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1.
Daniela Fenoglio Paolo Traverso Alessia Parodi Laura Tomasello Simone Negrini Francesca Kalli Florinda Battaglia Francesca Ferrera Stefania Sciallero Giuseppe Murdaca Maurizio Setti Alberto Sobrero Francesco Boccardo Giuseppe Cittadini Francesco Puppo Domenico Criscuolo Giorgio Carmignani Francesco Indiveri Gilberto Filaci 《Cancer immunology, immunotherapy : CII》2013,62(6):1041-1052
Background
Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod.Objective
The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints.Experimental design
GX301 was administered by intradermally injecting 500 μg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization.Results
No grade 3–4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses.Conclusion
GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy. 相似文献2.
L Rhoda Molife Li Yan Joanna Vitfell-Rasmussen Adriane M Zernhelt Daniel M Sullivan Philippe A Cassier Eric Chen Andrea Biondo Ernestina Tetteh Lillian L Siu Amita Patnaik Kyriakos P Papadopoulos Johann S de Bono Anthony W Tolcher Susan Minton 《Journal of hematology & oncology》2014,7(1):1-12
Background
Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies.Methods
Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested.Results
MTD of MK-2206 (N?=?72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months.Conclusion
MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity.Trial registration
ClinicalTrials.gov: NCT00848718. 相似文献3.
4.
Joshua M. Judge Louis B. Brill II Kelly T. Smith Donna H. Deacon James W. Patterson William W. Grosh Achim A. Jungbluth Sacha Gnjatic Craig L. Slingluff Jr. 《Cancer immunology, immunotherapy : CII》2013,62(8):1327-1334
Purpose
Survival after amputation for melanoma is short; however, rare long-term survivors are reported. The mechanism for durable systemic tumor control in patients with regional failure is not known. To explore whether systemic tumor immunity may be implicated, tumor and circulating immune responses were examined in a patient who survived disease-free 14 years after hip disarticulation.Methods
A 71-year-old female with extensive regional metastases of melanoma in the left lower extremity underwent amputation for palliative reasons. Tumor was collected at surgery, and blood was collected during follow-up. Tumor sections were evaluated for lymphocytic infiltration and NY-ESO-1 expression by immunohistochemistry. Cellular immune responses to defined tumor antigens were evaluated by ELISPOT assay, and antibody responses to a panel of tumor antigens were assayed by ELISA.Results
The patient’s tumor had minimal lymphocytic infiltrate (immunotype A). NY-ESO-1 was strongly expressed by the melanoma cells. Circulating T-cell responses to NY-ESO-1 peptides were observed 6 and 12 years postoperatively, and antibodies to NY-ESO-1 were detected 2–6 years after surgery.Conclusion
The patient described in this report experienced relentless regional tumor progression, with intravascular metastases, and then 14-year systemic disease-free survival after palliative resection, without evidence of melanoma recurrence before death from other causes. Her immune response to NY-ESO-1 likely failed to control established regional metastases because T cells were unable to infiltrate them. It is possible, however, that among other factors, the host immune response may have contributed to systemic protection. 相似文献5.
Nadeem A. Sheikh Daniel Petrylak Philip W. Kantoff Corazon dela Rosa Frances P. Stewart Ling-Yu Kuan James B. Whitmore James B. Trager Christian H. Poehlein Mark W. Frohlich David L. Urdal 《Cancer immunology, immunotherapy : CII》2013,62(1):137-147
Purpose
Sipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS).Methods
Sipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies (N = 737). Antigen-specific cellular and humoral responses were assessed in a subset of subjects. The relationships between these parameters and OS were assessed.Results
APC activation occurred in the first dose preparation [6.2-fold, (4.65, 7.70); median (25th, 75th percentile)] and increased in the second [10.6-fold (7.83, 13.65)] and third [10.5-fold (7.89, 13.65)] dose preparations. Cytokines and chemokines associated with activated APCs were produced during the manufacture of each dose; T-cell activation-associated cytokines were detected in the second and third dose preparations. Antigen-specific T cells were detectable after administration of the first sipuleucel-T dose. Cumulative APC activation, APC number, and TNC number correlated with OS (P < 0.05). Antigen-specific immune responses were observed in 78.8 % of monitored subjects and their presence correlated with OS (P = 0.003).Conclusion
Sipuleucel-T broadly engages the immune system by activating APCs ex vivo and inducing long-lived immune responses in vivo. These data indicate antigen-specific immune activation as a mechanism by which sipuleucel-T prolongs OS. 相似文献6.
Christoph Domschke Yingzi Ge Isa Bernhardt Sarah Schott Sophia Keim Simone Juenger Mariana Bucur Luisa Mayer Maria Blumenstein Joachim Rom Joerg Heil Christof Sohn Andreas Schneeweiss Philipp Beckhove Florian Schuetz 《Cancer immunology, immunotherapy : CII》2013,62(6):1053-1060
Background
The bone marrow (BM) of breast cancer patients harbors tumor-reactive memory T cells (TCs) with therapeutic potential. We recently described the immunologic effects of adoptive transfer of ex vivo restimulated tumor-reactive memory TCs from the BM of 12 metastasized breast cancer patients in a clinical phase-I study. In this trial, adoptive T cell transfer resulted in the occurrence of circulating tumor antigen-reactive type-1 TCs. We here describe the long-term clinical outcome and its correlation with tumor-specific cellular immune response in 16 metastasized breast cancer patients, including 12 included in the original study.Methods
Sixteen metastatic breast cancer patients with preexisting tumor-reactive BM memory TCs were included into the study. The study protocol involved one transfusion of TCs which were reactivated in vitro with autologous dendritic cells pulsed with lysates of MCF-7 breast cancer cells as source of tumor antigens. The presence of tumor-reactive memory TCs was analyzed by IFN-γ ELISpot assays.Results
Tumor-reactive memory TCs in the peripheral blood were induced de novo in 7/16 patients (44 %) after adoptive TC transfer. These patients were considered immunologic responders to the therapy. Positive adoptive immunotherapy (ADI) response was observed significantly more often in patients without bone metastases (p = 0.0051), in patients with high levels of tumor-reactive BM TCs prior to therapy (p = 0.036) and correlated significantly with the estimated numbers of transferred tumor-reactive TCs (p = 0.0021). After the treatment, we observed an overall median survival of 33.8 months in the total cohort with three patients alive at last follow-up and more than 7 years after ADI. Numbers of transferred tumor-reactive TCs correlated significantly with the overall survival of patients (p = 0.017). Patients with an immunologic response to ADI in the peripheral blood had a significantly longer median survival than nonresponders (median survival 58.6 vs. 13.6 months; p = 0.009).Conclusion
In metastasized breast cancer patients, adoptive transfer of BM TCs can induce the presence of tumor antigen-reactive type-1 TCs in the peripheral blood. Patients with immunologic response after ADI show a significantly longer overall survival. Patients with bone metastases significantly less frequently respond to the treatment and, therefore, might not be optimal candidates for ADI. Although the present study does not yet prove the therapeutic effect of ADI, these findings shed light on the relation between immune response and cancer prognosis and suggest that transfer of reactivated BM TCs might bear therapeutic potential. 相似文献7.
Alexia Buzzonetti Marco Fossati Valentina Catzola Giovanni Scambia Andrea Fattorossi Alessandra Battaglia 《Cancer immunology, immunotherapy : CII》2014,63(10):1037-1045
Purpose
To determine whether abagovomab induces protective immune responses in ovarian cancer patients in first clinical remission. The present analysis is a substudy of monoclonal antibody immunotherapy for malignancies of the ovary by subcutaneous abagovomab trial (NCT00418574).Methods
The study included 129 patients, 91 in the abagovomab arm and 38 in the placebo arm. Circulating CA125-specific cytotoxic T lymphocytes (CTL) were measured by a flow cytometry-based interferon-γ producing assay. Human antimouse antibody and anti-anti-idiotypic (Ab3) were assessed by ELISA. Patients were evaluated before starting the treatment and at different time points during induction and maintenance phases.Results
A similar percentage of patients in both the placebo and abagovomab arms had CA125-specific CTL (26.3 and 31.8 %, respectively; p = 0.673 by Fisher’s exact test). Patients with CA125-specific CTL in both arms tended to have an increased relapse-free survival (RFS, log-rank test p = 0.095) compared to patients without. Patients (n = 27) in the abagovomab arm without CA125-specific CTL but that developed Ab3 above the cutoff (defined as median Ab3 level at week 22) had a prolonged RFS compared to patients (n = 24) that did not develop Ab3 above the cutoff (log-rank test p = 0.019).Conclusion
Abagovomab does not induce CA125-specific CTL. However, patients with CA125-specific CTL perform better than patients without, irrespective of abagovomab treatment. Abagovomab-induced Ab3 associate with prolonged RFS in patients without CA125-specific CTL. Further studies are needed to confirm these data and to assess the potential utility of these immunological findings as a tool for patient selection in clinical trial. 相似文献8.
Chun Hei Antonio Cheung Xueying Sun Jagat R Kanwar Ji-Zhong Bai LiTing Cheng Geoffrey W Krissansen 《Cancer cell international》2010,10(1):1-11
Background
Survivin is a member of the inhibitor-of-apoptosis (IAP) family which is widely expressed by many different cancers. Overexpression of survivin is associated with drug resistance in cancer cells, and reduced patient survival after chemotherapy and radiotherapy. Agents that antagonize the function of survivin hold promise for treating many forms of cancer. The purpose of this study was to investigate whether a cell-permeable dominant-negative survivin protein would demonstrate bioactivity against prostate and cervical cancer cells grown in three dimensional culture.Results
A dominant-negative survivin (C84A) protein fused to the cell penetrating peptide poly-arginine (R9) was expressed in E. coli and purified by affinity chromatography. Western blot analysis revealed that dNSurR9-C84A penetrated into 3D-cultured HeLa and DU145 cancer cells, and a cell viability assay revealed it induced cancer cell death. It increased the activities of caspase-9 and caspase-3, and rendered DU145 cells sensitive to TNF-α via by a mechanism involving activation of caspase-8.Conclusions
The results demonstrate that antagonism of survivin function triggers the apoptosis of prostate and cervical cancer cells grown in 3D culture. It renders cancer cells sensitive to the proapoptotic affects of TNF-α, suggesting that survivin blocks the extrinsic pathway of apoptosis. Combination of the biologically active dNSurR9-C84A protein or other survivin antagonists with TNF-α therapy warrants consideration as an approach to cancer therapy. 相似文献9.
Sandip Pravin Patel Andrew Bristol Olga Saric Xue-Ping Wang Alex Dubeykovskiy Philip M. Arlen Michael A. Morse 《Cancer immunology, immunotherapy : CII》2013,62(6):1011-1019
Purpose
NPC-1C is a chimeric immunoglobulin IgG1 developed from antigen tested in the Hollinshead tumor vaccine trials that recognizes an immunogenic MUC5AC-related tumor-associated antigen. In this article, we describe the pre-clinical characterization of this antibody that is currently being tested in human clinical trials.Experimental design
The specificity of NPC-1C for pancreatic and colorectal cancer cell lines was tested by flow cytometry assays and immunohistochemical staining. Antibody-dependent cell cytotoxicity was measured using a tumor cell line lysis assay. Anti-tumor efficacy and biodistribution were assessed in nude mice bearing human pancreatic tumor xenografts.Results
Human tumor cell binding measured by flow cytometry ranged from 52 to 94 % of cells stained positive with NPC-1C in three colorectal and one pancreatic cell lines, while IHC demonstrated staining of 43 % of colon cancers and 48 % of pancreatic cancer tissues, with little or no cross-reactivity of NPC-1C with normal colon or pancreas tissues. In vitro NPC-1C-mediated tumor cell killing occurred in a median of 44.5 % of four colorectal and three pancreatic tumor cell lines. In vivo anti-tumor efficacy in a human pancreatic CFPAC-1 tumor xenograft model was demonstrated with a twofold to threefold reduction in tumor growth in the NPC-1C-treated mice compared to saline and human IgG controls. Pharmacodynamic studies indicate NPC-1C localizes in antigen-positive tumors and has minimal uptake in normal mouse tissues.Conclusions
NPC-1C, a chimeric monoclonal antibody that reacts with a MUC5AC-related antigen expressed by pancreatic and colorectal tumor tissues, has promising preclinical activity in pancreatic and colorectal adenocarcinoma. 相似文献10.
David A. Smith Paul Conkling Donald A. Richards John J. Nemunaitis Thomas E. Boyd Alain C. Mita Guillaume de La Bourdonnaye David Wages Alice S. Bexon 《Cancer immunology, immunotherapy : CII》2014,63(8):787-796
Background
IMO-2055 is a Toll-like receptor 9 (TLR9) agonist that potentially enhances the efficacy of antitumor agents through immune stimulation. The objective of this phase Ib dose-escalation trial (3 + 3 design) was to determine the recommended phase II dose (RP2D) of IMO-2055 when combined with erlotinib and bevacizumab in patients with advanced non-small cell lung cancer (NSCLC).Methods
Patients with stage 3/4 NSCLC and progressive disease (PD) following chemotherapy received IMO-2055 0.08, 0.16, 0.32, or 0.48 mg/kg once weekly plus erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients could receive treatment until PD or unacceptable toxicity.Results
Thirty-six patients were enrolled; 35 received at least one treatment dose. Two dose-limiting toxicities were observed across the dose range (Grade 3 dehydration and fatigue) with neither suggestive of a consistent toxicity pattern. IMO-2055 0.32 mg/kg was adopted as RP2D based on clinical and pharmacodynamic data. The most common treatment-emergent adverse events (TEAEs) were diarrhea (74 %), nausea (51 %), fatigue (51 %), rash (51 %), and injection-site reactions (49 %). Four patients experienced serious TEAEs considered to be study drug related. Five patients died, all due to PD. High-grade neutropenia and electrolyte disturbances previously reported with TLR9 agonists combined with platinum-based therapy were not observed in this study. Five of 33 patients evaluable for response (15 %) achieved partial response; another 20 (61 %) had stable disease, including 13 with stable disease ≥4 months.Conclusions
IMO-2055 demonstrated good tolerability and possible antitumor activity in combination with erlotinib and bevacizumab in heavily pretreated patients with advanced NSCLC. 相似文献11.
Adam Dangoor Paul Lorigan Ulrich Keilholz Dirk Schadendorf Adrian Harris Christian Ottensmeier John Smyth Klaus Hoffmann Richard Anderson Martin Cripps Joerg Schneider Robert Hawkins 《Cancer immunology, immunotherapy : CII》2010,59(6):863-873
Background
Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens.Methods
Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-γ ELISPOT assays. Safety and clinical responses were monitored.Results
Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit—one PR (24 months+), five SD (5 months+) and two mixed responses—seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions.Conclusions
DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation. 相似文献12.
13.
Ryan M. Stephenson Chwee Ming Lim Maura Matthews Gregory Dietsch Robert Hershberg Robert L. Ferris 《Cancer immunology, immunotherapy : CII》2013,62(8):1347-1357
Background
Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that prolongs survival in the treatment for head and neck cancer (HNC), but only in 10–20 % of patients. An immunological mechanism of action such as natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells.Objective
To determine the capability of TLR8-stimulation to enhance the activation and function of NK cells and dendritic cells (DC) in the presence of cetuximab-coated HNC cells.Methods
Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8+ T cells were isolated and analyzed using 51Cr release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR853-861 tetramer staining.Results
TLR8 stimulation of unfractionated PBMC led to enhanced cetuximab-mediated ADCC in healthy donors (p < 0.01) and HNC patients (p < 0.001), which was dependent on NK cells. Secretion of Th1 cytokines TNFα (p < 0.0001), IFNγ (p < 0.0001), and IL-12p40 (p < 0.005) was increased. TLR8 stimulation of PBMC augmented cetuximab-enhanced NK cell degranulation (p < 0.001). TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in co-culture with cetuximab-treated HNC cells. TLR8 stimulation of NK-DC co-cultures significantly increased DC priming of EGFR-specific CD8+ T cells in the presence of cetuximab.Discussion
VTX-2337 and cetuximab combination therapy can activate innate and adaptive anti-cancer immune responses. Further investigation in human trials will be important for determining the clinical benefit of this combination and for determining biomarkers of response. 相似文献14.
Background
The age-related weakening of the immune system makes elderly subjects less responsive to influenza vaccination. In the last years, two “enhanced vaccines” were licensed for individuals aged ≥65 years, one being a subunit vaccine (Fluad®) containing the MF59 adjuvant administered intramuscularly (IM-MF59) and the other one a split non-adjuvanted vaccine administered intradermally (Intanza® 15mcg) (ID). In the present study, we evaluated and compared the antibody responses against the three vaccine antigens and heterovariant A(H3N2) circulating viruses induced by IM-MF59 and ID influenza vaccines in 80 elderly institutionalized volunteers (40 per group) during the Winter season 2011–2012.Results
Hemagglutination inhibiting (HI) antibody titers were assessed in blood samples collected before, 1 and 6 months after vaccination. One month after vaccination both the IM-MF59 and ID vaccines induced increases in HI titers against all the three vaccine strains. The results in the two groups were similar against the A(H3N2) and A(H1N1) strains. Responses against the B strain typically tended to be higher after ID than IM-MF59, yet both vaccines stimulated lower responses against the B strain than against the two A strains. The two vaccines induced favorable results also against four epidemic drifted A(H3N2) viruses circulating in Winter 2011–2012. Six months after vaccination, the HI titers decreased in both groups.Conclusion
The responses induced by IM-MF59 and ID vaccines in institutionalized elderly people were similar against the A(H3N2) and A(H1N1) strains but frequently higher, for the ID, against the B strain. The two vaccines induced positive responses against drifted A(H3N2) circulating viruses.15.
Einar Osland Vik-Mo Marta Nyakas Birthe Viftrup Mikkelsen Morten Carstens Moe Paulina Due-Tønnesen Else Marit Inderberg Suso Stein Sæbøe-Larssen Cecilie Sandberg Jan E. Brinchmann Eirik Helseth Anne-Marie Rasmussen Knut Lote Steinar Aamdal Gustav Gaudernack Gunnar Kvalheim Iver A. Langmoen 《Cancer immunology, immunotherapy : CII》2013,62(9):1499-1509
Background
The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting.Methods
We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9–18 vaccines containing 107 cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456.Results
Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test).Conclusion
These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival. 相似文献16.
Jürgen C. Becker Mads H. Andersen Valeska Hofmeister-Müller Marion Wobser Lidia Frey Christiane Sandig Steffen Walter Harpreet Singh-Jasuja Eckhart K?mpgen Andreas Opitz Marc Zapatka Eva-B. Br?cker Per thor Straten David Schrama Selma Ugurel 《Cancer immunology, immunotherapy : CII》2012,61(11):2091-2103
Background
Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets.Patients and methods
This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS).Results
Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR?+?PR?+?SD) more often showed SSTRs than patients with disease progression (p?=?0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6?months; p?=?0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p?=?0.013). The induction of SSTRs was associated with gender (female vs. male; p?=?0.014) and disease stage (M1a/b vs. M1c; p?=?0.010), but not with patient age, HLA type, performance status, or vaccination regimen.Conclusion
Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma. 相似文献17.
R. Jansen P. A. M. Kracht M. J. Cramer W. J. Tietge L. A. van Herwerden R. J. M. Klautz J. Kluin S. A. J. Chamuleau 《Netherlands heart journal》2013,21(11):487-496
Purpose
Exercise echocardiography can assess the dynamic component of mitral valve (MV) disease and may therefore be helpful for the clinical decision-making by the heart team. The purpose of this study is to determine the role of exercise echocardiography in the management of disproportionately symptomatic or otherwise atypical patients with mitral regurgitation (MR) and stenosis (MS) in clinical practice.Methods
Data of 14 MR and 14 MS patients, including echocardiograms at rest, were presented retrospectively to an experienced heart team to determine treatment strategy. Subsequently, exercise echo data were provided whereupon once again the treatment strategy was determined. This resulted in: value of exercise echo by means of 1) alteration or 2) confirmation of treatment strategy or 3) no additional value.Results
During exercise the echocardiographic severity of MV disease increased in 9 (64 %) MR and 8 (57 %) MS patients. Based upon alteration or confirmation of the treatment strategy, the value of exercise echocardiography in the management of MR and MS was 86 % and 57 %, respectively.Conclusion
This study showed that physical exercise echo can have an important role in the clinical decision-making of challenging patients with MV disease. Exercise echocardiography had additional value to the treatment strategy in 71 % of these patients. 相似文献18.
T. Yetgin M. M. J. M. van der Linden A. G. de Vries P. C. Smits R. van Mechelen S. C. Yap E. Boersma F. Zijlstra R.-J. M. van Geuns 《Netherlands heart journal》2014,22(1):20-27
Background
Medical discharge management of acute coronary syndromes (ACS) remains suboptimal outside randomised trials and constitutes an essential quality benchmark for ACS. We sought to evaluate the rates of key guideline-recommended pharmacological agents after ACS and characteristics associated with optimal treatment at discharge.Methods
The Rijnmond Collective Cardiology Research (CCR) registry is an ongoing prospective, observational study in the Netherlands that aims to enrol 4000 patients with ACS. We examined discharge and 1-month follow-up medication use among the first 1000 patients enrolled in the CCR registry. Logistic regression was performed to identify patient and hospital characteristics associated with collective guideline-recommended pharmacotherapy at hospital discharge.Results
At discharge, 94 % of patients received aspirin, 100 % thienopyridines, 80 % angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers, 87 % β-blockers, 96 % statins, and 65 % the combination of all 5 agents. ST-segment elevation myocardial infarction, hypertension, hypercholesterolaemia, and enrolment in an interventional centre were positive independent predictors of 5-drug combination therapy at discharge. Negative independent predictors were unstable angina and advanced age.Conclusion
Current data from the CCR registry reflect a high quality of care for ACS discharge management in the Rotterdam-Rijnmond region. However, potential still remains for further optimisation. 相似文献19.
Ya-Lin Hu En-Rong Yan Woo-Jung Choi Francis Salifu Xiao Tan Z. Chi Chen De-Hui Zeng Scott X. Chang 《Plant and Soil》2014,374(1-2):399-409
Aims
Seed germination and seedling emergence are vulnerable to water stress in arid environments. When precipitation is low and unpredictable during the early growing season, seeds near the sand surface often suffer from hydration/dehydration during germination. We investigated the responses of seedling emergence and survival of a sand dune grass with high sand stabilization value to amount and frequency of precipitation and depth of burial in sand.Methods
Effects of amount and frequency of precipitation, burial and hydration/dehydration on seedling emergence of Leymus secalinus, were examined using standard procedures.Results
Seedling emergence was affected by amount and frequency of monthly precipitation and depth of burial, and it decreased as precipitation frequency decreased with same amount of precipitation. Highest emergence percentage was obtained with 100 or 150 mm precipitation at 1–4 cm depth. Hydration/dehydration treatments decreased germination and increased dormancy percentage. Young seedlings with root lengths of 0–1 mm desiccated up to 30 days revived after rehydration.Conclusions
Seedling emergence of L. secalinus is adapted to 150 mm monthly precipitation with frequency of 10–30 times per month, 1–4 cm burial depth and dehydration interval of 1–2 days. Alteration of amount and/or frequency of precipitation caused by climate change could markedly affect seedling emergence and population regeneration of this species. 相似文献20.
Neumann F Kubuschok B Ertan K Schormann C Stevanovic S Preuss KD Schmidt W Pfreundschuh M 《Cancer immunology, immunotherapy : CII》2011,60(9):1333-1346