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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

Immunomonitoring reveals interruption of anergy after vaccination in a case of type-2-papillary renal cell carcinoma.
März 2017 | Clavijo-Salomon, Maria A; Bergami-Santos, Patricia C; M Barbuto, José Alexandre
With the enormous and growing interest in the clinical application of immunotherapy, we are currently facing the need to accurately monitor the immune function of cancer patients. Here, we describe changes in the immune status of a patient with metastatic type-2-papillary renal cell carcinoma, before and after surgery and subsequent immunotherapy with a dendritic cell-tumor cell hybrid vaccine. Through the accurate assessment of monocyte-derived dendritic cells (Mo-DCs) function, we show that Mo-DCs were freed from tumor-induced maturation blockage by tumor resection surgery, while Mo-DCs-tumor induced suppression and anergy were only interrupted by the vaccination treatment. Our data suggest that the evaluation of Mo-DCs' function may provide a powerful and precise tool to monitor immune restoration in cancer patients. PMID 28303767

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

Human renal carcinoma cells respond to Newcastle disease virus infection through activation of the p38 MAPK/NF-κB/IκBα pathway.
Aug. 2015 | Ch'ng, Wei-Choong; Abd-Aziz, Noraini; Ong, Meng-Hua; Stanbridge, Eric J; Shafee, Norazizah
Newcastle disease virus (NDV) is an oncolytic virus that is known to have a higher preference to cancer cells than to normal cells. It has been proposed that this higher preference may be due to defects in the interferon (IFN) responses of cancer cells. The exact mechanism underlying this process, however, remains to be resolved. In the present study, we examined the antiviral response towards NDV infection of clear cell renal cell carcinoma (ccRCC) cells. ccRCC is associated with mutations of the von Hippel-Lindau tumor suppressor gene VHL, whose protein product is important for eliciting cellular responses to changes in oxygen levels. The most common first line treatment strategy of ccRCC includes IFN. Unfortunately, most ccRCC cases are diagnosed at a late stage and often are resistant to IFN-based therapies. Alternative treatment approaches, including virotherapy using oncolytic viruses, are currently being investigated. The present study was designed to investigate the mechanistic pathways underlying the response of ccRCC cells to oncolytic NDV infection. PMID 25930675

Matched-pair analysis of dendritic cell versus targeted-therapy in patients with metastatic renal cell carcinoma.
März 2015 | Isaak, Alexander; Hauser, Stefan; Rogenhofer, Sebastian; Schmidt-Wolf, Ingo G H
Although targeted-therapy (TT) for patients with metastatic renal cell cancer (mRCC) has shown an improved outcome, their prognosis is still very poor. Immunotherapy with dendritic cells (DC) as one promising new treatment tries to fight cancer by boosting the patient's own immune system. The present analysis matches two different methods of treatment against mRCC, namely sequential TT versus DC vaccine therapy, by comparison of long-term overall survival (OS). PMID 25750313

Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice.
Dez. 2014 | Gu, Xiaoyu; Erb, Ulrike; Büchler, Markus W; Zöller, Margot
Leukemia immunotherapy frequently does not meet expectation, one of the handicaps being tumor exosome (TEX)-promoted immunosuppression. We here asked, using the mouse myeloid leukemia WEHI3B and the renal cell carcinoma line RENCA, whether dendritic cell (DC) vaccination suffices to counterregulate TEX-induced immunosuppression and whether TEX could serve as tumor antigen for DC-loading. DC-vaccination significantly prolonged the survival time of WEHI3B-bearing mice, TEX-loaded DC (DC-TEX) being superior to lysate-loaded DC (DC-lys), even an excess of TEX not interfering with immune response induction. The superior response to DC-TEX was accompanied by an increase in WEHI3B-specific CD4+ T cells, evaluated by trogocytosis and proliferation. Similar findings accounted for DC loaded with RENCA TEX. TEX was efficiently taken-up by DC and TEX uptake supported CD11c, MHCII and IL12 upregulation in DC. Importantly, TEX was partly recruited into the MHCII-loading compartment such that "TEX" presentation time and recovery in T cells significantly exceeded that of tumor-lysate. Thus, TEX did not drive DC into a suppressive phenotype and were a superior antigen due to higher efficacy of TEX-presentation that is supported by prolonged persistence, preferential processing in the MHCII-loading compartment and pronounced trogocytosis by T helper cells. TEX is present in tumor patients' sera. TEX, recovered and enriched from patients' sera, might well provide an optimized, individual-specific antigen source for DC-loading and vaccination. PMID 25066479

Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.
Okt. 2014 | Ridolfi, Laura; de Rosa, Francesco; Ridolfi, Ruggero; Gentili, Giorgia; Valmorri, Linda; Scarpi, Emanuela; Parisi, Elisabetta; Romeo, Antonino; Guidoboni, Massimo
Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines. PMID 25245327

Allogeneic partially HLA-matched dendritic cells pulsed with autologous tumor cell lysate as a vaccine in metastatic renal cell cancer: a clinical phase I/II study.
Okt. 2013 | Flörcken, Anne; Kopp, Joachim; van Lessen, Antje; Movassaghi, Kamran; Takvorian, Anna; Jöhrens, Korinna; Möbs, Markus; Schönemann, Constanze; Sawitzki, Birgit; Egerer, Karl; Dörken, Bernd; Pezzutto, Antonio; Westermann, Jörg
Multi-kinase inhibitors have been established for the treatment of advanced renal cell cancer, but long-term results are still disappointing and immunotherapeutic approaches remain an interesting experimental option particularly in patients with a low tumor burden. DC are crucial for antigen-specific MHC-restricted T cell immunity. Furthermore, allogeneic HLA-molecules pose a strong immunogenic signal and may help to induce tumor-specific T cell responses. In this phase I/II trial, 7 patients with histologically confirmed progressive metastatic RCC were immunized repetitively with 1 × 10 (7) allogeneic partially HLA-matched DC pulsed with autologous tumor lysate following a schedule of 8 vaccinations over 20 weeks. Patients also received 3 Mio IE IL-2 s.c. once daily starting in week 4. Primary endpoints of the study were feasibility and safety. Secondary endpoints were immunological and clinical responses. Vaccination was feasible and safe with no severe toxicity being observed. No objective response could be documented. However, while all patients had documented progress at study entry, 29% of the patients showed SD throughout the study with a mean TTP of 24.6 weeks (range 5 to 96 weeks). In 3/7 patients, TH1-polarized immune responses against RCC-associated antigens were observed. In one patient showing a minimal clinical response and a TTP of 96 weeks, clonally proliferated T cells against yet undefined antigens were induced by the vaccine. Vaccination with tumor antigen loaded DC remains an interesting experimental approach, but should rather be applied in the situation of minimal residual disease after systemic therapy. Additional depletion of regulatory cells might be a promising strategy. PMID 23458999

The oncolytic activity of Newcastle disease virus in clear cell renal carcinoma cells in normoxic and hypoxic conditions: the interplay between von Hippel-Lindau and interferon-β signaling.
Juli 2013 | Ch'ng, Wei-Choong; Stanbridge, Eric J; Yusoff, Khatijah; Shafee, Norazizah
Viral-mediated oncolysis is a promising cancer therapeutic approach offering an increased efficacy with less toxicity than the current therapies. The complexity of solid tumor microenvironments includes regions of hypoxia. In these regions, the transcription factor, hypoxia inducible factor (HIF), is active and regulates expression of many genes that contribute to aggressive malignancy, radio-, and chemo-resistance. To investigate the oncolytic efficacy of a highly virulent (velogenic) Newcastle disease virus (NDV) in the presence or absence of HIF-2α, renal cell carcinoma (RCC) cell lines with defective or reconstituted wild-type (wt) von Hippel-Lindau (VHL) activity were used. We show that these RCC cells responded to NDV by producing only interferon (IFN)-β, but not IFN-α, and are associated with increased STAT1 phosphorylation. Restoration of wt VHL expression enhanced NDV-induced IFN-β production, leading to prolonged STAT1 phosphorylation and increased cell death. Hypoxia augmented NDV oncolytic activity regardless of the cells' HIF-2α levels. These results highlight the potential of oncolytic NDV as a potent therapeutic agent in the killing of hypoxic cancer cells. PMID 23506478

Quality of life during dendritic cell vaccination against metastatic renal cell carcinoma.
Aug. 2012 | Leonhartsberger, Nicolai; Ramoner, Reinhold; Falkensammer, Claudia; Rahm, Andrea; Gander, Hubert; Höltl, Lorenz; Thurnher, Martin
Patients with metastatic renal cell carcinoma (RCC) undergoing cytokine or targeted therapies may show a remarkable decline in quality of life (QoL). We wanted to evaluate QoL in patients with metastatic RCC undergoing therapeutic vaccination with dendritic cells (DCs). In a cross-sectional analysis, QoL was therefore assessed in RCC patients participating in three consecutive clinical trials of DC vaccination. Before the first and after the third vaccination with DCs, patients completed a QoL questionnaire (EORTC QLQ-C30, version 3). Data were transformed into scale scores and analysed using SPSS 12.0 software. Mean values of the resulting scores obtained before and after DC vaccination were compared using students t test and Wilcoxon rank-sum test. P < 0.05 was considered statistically significant. The questionnaire was completed by 55 of 71 patients (compliance rate, 77.5%) who had a median age of 58.7 years (from 30 to 75 years). No significant reductions in functioning scales including physical, emotional and social criteria as well as symptom scores, which assess typical symptoms of tumour therapies, were observed indicating that QoL remained high during DC vaccination. Significant correlations were found between overall survival and functional as well as symptom scores. Our data indicate that DC vaccination, which is a personalised treatment modality, maintains QoL and thus represents an attractive nontoxic treatment option for patients with metastatic RCC. It will be important to identify the most effective conditions of DC vaccination including combinations with other therapeutics to maximise clinical efficacy while still preserving QoL. PMID 22278360

Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial.
Nov. 2011 | Baek, Soyoung; Kim, Choung-Soo; Kim, Sung-Bae; Kim, Yong-Man; Kwon, Seog-Woon; Kim, YongMan; Kim, Hyunsoo; Lee, Hyunah
Ten cancer patients (Six renal cell carcinoma and four breast cancer patients) were treated in a phase I/II study with a vaccine composed of autologous dendritic cells (DCs) and IL-2 to evaluate the DC vaccine-related toxicity and antigen-specific immune alteration. PMID 22013914

Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis.
Mai 2011 | Draube, Andreas; Klein-González, Nela; Mattheus, Stefanie; Brillant, Corinne; Hellmich, Martin; Engert, Andreas; von Bergwelt-Baildon, Michael
More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis. PMID 21533099

Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma.
Nov. 2010 | Middel, Peter; Brauneck, Sven; Meyer, Werner; Radzun, Heinz-Joachim
Renal cell carcinoma (RCC) represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs) in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking. PMID 20969772

Increase of circulating CD4+CD25highFoxp3+ regulatory T cells in patients with metastatic renal cell carcinoma during treatment with dendritic cell vaccination and low-dose interleukin-2.
Apr. 2010 | Berntsen, Annika; Brimnes, Marie Klinge; thor Straten, Per; Svane, Inge Marie
Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2 in patients with metastatic renal cell carcinoma on the frequency of CD4+CD25highFoxp3+ Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P<0.0001). The frequency of Treg cells decreased when patients had been off IL-2 treatment for only 8 days, but remained higher than pretreatment levels. A functional assay showed that isolated Treg cells were capable of inhibiting proliferation of responder cells. Also, in vitro studies showed that coculture of mature DCs, autologous T cells and IL-2 leads to an increase in the number of Treg cells whereas IL-21 does not stimulate the induction of Treg cells. These findings demonstrate that even low doses of IL-2 in combination with DC vaccination are able to expand CD4+CD25+Foxp3+ Treg cells in vivo in metastatic renal cell carcinoma patients. Further, the results indicate that the IL-2-induced effect on Treg cells is reversible and declines shortly after termination of IL-2 treatment. Our data suggest that approaches combining DC-mediated immunotherapy and depletion of Treg cells may be necessary to enhance the ability of vaccination therapy to elicit effective antitumor responses in cancer patients. Also, adjuvant IL-21 administration may lead to immune enhancement without simultaneous induction of Treg cells. PMID 20386464

Immune responses in patients with metastatic renal cell carcinoma treated with dendritic cells pulsed with tumor lysate.
Okt. 2009 | Soleimani, A; Berntsen, A; Svane, I M; Pedersen, A E
Patients with metastatic renal cell carcinoma (mRCC) have a limited life expectancy but still a subset of these patients develop immune and clinical responses after immunotherapy including dendritic cell (DC) vaccination. In a recently published phase I/II trials, fourteen HLA-A2 negative patients with progressive mRCC were vaccinated with autologous DC pulsed with allogeneic tumour lysate. Low-dose IL-2 administered subcutaneously was given concomitantly. In this study, we analysed lysate specific proliferation of PBMCs from these patients together with the TH1/TH2 balance of the responding T cells. Also, serum concentrations of IL-10, IL-12, IL-15, IL-17 and IL-18 from these patients and additional thirteen HLA-A2 positive mRCC patients treated with autologous DC pulsed with survivin and telomerase peptides were analysed during vaccination to identify systemic immune responses and potential response biomarkers. In HLA-A2 negative mRCC patients a spontaneous predominance of TH1 secreting tumour lysate specific T cells was observed prior to vaccination in patients attaining stable disease (SD) during treatment whereas patients with continued progressive disease (PD) had a mixed TH1/TH2 response. The TH1/TH2 balance was unchanged during vaccination also when tumour lysate specific T cell responses increased. An increase in IL-12, IL-17 and IL-18 serum concentrations was observed during vaccination but no difference between patients with SD and PD was observed. IL-10 or IL-15 was not measurable in serum. PMID 19874553

Vaccine therapy in patients with renal cell carcinoma.
Juli 2009 | Van Poppel, Hein; Joniau, Steven; Van Gool, Stefaan W
Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans. Although immunotherapy is currently much less used than in the past, it remains an important option that warrants further exploration. PMID 19201522

Massive expansion of regulatory T-cells following interleukin 2 treatment during a phase I-II dendritic cell-based immunotherapy of metastatic renal cancer.
Juli 2009 | Lemoine, François M; Cherai, Mustapha; Giverne, Camille; Dimitri, Dalia; Rosenzwajg, Michelle; Trebeden-Negre, Helene; Chaput, Nathalie; Barrou, Benoit; Thioun, Nicolas; Gattegnio, Bernard; Selles, Frederic; Six, Alain; Azar, Nabih; Lotz, Jean Pierre; Buzyn, Agnes; Sibony, Mathilde; Delcourt, Annick; Boyer, Olivier; Herson, Serge; Klatzmann, David; Lacave, Roger
Cytotoxic chemotherapy is ineffective in metastatic renal cancer. However, systemic administration of interleukin 2 (IL-2) or infusion of dendritic cells (DCs) loaded with tumor extracts can lead to some response rates with concomitant survival improvements. We report the results of a phase I-II pilot study combining DCs and IL-2 where six patients were included. DCs were derived from bone marrow CD34+ cells and loaded with autologous tumor extracts. CD34-DC vaccines were infused subcutaneously at day 45, 52, 59, 90 and 120 following surgery in combination with IL-2, that was subsequently administrated after the 3rd and 4th DC vaccinations. Preparation of tumor extracts and CD34-DCs were satisfactory in all patients but one. Due to rapid tumor progression, one patient was excluded before vaccination. In the 4 remaining patients, two received 3 vaccinations, while the 2 others received 5 vaccinations and the full IL-2 treatment. No adverse effect due to the vaccinations was observed. A specific immune response against autologous tumor cells was observed in the 2 patients who completed the treatment. Interestingly, these 2 patients had a more prolonged survival than the patients receiving 3 vaccinations. Importantly, a transient and massive increase of circulating natural regulatory T-cells (nTregs) was evidenced in 3 patients following IL-2 administration. Overall, the use of CD34-DC vaccines is feasible, safe and non-toxic. A specific anti-tumor immune response can be detected. However, our data highlights that IL-2 is a potent inducer of nTregs in vivo and as such may have a negative impact on cancer immunotherapy. PMID 19639177

Patient-derived renal cell carcinoma cells fused with allogeneic dendritic cells elicit anti-tumor activity: in vitro results and clinical responses.
Juli 2009 | Zhou, Jun; Weng, Desheng; Zhou, Fangjian; Pan, Ke; Song, Haifeng; Wang, Qijing; Wang, Huan; Wang, Hui; Li, Yongqiang; Huang, Lixi; Zhang, Huakun; Huang, Wei; Xia, Jianchuan
Renal cell carcinoma (RCC) has been shown to be susceptible to immunotherapeutic treatment strategies. In the present study, patient-derived tumor cells were fused with allogeneic dendritic cells (DC) to elicit anti-tumor activity against RCC. DC from HLA-A2+ healthy donors were fused with primary RCC cells from ten patients. Phenotype of fusion cells were characterized by flow cytometer and confocal microscopy. In vitro, T cell proliferation, IFN-gamma secretion and cytotoxic T lymphocytes (CTL) activity elicited by allogeneic DC/RCC fusion cells were assessed. Clinically, ten patients were vaccinated with allogeneic DC/RCC fusion vaccine. The adverse effects and toxicity were observed. The clinical response was evaluated by CT scans. After fusion, the created hybrids expressed both tumor associated antigen and DC-derived molecules and could stimulate the proliferation and IFN-gamma secretion of T cells as well as elicit strong CTL activity against RCC cells in vitro. In vivo, no serious adverse effects, toxicity, or signs of autoimmune disease were observed after vaccination therapy. Percentage of T lymphocyte subsets in peripheral blood of patients was increased significantly. One of ten patients exhibited a partial response with regression of lung metastases. Six patients showed stable disease with stabilization of previously progressive disease (follow up 1.5 years). The PR and SD responses, exhibited by 7/10 patients who received the allogeneic DC/RCC fusion vaccine treatment, suggest that this approach is safe and can elicit immunological responses in a significant portion of patients with RCC. PMID 19221746

Vaccination strategies in patients with renal cell carcinoma.
Apr. 2009 | Asemissen, Anne Marie; Brossart, Peter
Although new treatment options for patients with advanced renal cell cancer (RCC) have been developed within recent years, vaccination is still a promising emerging treatment option. An increasing number of tumor-associated antigens (TAA) available for RCC are currently used and analyzed for their efficacy for antigen-specific vaccine strategies. Recently, antigen-specific vaccination with dendritic cells in patients with metastatic RCC was shown to induce cytotoxic T cell response associated with objective clinical responses in some of the patients. Furthermore, current studies focus on the development of more effective vaccine regimes, such as the application of polyvalent, HLA-independent RNA coding for multiple TAA and adjuvants. First results demonstrate promising clinical and immunological efficacy. The efficacy of antigen-specific vaccination might be improved by a combination of tyrosine kinase inhibitors, since sunitinib was shown to promote T cell induction following vaccination in a mouse model and elimination of regulatory T cells. PMID 19360405

Vaccination with transforming growth factor-beta insensitive dendritic cells suppresses pulmonary metastases of renal carcinoma in mice.
Okt. 2008 | Tian, Feng; Wang, Longxin; Qin, Weijun; Wang, Fuli; Song, Bin; Li, Yu; Wen, Weihong; Zhang, Zheng; Zhu, Kaichang; Zhang, Qiang; Lee, Chung; Zhong, Weide; Guo, Yinglu; Wang, He
Dendritic cells (DCs) have been widely used as cancer vaccines. However, their functional abilities have often been suppressed by tumor-secreted immunosuppressants such as transforming growth factor-beta (TGF-beta). We developed a new strategy using a TGF-beta insensitive DC as cancer vaccine. The effect of this vaccine was tested in a murine pulmonary metastases model of renal carcinoma (Renca). Tumor lysate-pulsed DCs (TP-DCs) were infected with retrovirus containing gene of dominant negative TGF-beta type II receptor (TbetaRIIDN) and thus made TGF-beta insensitive. Vaccination of the mice bearing Renca pulmonary metastases with the TbetaRIIDN TP-DC induced powerful tumor-specific cytotoxic T lymphocyte (CTL) responses, suppressed pulmonary metastases, and prolonged survival times. These results suggest TGF-beta-insensitive TP-DC vaccine can be used to enhance the antitumor efficacy of DC vaccine. PMID 18675506

Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial.
Sep. 2008 | Berntsen, Annika; Trepiakas, Redas; Wenandy, Lynn; Geertsen, Poul F; thor Straten, Per; Andersen, Mads H; Pedersen, Anders E; Claesson, Mogens H; Lorentzen, Torben; Johansen, Julia S; Svane, Inge Marie
Therapeutic dendritic cell (DC) vaccination against cancer is a strategy aimed at activating the immune system to recognize and destroy tumor cells. In this nonrandomized phase 1/2 trial, we investigated the safety, feasibility, induction of T-cell response, and clinical response after treatment with a DC-based vaccine in patients with metastatic renal cell carcinoma. Twenty-seven patients with progressive cytokine-refractory metastatic renal cell carcinoma were vaccinated with DCs loaded with either a cocktail of survivin and telomerase peptides or tumor lysate depending on their HLA-A2 haplotype, and low-dose IL-2 was administered concomitantly. Tumor response, immune response, and serum IL-6 and YKL-40 were measured during treatment. Vaccine generation was successful in all patients and no serious adverse events were observed. None of the patients had an objective response but 13/27 patients obtained disease stabilization (SD) for more than 8 weeks. An antigen-specific immune response was demonstrated in 6/6 patients tested. Furthermore, significant alterations in serum YKL-40 and IL-6 were found during treatment. In conclusion, DC vaccination in our setting is feasible and without severe toxicity. Almost half of the patients obtained SD, and in more than 1/3 of the patients, SD persisted for more than 6 months. However, the evaluation of SD is difficult to interpret in the absence of a randomized trial and, therefore, these results should be interpreted with caution. Antigen-specific immune responses were observed in a subset of the treated patients. PMID 18779742

Delivery of whole tumor lysate into dendritic cells for cancer vaccination.
März 2008 | Liu, Linda N; Shivakumar, Rama; Allen, Cornell; Fratantoni, Joseph C
Results from multiple human studies have continued to spur the development of dendritic cells (DCs) as therapeutic vaccines for the treatment of cancer, chronic viral infections, and autoimmune diseases. The antigen-specific activity of DCs is dependent on the ability of the DCs to take up and process tumor-associated antigens for presentation to the immune system. Although immature DCs have been shown to naturally take up tumor-associated antigens by phagocytosis, approaches that significantly affect antigen delivery need further evaluation, especially if such methodologies can be demonstrated to result in the elicitation of more robust and comprehensive immune responses. We have developed a rapid, robust, scalable, and regulatory-compliant process for loading DCs with whole tumor lysate. The use of whole tumor lysate facilitates the generation of a more robust immune response targeting multiple unique antigenic determinants in patient's tumors and likely reduces the tumor's potential of immune escape. We demonstrate that DCs electroloaded with tumor lysate elicit significantly stronger antitumor responses both in a tumor challenge model and in a therapeutic vaccination model for preexisting metastasic disease. These effects are observed in a processing scheme that requires 20- to 40-fold lower amounts of tumor lysate when compared with the standard coincubation/coculture methods employed in loading DCs. PMID 18370195

Apoptic renal carcinoma cells are better inducers of cross-presenting activity than their primary necrotic counterpart.
Jan. 2008 | D' Hooghe, E; Buttiglieri, S; Bisignano, G; Brusa, D; Camussi, G; Matera, L
Vaccination with tumor-loaded dendritic cells (DC) is a promising treatment strategy for patients with renal cell carcinoma (RCC). Cells undergoing cell death proved useful as a source of tumor antigen for DC loading. Both apoptotic and necrotic tumor cells have been shown to efficiently load RCC-tumor antigens on DC. However, no direct comparison of these two kinds of death has been attempted in the same RCC. We compared DC pulsed with apoptotic cells, whole cell lysates or their supernatants of the cell line K1, derived from a patient with clear cell RCC, to determine their ability to activate T cells. Monocyte-derived DCs were pulsed with the different sources of tumor antigen, matured and co-cultured with autologouos peripheral blood lymphocytes. After three weekly re-stimulations with DCs, generation of cytotoxic T lymphocytes CTL was assessed by IFN-gamma release in an ELISpot assay in the presence of the sensitizing target. By comparison with lysate, apoptotic tumor cells induced a higher frequency of MHC class I-restricted IFN-gamma releasing lymphocytes. A higher CTL response was induced by pulsing DCs with cell lysate supernatant compared with whole cell lysate. These results indicate that, although necrotic death has been regarded as highly permissive when compared to apoptotic death, the immunogenicity of the death treatment may vary from one tumor to another. PMID 18179743

Phase I/II study of immunotherapy using autologous tumor lysate-pulsed dendritic cells in patients with metastatic renal cell carcinoma.
Nov. 2007 | Kim, Jung Han; Lee, Yoon; Bae, Yong-Soo; Kim, Won Seog; Kim, Kihyun; Im, Ho Yeong; Kang, Won Ki; Park, Keunchil; Choi, Han Yong; Lee, Hyun Moo; Baek, So-Young; Lee, Hyunah; Doh, Hyounmie; Kim, Byong-Moon; Kim, Chae Young; Jeon, ChoonJu; Jung, Chul Won
This phase I/II study was conducted to evaluate the feasibility, safety and efficacy of immunotherapy using tumor lysate (TL)-pulsed dendritic cells (DC) in patients with metastatic renal cell carcinoma (RCC). DC were generated by culturing peripheral blood mononuclear cells in the presence of GM-CSF and IL-4 and were pulsed with autologous TL and keyhole limpet hemocyanin (KLH). Maturation of DC was induced by a combined treatment of CD40 ligand, IFN and monocyte-conditioned medium. The patients were administered two cycles of TL-pulsed DCs vaccination, each of which comprised of four doses injected subcutaneously at biweekly intervals. Nine patients were included. The immunotherapy was well tolerated without severe side effects. One patient achieved an objective partial response (PR). Five patients showed stable disease (SD), and the remaining three had progressive disease (PD). With a median follow-up of 17.5 months, the median time to progression was 5.2 months and the median overall survival was 29 months. In the antigen-specific lymphocyte proliferation assay, eight patients showed a proliferative response, which tended to be stronger in patients with SD or PR than in patients with PD. The ELISPOT assay was performed in two patients and indicated that one patient with PR showed a much stronger response than another with PD. Our results suggest that TL-pulsed DC immunotherapy in combination with nephrectomy affect the natural course of RCC and are associated with clinical benefits for patients with metastatic diseases. PMID 17916447

Phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma.
Sep. 2007 | Avigan, David E; Vasir, Baldev; George, Daniel J; Oh, William K; Atkins, Michael B; McDermott, David F; Kantoff, Philip W; Figlin, Robert A; Vasconcelles, Michael J; Xu, Yuanxin; Kufe, Donald; Bukowski, Ronald M
In the present study, we assessed the feasibility, toxicity, immunologic response, and clinical efficacy of vaccination with allogeneic dendritic cell (DC)/tumor fusions in patients with metastatic renal cell carcinoma (RCC). Patients with stage IV RCC with accessible tumor lesions or independent therapeutic indications for nephrectomy were eligible for enrollment. Tumors were processed into single cell suspensions and cryopreserved. DCs were generated from adherent peripheral blood mononuclear cells isolated from normal volunteers and cultured with granulocyte macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha. DCs were fused to patient derived RCC with serial electrical pulses. Patients received up to 3 vaccinations at a fixed dose of 4x10(7) to 1x10(8) cells administered at 6-week intervals. Twenty-four patients underwent vaccination. Twenty-one and 20 patients were evaluable for immunologic and clinical response, respectively. DCs demonstrated a characteristic phenotype with prominent expression of HLA class II and costimulatory molecules. A mean fusion efficiency of 20% was observed, determined by the percent of cells coexpressing DC and tumor antigens. No evidence of significant treatment related toxicity or auto-immunity was observed. Vaccination resulted in antitumor immune responses in 10/21 evaluable patients as manifested by an increase in CD4 and/or CD8 T-cell expression of interferon-gamma after ex vivo exposure to tumor lysate. Two patients demonstrated a partial clinical response by Response Evaluation Criteria in Solid Tumors criteria and 8 patients had stabilization of their disease. Vaccination of patients with RCC with allogeneic DC/tumor fusions was feasible, well tolerated, and resulted in immunologic and clinical responses in a subset of patients. PMID 17893567

DC immunotherapy is highly effective for the inhibition of tumor metastasis or recurrence, although it is not efficient for the eradication of established solid tumors.
Aug. 2007 | Lim, Dae-Seog; Kim, Jeong-Hwan; Lee, Dong-Seong; Yoon, Cheol-Hee; Bae, Yong-Soo
Dendritic cell (DC)-based immunotherapy has not been as effective as expected in most solid tumors even in the murine model, particularly in renal cell carcinoma (RCC). Our investigation was initiated to identify what causes the limitations of DC-based immunotherapy in solid RCC. We have investigated immunosuppressive factors from tumors and their effects on DC migration, as well as cytotoxic T lymphocyte (CTL) response and lymphocyte infiltration into the tumor mass upon vaccination with mouse renal adenocarcinoma (Renca) cell lysate-pulsed bone marrow (Bm)-derived DC in tumor-bearing mice. We also investigated pulmonary metastasis- and tumor recurrence-inhibitory effects of DC-vaccination in the solid tumor-bearing mice. In these experiments, we found that the limitations of DC-based immunotherapy to solid RCC likely result from tumor-mediated TGF-beta hindrance of immune attack rather than insufficient immune induction by DC therapy. In fact, the CTL response induced by DC therapy was quite sufficient and functional for the inhibition of tumor recurrence after surgery or of tumor metastasis induced by additional tumor-challenge to the tumor-bearing mice. Taken together, our present results obtained in mouse model suggest the potential of DC immunotherapy in tumor patients for hindering or blocking disease progression by inhibition of tumor metastasis and/or tumor recurrence after surgery. PMID 17443323

Cell technologies in immunotherapy of cancer.
Aug. 2007 | Moiseyenko, Vladimir; Imyanitov, Evgeny; Danilova, Anna; Danilov, Alexey; Baldueva, Irina
Tumor growth is accompanied by active immune reactions even on the early stages. Vaccine therapy implies the use of single antigen or combination of antigens, either with or without adjuvants, for the modulation of immune response. N.N. Petrov Institute of Oncology joined the field of antitumor vaccine therapy and related cellular technologies in 1998. The following activities are held: (1) Optimization of the preparation of autologous and allogeneic antitumor vaccines and development of tumor cell culture bank for the experiments on allogeneic vaccination. (2) Clinical evaluation of autologous vaccine therapy by (a) bone marrow precursors of dendritic cells (DCs), which are loaded with tumor lysates; (b) genetically modified tumor cells; (c) intact tumor cells used in combination with various adjuvants (BCG, IL-1beta, and IL-1beta combined with low doses of cyclophosphamide) in patients with disseminated melanoma, metastatic kidney cancer, and colorectal cancer. Total 117 patients have received non-modified vaccine (48 patients: 2-6 intracutaneous BCG injections; 54 patients: 4-6 intracutaneous IL-1beta injections; 15 patients: up to 6 injections of IL-1beta in combination with low doses of cyclophosphamide). Clinical trial of genetically modified vaccine included 59 patients (clinical results: I PR (partial response) / 8 SD (disease stabilization)--melanoma, 2 PR/ 2 MR (minimal response) / 3 SD--renal cancer). Vaccine prepared from tumor cell-activated DC bone marrow precursors was administered to 18 patients (clinical results: 2 MR and 6 SD). PMID 17713028

Targeting molecular and cellular inhibitory mechanisms for improvement of antitumor memory responses reactivated by tumor cell vaccine.
Aug. 2007 | Webster, W Scott; Thompson, R Houston; Harris, Kimberley J; Frigola, Xavier; Kuntz, Susan; Inman, Brant A; Dong, Haidong
Development of effective vaccination approaches to treat established tumors represents a focus of intensive research because such approaches offer the promise of enhancing immune system priming against tumor Ags via restimulation of pre-existing (memory) antitumoral helper and effector immune cells. However, inhibitory mechanisms, which function to limit the recall responses of tumor-specific immunity, remain poorly understood and interfere with therapies anticipated to induce protective immunity. The mouse renal cell carcinoma (RENCA) tumor model was used to investigate variables affecting vaccination outcomes. We demonstrate that although a whole cell irradiated tumor cell vaccine can trigger a functional antitumor memory response in the bone marrows of mice with established tumors, these responses do not culminate in the regression of established tumors. In addition, a CD103+ regulatory T (Treg) cell subset accumulates within the draining lymph nodes of tumor-bearing mice. We also show that B7-H1 (CD274, PD-L1), a negative costimulatory ligand, and CD4+ Treg cells collaborate to impair the recall responses of tumor-specific memory T cells. Specifically, mice bearing large established RENCA tumors were treated with tumor cell vaccination in combination with B7-H1 blockade and CD4+ T cell depletion (triple therapy treatment) and monitored for tumor growth and survival. Triple treatment therapy induced complete regression of large established RENCA tumors and raised long-lasting protective immunity. These results have implications for developing clinical antitumoral vaccination regimens in the setting in which tumors express elevated levels of B7-H1 in the presence of abundant Treg cells. PMID 17709500

Combined treatment of dendritoma vaccine and low-dose interleukin-2 in stage IV renal cell carcinoma patients induced clinical response: A pilot study.
Aug. 2007 | Wei, Yanzhang C; Sticca, Robert P; Li, Jinhua; Holmes, Lillia M; Burgin, Kelly E; Jakubchak, Susan; Bouton-Verville, Hilary; Williamson, Jane; Meyer, Karen; Evans, Lyndon; Martin, Julie; Stephenson, Joseph J; Trocha, Steven; Smith, Sam; Wagner, Thomas E
Vaccination using dendritic/tumor cell hybrids represents a novel and promising cancer immunotherapy. We have developed a technology that can instantly purify the hybrids (dendritomas) from the fusion mixture of dendritic cells (DCs) and tumor cells. Our animal studies and a phase I study of stage IV melanoma patients demonstrated that dendritoma vaccination could be conducted without major toxicity and induced tumor cell-specific immunological and clinical responses. In this pilot study, ten stage IV renal cell carcinoma patients were studied. Dendritomas were made from autologous DCs and tumor cells and administered by subcutaneous injection. After initial vaccination, three escalating doses of IL-2 (3, 6, and 9 million units each) were followed within five days. This treatment regimen was tolerated well without severe adverse events directly related to the dendritoma vaccine. Most adverse events were related to IL-2 administration or pre-existing disease. Patient-specific immune responses were evaluated by flow cytometric measurement of interferon-gamma-producing T-cells before and after vaccination in response to stimulation with tumor antigens. Nine out of nine patients eligible for the analysis showed an increase of IFN-gamma-expressing CD4+ T cells after vaccination(s); while five out of eight patients eligible for the analysis showed an increase of IFN-gamma-expressing CD8+ T cells. Clinical responses were documented in 40% of the patients, three with stabilization of disease and one with a partial response documented by a reduction in tumor size. This pilot study demonstrated that dendritoma vaccines could be administered safely to patients with metastatic renal cell carcinoma, while producing both clinical and immunologic evidence of response. PMID 17671717

Dendritic cell vaccination.
Aug. 2007 | Proudfoot, Owen; Pouniotis, Dodie; Sheng, Kuo-Ching; Loveland, Bruce E; Pietersz, Geoffrey A
There has been a surge of interest in the use of dendritic cell (DC) vaccination as cellular immunotherapy for numerous cancers. Despite some encouraging results, this therapeutic modality is far from being considered as a therapy for cancer. This review will first discuss preclinical DC vaccination in murine models of cancer, with an emphasis on comparative studies investigating different methods of antigen priming. We will then comment on the various murine DC subsets and how these relate to human DC preparations used for clinical studies. Finally, the methodology used to generate human DCs and some recent clinical trials in several cancers are reviewed. PMID 17669014

Radiation-induced apoptosis along with local and systemic cytokine elaboration is associated with DC plus radiotherapy-mediated renal cell tumor regression.
Juni 2007 | Huang, Jianhua; Wang, Yao; Guo, Jia; Lu, Haiyan; Lin, Xingshi; Ma, Lin; Teitz-Tennenbaum, Seagal; Chang, Alfred E; Li, Qiao
Utilizing melanoma and sarcoma tumor models syngeneic to C57BL/6 mice, we previously reported the antitumor effects of intratumoral (i.t.) administration of dendritic cells (DC) combined with localized radiotherapy (RT). However, the mechanisms underlying the augmented therapeutic effects have yet to be fully defined. Using the BALB/c host, we explored in this study the capacity of RT to augment the therapeutic efficacy of DC in the syngeneic renal cell cancer, Renca. I.t. DC administration combined with RT inhibited tumor growth in a synergistic manner. This extends our previous findings using a different host strain and two histologically distinct tumor models. More importantly, we provide evidence in this report that RT induced significant apoptosis and necrosis in Renca tumor cells, which involved down-regulated expression of Bcl-2 and a concurrent up-regulated expression of Bax. We also found significantly elevated expression of TNFalpha in RT plus DC-treated Renca tumors. Furthermore, splenocytes isolated from DC plus RT-treated mice elaborated higher levels of IL-2, IL-4, IFNgamma and IgG, IgM in response to tumor cells compared with splenocytes from monotherapy-treated hosts. These data support the conclusion that radiotherapy enhanced DC vaccination by inducing tumor cell apoptosis in BABL/c host, and the significantly augmented therapeutic efficacy by RT+DC treatment was associated with an increased local production of TNFalpha as well as an amplified systemic antitumor responses conferred by the combined therapy. I.t. DC administration in concert with localized RT may represent a promising novel regimen for human cancer therapy. PMID 17449328

Antigen-independent immune responses after dendritic cell vaccination.
März 2007 | Leonhartsberger, Nicolai; Ramoner, Reinhold; Putz, Thomas; Gander, Hubert; Rahm, Andrea; Falkensammer, Claudia; Bartsch, Georg; Thurnher, Martin
The ability of cultured, antigen-loaded dendritic cells (DCs) to induce antigen-specific T cell immunity in vivo has previously been demonstrated and confirmed. Immune monitoring naturally focuses on immunity against vaccine antigens and may thus ignore other effects of DC vaccination. Here we therefore focused on antigen-independent responses induced by DC vaccination of renal cell carcinoma patients. In addition to the anticipated response against the vaccine antigen KLH, vaccination with CD83(+) monocyte-derived DCs resulted in a strong increase in the ex vivo proliferative and cytokine responses of PBMCs stimulated with LPS or BCG. In addition, LPS strongly enhanced the KLH-induced proliferative and cytokine response of PBMCs. Moreover, proliferative and cytokine responses of PBMCs stimulated with the homeostatic cytokines IL-7 and IL-15 were also clearly enhanced after DC vaccination. In contrast to LPS induced proliferation, which is well known to depend on monocytes, IL-7 induced proliferation was substantially enhanced after monocyte depletion indicating that monocytes limit IL-7 induced lymphocyte expansion. Our data indicate that DC vaccination leads to an increase in the ex vivo responsiveness of patient PBMCs consistent with a DC vaccination induced enhancement of T cell memory. Our findings also suggest that incorporation of bacterial components and homeostatic cytokines into immunotherapy protocols may be useful in order to enhance the efficacy of DC vaccination and that monocytes may limit DC vaccination induced immunity. PMID 17106716

Dendritic cell vaccine strategies for renal cell carcinoma.
Jan. 2007 | Schendel, Dolores J
Dendritic cell (DC) vaccines are an important experimental immunotherapy for renal cell carcinomas. DC vaccines have proven safe, but only minimal clinical efficacy has been observed to date. DC vaccine strategies reflect the continually evolving understanding of DC biology. The use of mature DCs is particularly important to avoid the induction of regulatory T cells. Better defined sources of immunizing antigens and more efficient antigen-loading will contribute to DC vaccines of better quality. Improved clinical efficacy may also be achieved using DCs that secrete biologically active IL-12, which fosters innate immunity and polarizes T helper type 1 responses that contribute to optimal antitumor immunity. Furthermore, combination therapies that treat systemic immune suppression will be crucial for obtaining improved clinical responses to DC vaccines in patients with advanced disease. PMID 17250460

Hyperthermia and immunity. A brief overview.
Jan. 2007 | Baronzio, Gianfranco; Gramaglia, Alberto; Fiorentini, Gianmaria
After many years, hyperthermia (HT) is experiencing a new resurgence as seen by the positive results of many randomized trials all over the world. Tumour immunity similarly is suggested as the fourth modality of therapy for metastatic tumours from renal carcinoma and melanoma. An overwhelming amount of data from animal models and human patients indicate that whole body and locoregional hyperthermia exerts many biological and therapeutic effects on immune competent cells and cytokines. Among these effects, hyperthermia has recently been demonstrated to enhance the antigen presentation and consequently the activity of dendritic cells. This improvement is obtained through several mechanisms: a) increased lymphocyte recruitment and trafficking into the tumour area; b) increased immunogenicity of heat treated tumour cells; and c) increased production of the heat-shock proteins and costimulatory molecules. The effects and mechanisms of HT on immunity, lymphocyte recruitment and dendritic cell stimulation by heat shock proteins are reviewed here. Moreover the use of HT as an innate immunity booster in association with biological response modifiers is suggested. PMID 17203747

Preliminary analysis of patients with progressive renal cell carcinoma vaccinated with CA9-peptide-pulsed mature dendritic cells.
Jan. 2007 | Bleumer, Ivar; Tiemessen, Dorien M; Oosterwijk-Wakka, Jeannette C; Völler, Maureen C W; De Weijer, Kim; Mulders, Peter F A; Oosterwijk, Egbert
Carbonic anhydrase-IXG250/MN (CA9) is a renal cell carcinoma (RCC)-associated antigen ubiquitously expressed in the clear-cell subtype of RCC. Two CA9-derived peptides have been identified defining a cytotoxic T-lymphocyte epitope and human leukocyte antigen (HLA)-DR epitope, able to induce T-cell responses in vitro. A phase I clinical trial was performed with CA9-peptide-loaded dendritic cells (DCs) in patients with progressive, cytokine-refractory metastatic RCC to assess the safety, toxicity, and induction of CA9-specific immunity. Patients with objective progressive metastatic RCC received 5 vaccinations of mature DCs pulsed with the CA9-derived peptides and keyhole limpet hemocyanine (KLH). Peripheral blood was collected at regular intervals, delayed-type hypersensitivity (DTH) was tested at baseline and after the last vaccination, and skin biopsies of positive DTH sites were collected for immunomonitoring purposes. Patients were also monitored for clinical responses. No significant toxicity was observed. All patients developed humoral responses against KLH, and demonstrated DTH conversion. Evaluation of biopsy material suggested an increased influx of T-helper cells. In none of the immunomonitoring assays was evidence for the induction of CA9-peptide-specific immunity observed. No clinical responses were observed. The vaccination of DCs pulsed with KLH and 2 CA9-derived peptides was well tolerated. The lack of induction of CA9-peptide-specific immune responses indicates that this particular vaccine regimen is poor in inducing CA9-peptide-specific immune responses. PMID 17198090

Therapeutic dendritic cell vaccination of patients with renal cell carcinoma.
Juni 2006 | Berntsen, Annika; Geertsen, Poul F; Svane, Inge Marie
Dendritic cell (DC) vaccination against cancer is a new specific immunotherapeutic approach given with either therapeutic or adjuvant intent. We provide a review of DC vaccination as a treatment for metastatic renal cell carcinoma (RCC). PMID 16675096

Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients.
Juni 2006 | Wierecky, Jan; Müller, Martin R; Wirths, Stefan; Halder-Oehler, Edith; Dörfel, Daniela; Schmidt, Susanne M; Häntschel, Maik; Brugger, Wolfram; Schröder, Stephen; Horger, Marius S; Kanz, Lothar; Brossart, Peter
A phase I trial was conducted to evaluate the feasibility, safety, and efficacy of a dendritic cell-based vaccination in patients with metastatic renal cell carcinoma (RCC). Autologous mature dendritic cells derived from peripheral blood monocytes were pulsed with the HLA-A2-binding MUC1 peptides (M1.1 and M1.2). For the activation of CD4(+) T-helper lymphocytes, dendritic cells were further incubated with the PAN-DR-binding peptide PADRE. Dendritic cell vaccinations were done s.c. every 2 weeks for four times and repeated monthly until tumor progression. After five dendritic cell injections, patients additionally received three injections weekly of low-dose interleukin-2 (1 million IE/m(2)). The induction of vaccine-induced T-cell responses was monitored using enzyme-linked immunospot and Cr release assays. Twenty patients were included. The treatment was well tolerated with no severe side effects. In six patients, regression of the metastatic sites was induced after vaccinations with three patients achieving an objective response (one complete response, two partial responses, two mixed responses, and one stable disease). Additional four patients were stable during the treatment for up to 14 months. MUC1 peptide-specific T-cell responses in vivo were detected in the peripheral blood mononuclear cells of the six patients with objective responses. Interestingly, in patients responding to the treatment, T-cell responses to antigens not used for vaccinations, such as adipophilin, telomerase, or oncofetal antigen, could be detected, indicating that epitope spreading might occur. This study shows that MUC1 peptide-pulsed dendritic cells can induce clinical and immunologic responses in patients with metastatic RCC. PMID 16740731

[Efficacy of autologous renal tumor cell lysate-loaded dendritic cell vaccine in combination with cytokine-induced killer cells on advanced renal cell carcinoma--a report of ten cases].
Mai 2006 | Wang, Huan; Zhou, Fang-Jian; Wang, Qi-Jing; Qin, Zi-Ke; Huang, Li-Xi; Liu, Zhuo-Wei; Han, Hui; Li, Yong-Qiang; Chen, Shi-Ping; Xia, Jian-Chuan
Nowadays, operation is the main treatment for renal cell carcinoma (RCC). But the prognosis of advanced RCC is poor because of its high recurrence rate and resistance to conventional treatments, such as chemotherapy and radiotherapy. Hence, novel and more effective therapeutic options for advanced RCC are needed. This study was to evaluate the clinical efficacy of autologous renal tumor lysate-loaded dendritic cells (DCs) in combination with cytokine-induced killer (CIK) cells on advanced RCC. PMID 16687087

Dendritic cell-based cancer immunotherapy targeting MUC-1.
Dez. 2005 | Wierecky, J; Mueller, M; Brossart, P
Vaccination therapy using dendritic cells (DC) as antigen presenting cells (APC) has shown significant promise in laboratory and animal studies as a potential treatment for malignant diseases. Pulsing of autologous DCs with tumor-associated antigens (TAA) is a method often used for antigen delivery and choice of suitable antigens plays an important role in designing an effective vaccine. We identified two HLA-A2 binding novel 9-mer peptides of the TAA MUC1, which is overexpressed on various hematological and epithelial malignancies. Cytotoxic T cells generated after pulsing DC with these peptides were able to induce lysis of tumor cells expressing MUC1 in an antigen-specific and HLA-restricted fashion. Within two clinical studies, we demonstrated that vaccination of patients with advanced cancer using DCs pulsed with MUC1 derived peptides is well tolerated without serious side effects and can induce immunological responses. Of 20 patients with metastatic renal cell carcinoma, 6 patients showed regression of metastases with 3 objective responses (1 CR, 2 PR). Furthermore, we found that in patients responding to treatment T cell responses for antigens not used for treatment occurred suggesting that antigen spreading in vivo might be a possible mechanism of mediating antitumor effects. These results demonstrate that immunotherapy in patients with advanced malignancies using autologous DCs pulsed with MUC1 derived peptides can induce immunological and clinical responses. However, further clinical studies are needed to identify the most potent treatment regimen that can consistently mediate an antitumor immune response in vivo. PMID 15864588

Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide.
Mai 2005 | Höltl, Lorenz; Ramoner, Reinhold; Zelle-Rieser, Claudia; Gander, Hubert; Putz, Thomas; Papesh, Christine; Nussbaumer, Walter; Falkensammer, Claudia; Bartsch, Georg; Thurnher, Martin
In this phase I/II study, we evaluated the feasibility, safety and efficacy of allogeneic dendritic cells (DCs) with or without cyclophosphamide in the treatment of patients with metastatic renal cell carcinoma (RCC). Immunomagnetic beads were used to isolate CD14(+) monocytes from healthy donor leukapheresis products, and CD83(+) antigen-pulsed monocyte-derived DCs (moDCs) loaded with tumor lysate and keyhole limpet hemocyanin (KLH) were generated. Twelve patients were treated with allogeneic moDCs alone, while ten patients also received cyclophosphamide on days 4 and 3 prior to vaccination. Of the 22 patients enrolled, 20 received full treatment consisting of at least three vaccinations at monthly intervals. Two mixed responses with substantial tumor regression were observed. In 3 patients, disease stabilization occurred, in 13 patients disease progressed and 4 patients were lost to follow-up. Overall, immune responses against KLH and tumor lysate were weak or absent; however, the strongest increases in antigen-independent and KLH-specific responses were observed in the 2 patients with mixed responses. In addition, 1 of them showed a substantial increase in oncofetal antigen (OFA)-specific IFN-gamma production. Importantly, the 2 mixed responders and 1 patient with stable disease belonged to the cyclophosphamide group. Median overall survival in the cyclophosphamide group was 23.2 and 20.3 months in the group that received allogeneic moDCs alone. Allogeneic immunotherapy with moDCs is feasible and well tolerated. However, the immunogenicity of allogeneic moDCs is clearly less pronounced than that of autologous moDC immunotherapy. Cyclophosphamide may have the capacity to augment DC-induced antitumor immunity. PMID 15918076

Whole body hyperthermia in adjuvant therapy of children with renal cell carcinoma.
Mai 2005 | Ismail-Zade, Reiman S; Zhavrid, Edvard A; Potapnev, Michael P
Whole body hyperthermia (WBH) in combination with chemotherapy has been proven to be effective in some patients with advanced malignancies. However, only limited experience exists regarding the application of WBH with chemotherapy in children. We present the results of applying WBH and chemotherapy in five children with advanced renal cell carcinoma (RCC). WBH (3 hr, 41.8-42.5 degrees C) combined with doxorubicin (50 mg/m2) and interferon-alpha (3 MU/m2) were applied to patients after nephrectomy and lymph node dissection. Each patient received three to eight courses of treatment three times weekly. All children tolerated the combined therapy well without complications. Follow-up of 7-68 months (median: 22 months) showed no tumor progression in patients with locoregional (n = 3) and metastatic (n = 2) disease. WBH with moderate dose doxorubicin and INF-alpha might be a feasible treatment option in childhood RCC. PMID 15700247

Cellular and humoral immune responses in patients with metastatic renal cell carcinoma after vaccination with antigen pulsed dendritic cells.
März 1999 | Höltl, L; Rieser, C; Papesh, C; Ramoner, R; Herold, M; Klocker, H; Radmayr, C; Stenzl, A; Bartsch, G; Thurnher, M
Dendritic cells are the most potent stimulators of immune responses including antitumor responses. We performed a pilot study of cultured antigen loaded dendritic cells in patients with metastatic renal cell carcinoma. PMID 10022683