mode of action with the use of Ag85A engineered DC vaccination in anti-cancer immunotherapy. PMID 22884511

[Combined radiotherapy and endovascular x-ray therapy for invasive cancer of the urinary bladder].
Okt. 2006 | Zharinov, G M; Agafonova, M V; Tarazov, P G; Suvorova, Iu V; Kozlov, A A; Metelev, V V; Neklasova, N Iu
The data are presented on treatment of 131 patients with transitional cell carcinoma of the urinary bladder. Radiotherapy was received by 57, regional intraarterial chemotherapy (RIAT)--27. Radiotherapy was combined with RIAT and selective hyperglycemia (HG) in 18 cases. Local super high-frequency (SHF) hyperthermia was given additionally to another 29 patients. Radiotherapy alone was followed by primary clinical cure, a 9.6-months relapse-free period and 3-months survival (36.8%), mean survival time being 26 months. In the RIAT group, these indices were 29.6%, 10.8 mos, 51.9% and 36 mos, respectively. Combination of radiotherapy, RIAT and selective HG yielded significantly improved indices: complete response--44.4%, relapse-free period--13.6 mos, 3-year survival--66.7% and mean survival time--43 mos. After addition of SHF hyperthermia, complete response rose to 69.0%, relapse-free period--18.2 mos, 3-year survival--75.8% and mean survival time--61 mos. Joint use of radiotherapy, RIAT, HG and SHF hyperthermia caused more damage to tumor, stimulated complete response and increased 3-year survival and mean survival time. PMID 17037035

The immunotherapy of prostate and bladder cancer.
Sep. 2005 | Totterman, Thomas H; Loskog, Angelica; Essand, Magnus
The role of the immune system in controlling the growth of tumour cells is highly complex and has been extensively debated. It is well documented that the immune system controls virally induced cancers, and there is evidence for a role of specific immunity in other types of tumours. The greater understanding of the regulation and optimization of adoptive, specific immune responses, and the better characterization of tumour-associated antigens indicate the way for active specific vaccination and cell therapy in urological tumours. Currently, bacille Calmette Guerin immunotherapy is established for localized bladder cancer and many experimental immunotherapies are under evaluation. Here we review some timely aspects of tumour immunology, and describe the current status and development of immunotherapy in prostate and bladder cancer. PMID 16144528

Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24-specific MAGE-3 peptide.
Feb. 2001 | Nishiyama, T; Tachibana, M; Horiguchi, Y; Nakamura, K; Ikeda, Y; Takesako, K; Murai, M
Recent investigations have demonstrated the efficacy of autologous dendritic cells (DCs) pulsed with tumor antigens to generate tumor-specific CTLs against cancer cells. Melanoma antigens (MAGE) are a family of tumor-specific antigens shown to be expressed in various tumors, including bladder cancers and melanoma, but not in normal tissues except for the testis. Because invasive bladder cancers are frequently reported to express MAGE, we explored the possibility of establishing a new immunotherapeutic modality against advanced bladder cancer using autologous DCs pulsed with one of the MAGE-3 epitope peptides (IMPKAGLLI), which is synthesized to bind specifically to HLA-A24. A MAGE-3-expressing bladder cancer cell line, FY, was newly established from a lymph node metastasis of bladder cancer in a HLA-A24+ patient. The FY cell-specific CTL response was significantly higher when CTL was induced by autologous DCs pulsed with IMPKAGLLI than by FY cells alone or by nonpulsed DCs in vitro. A total of four HLA-A24+ patients with advanced MAGE-3+ bladder cancers were treated with s.c. injections of autologous DCs pulsed with IMPKAGLLI every 2 weeks for a minimum of 6 and a maximum of 18 times. Three of four patients showed significant reductions in the size of lymph node metastases and/or liver metastasis. No significant untoward side effects were noted in these patients. This study indicated that, at sometime in the future, tumor-specific DC-based cancer immunotherapy may be useful as an additional treatment modality against advanced bladder cancer. PMID 11205913

Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts.
Apr. 1997 | Nair, S K; Snyder, D; Rouse, B T; Gilboa, E
Vaccination with tumor extracts circumvents the need to identify specific tumor rejection antigens and extends the use of active immunotherapy to the vast majority of cancers, in which specific tumor antigens have not yet been identified. In this study we examined the efficacy of tumor vaccines comprised of unfractionated tumor material presented by professional antigen-presenting cells (APC): dendritic cells (DC) or macrophages (M phi). To enhance the relevance of these studies for human patients we used 2 poorly immunogenic murine tumor models and evaluated the effectiveness of the vaccination protocols in tumor-bearing animals. APC (in particular DC) pulsed with unfractionated extracts from these "poorly immunogenic" tumors were highly effective in eliciting tumor-specific cytotoxic T lymphocytes. A measurable CTL response could be detected after even a single immunization with tumor extract-pulsed DC. DC or M phi pulsed with tumor extract were also effective vaccines in tumor-bearing animals. In the murine bladder tumor (MBT-2) model a modest extension of survival and 40% cure rate was seen in the animal groups immunized with DC or M phi pulsed with MBT-2 tumor extract. DC or M phi pulsed with B16/F10.9 tumor extract were also remarkably effective in the B16 melanoma lung metastasis model, as shown by the observation that treatment with APC caused a significant reduction in lung metastases. Cumulatively, the CTL and immunotherapy data from the two murine tumor systems suggest that APC (in particular DC) pulsed with unfractionated cell extracts as a source of tumor antigen may be equally or more effective than genetically modified tumor vaccines. PMID 9096653

Feasibility, toxicity, and preliminary results of weekly loco-regional hyperthermia and cisplatin in patients with previously irradiated recurrent cervical carcinoma or locally advanced bladder cancer.
Apr. 1996 | Rietbroek, R C; Bakker, P J; Schilthuis, M S; Postma, A J; Zum Vörde Sive Vording, P J; Gonzalèz Gonzalèz, D; Kurth, K H; Bakker, A J; Veenhof, C H
The biological rationale for combining locoregional hyperthermia (HT) with cisplatin (CDDP) is the potentiating effect of HT on CDDP uptake and cytotoxicity. Feasibility, toxicity, and preliminary results of a clinical trial of weekly loco-regional HT in combination with cisplatin are described in this article. PMID 8598366

Phase I/II trial of preoperative thermoradiotherapy in the treatment of urinary bladder cancer.
Mai 1994 | Masunaga, S I; Hiraoka, M; Akuta, K; Nishimura, Y; Nagata, Y; Jo, S; Takahashi, M; Abe, M; Terachi, T; Oishi, K
Between April 1984 and September 1988, preoperative radiotherapy or thermoradiotherapy was administered to 49 patients with bladder cancer (T1-4N0M0; UICC classification, 1987). Twenty-one patients were preoperatively treated by radiotherapy alone, with 4 Gy per fraction and three fractions per week to a total dose of 24 Gy (TDF = 53, group 1). The other 28 patients were treated by the same radiotherapy regimen in combination with hyperthermia (group 2). Regional hyperthermia was administered for 35-60 min immediately after irradiation (two sessions per week to a total of four sessions) using an 8 MHz RF capacitive heating device. Group 2 was divided into group 2 (high), in which the average intravesical temperature (T(av)) was > 41.5 degrees C, which was the mean value, and group 2 (low) with a T(av) < 41 x 5 degrees C. Group 2 (high) showed a significantly higher incidence of down-staging and tumour degeneration than both group 1 and group 2 (low). In addition, the local recurrence rate was lower and survival time was longer in group 2 than in group 1, although not significantly so. In particular, the patients with T3-4 or grade 3 bladder cancer in group 2 had a longer average survival than those in group 1, although the difference was not significant. The toxicity associated with hyperthermia was pain during treatment, and complications were not serious. PMID 8144986

Distribution of S-100 protein-positive dendritic cells and expression of HLA-DR antigen in transitional cell carcinoma of the urinary bladder in relation to tumour progression and prognosis.
Aug. 1993 | Inoue, K; Furihata, M; Ohtsuki, Y; Fujita, Y
The distribution of S-100 protein positive dendritic cells (S100-DCs) in cancer nests and the expression of HLA-DR antigen on cancer cells in 90 patients with transitional cell carcinoma of the urinary bladder were studied immunohistochemically. A dense infiltrate of S100-DCs (more than 10 S100-DCs/high power field) was detected in 47 out of 90 cases, while in the remaining tumours the infiltrate was sparse. HLA-DR positive cancer cells (DR-CCs) were detected in 24 cases, including 16 with dense DR-CCs (more than 100 DR-CCs/high power field); no expression was observed in the remaining tumours. In terms of the numbers of S100-DCs infiltrating the following statistically significant differences were observed: tumour grading G1 > G3, depth of penetration pT0 > pT3; (p < 0.05), G2 > G3, lymphatic invasion - > + and venous invasion - > +; (p < 0.01). A multivariate analysis demonstrated that the most important factor affecting prognosis was distant organ and/or lymph node metastasis (p < 0.01) the number of S100-DCs, with a hazard ratio (HR) of 0.26 (p < 0.01), and the number of DR-CCs with HR of 0.18 (p < 0.05); these were statistically significant. S100-DCs and DR-CCs may be regarded as independent prognostic factors of tumour growth and progression. PMID 8322450

[Distribution of S-100 protein-positive dendritic cells in transitional cell carcinoma of human bladder and its relation to clinical prognosis].
Apr. 1992 | Peng, R
Immunohistochemical technique (ABC method) was applied by using anti-S-100+ protein and anti-lysozyme antibodies to examine the local infiltration of dendritic cells (DC) and lysozyme positive (lys+) cells in 78 cases of transitional cell carcinoma of the bladder. 64 of the 78 cases were followed up. The results showed that DC were present in all carcinoma nests and stroma, being more numerous in the stroma than in the parenchyma. The number of DC was positively related to 5-year survival rate, which, in B group was significantly different from that in A group (P less than 0.05). It is also related to the degree of differentiation, the highly differentiated cases having larger number of DC than the moderately or lowly differentiated cases (P less than 0.01). There were more DC in the non-infiltrated muscle layers than in the infiltrated muscle layers. (P less than 0.01). This suggests that DC might participate in the anti-tumor immune reaction of the body, the intensity of which is related to the number and distribution of DC in the carcinomatous tissue. This may provide a reliable basis for evaluating the prognosis and choosing the operation methods, especially in recurrent carcinoma of the bladder. PMID 1665394