Biomedical subjects

Silke Gillessen

Publications and source records attributed to Silke Gillessen.

13 recordsLinked to original sources

PubMed2006

Successful treatment of acute disseminated intravascular coagulation in a patient with metastatic melanoma.

BACKGROUND: Acute disseminated intravascular coagulation (DIC) in cancer is rare and often fatal, whereas chronic forms are more frequent. CASE REPORT: A 37-year-old man with a known history of melanoma excised 6 years ago, presented with abdominal pain, fatigue and epistaxis. A computed tomography scan revealed diffuse metastatic disease of the liver, and laboratory analysis was consistent with accentuated DIC. After chemotherapy with dacarbacine, vinblastine and cisplatine, the acute DIC improved rapidly. After a second cycle, the tumor marker S-100 dropped from 15 to 3.1 microg/l (< 0.15 microg/l), suggesting that the improvement of the DIC was associated with a response to chemotherapy. After 2 cycles of chemotherapy, a palliative right hemihepatectomy was performed followed by 4 additional postoperative chemotherapy cycles. The patient survived 1 more year without relapse of the DIC. CONCLUSION: The cornerstone of managing DIC in cancer consists in treatment of the underlying disease. The rapid control of DIC in our patient can be explained by early diagnosis of the coagulopathy and the fast response of the tumor to the multidrug therapy. Thus, combination chemotherapy of metastatic melanoma is justified if an effective response has to be obtained in a limited time.

Adult↗

PubMed2006

Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma.

BACKGROUND: Dendritic cell (DC)-based immunotherapy is a promising approach to augment tumor antigen-specific T cell responses in cancer patients. However, tumor escape with down-regulation or complete loss of target antigens may limit the susceptibility of tumor cells to the immune attack. Concomitant generation of T cell responses against several immunodominant antigens may circumvent this potential drawback. In this trial, we determined the immunostimulatory capacity of autologous DC pulsed with multiple T cell epitopes derived from four different prostate-specific antigens in patients with advanced hormone-refractory prostate cancer. PATIENTS AND METHODS: Autologous DC of HLA-A*0201(+) patients with hormone-refractory prostate cancer were loaded with antigenic peptides derived from prostate stem cell antigen (PSCA(14-22)), prostatic acid phosphatase (PAP(299-307)), prostate-specific membrane antigen (PSMA(4-12)), and prostate-specific antigen (PSA(154-163)). DC were intradermally applied six times at biweekly intervals followed-in the case of an enhanced immune response-by monthly booster injections. Immune monitoring during the time of ongoing vaccinations (12-59 weeks) included ex vivo ELISPOT measurements, MHC tetramer analysis and in vitro cytotoxicity assays. RESULTS: Of the initial six patients, three qualified for long-term multi-epitope DC vaccination. This regime was tolerated well by all three patients. The vaccination elicited significant cytotoxic T cell responses against all prostate-specific antigens tested. In addition, memory T cell responses against the control peptides derived from influenza matrix protein and tetanus toxoid were efficiently boosted. Clinically, the long-term DC vaccination was associated with an increase in PSA doubling time. CONCLUSIONS: DC-based multi-epitope immunotherapy with repeated boosting in men with hormone-refractory prostate carcinoma is feasible and generates efficient cellular antitumor responses.

Acid Phosphatase↗

PubMed2005

Dendritic cells generated from patients with androgen-independent prostate cancer are not impaired in migration and T-cell stimulation.

BACKGROUND: Dendritic cell (DC)-based vaccination has been investigated as immunotherapy for several types of cancer. A potential drawback to vaccination with autologous monocyte-derived DCs (MoDCs) could be that MoDCs from patients are functionally impaired. In case of androgen-independent prostate cancer (CaP), the cancer itself, diverse prior therapies, and the hormone manipulation may affect the immune system. METHODS: MoDCs from patients suffering from androgen-independent CaP were generated according to a clinically applicable protocol to evaluate the phenotype, maturation capacity, migration, and T-cell stimulation of these cells compared with those generated from tumor-free donors. RESULTS: MoDCs generated from CaP patients could be fully matured and efficiently migrated towards the chemokine CCL21. They had a strong potency to activate allogeneic CD4+ and CD8+ T-cells and to present antigens to specific CTL. CONCLUSIONS: Our data suggest that MoDCs from patients with androgen-independent CaP are functionally intact and hence qualify as cellular vaccines for immunotherapy of advanced stage CaP.

Aged↗

PubMed2005

A phase II, open-label study of gefitinib (IRESSA) in patients with locally advanced, metastatic, or relapsed renal-cell carcinoma.

Epidermal growth factor receptor (EGFR) expression has been associated with clinical outcome in some studies of renal-cell carcinoma (RCC). We investigated the efficacy and safety of gefitinib (IRESSA), an EGFR tyrosine kinase inhibitor, in RCC patients. This phase II trial recruited 28 patients with advanced, metastatic, or relapsed RCC. Patients received oral gefitinib 500 mg/day. Objective responses (ORs) were assessed every 2 months according to RECIST. Baseline tumor biopsies were analyzed immunohistochemically for EGFR expression. At trial closure (March 2003), no ORs were seen but 14 patients (53.8%) had stable disease. At extended analysis (August 2004), median time to progression was 110 days (95% confidence interval [CI]: 55, 117); median overall survival was 303 days (95% CI 180, 444). Gefitinib was generally well tolerated. Skin rash and diarrhea were the most common drug-related adverse events (AEs) [54 and 39% of patients, respectively] and the most common drug-related grade 3/4 AEs (both 11%). The majority of tumor biopsies (91%) had > or =70% of tumor cells expressing membrane EGFR. Despite the lack of ORs in this study, disease control was observed in 53.8% of patients. Gefitinib was generally well tolerated and no unexpected drug-related AEs were observed.

Adult↗

PubMed2005

CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity.

CD1d-restricted T-cells are activated by glycolipids presented by the major histocompatibility complex class-Ib molecule CD1d, found on the surface of antigen-presenting cells (APC). This interaction between APC, most notably dendritic cells (DC), and CD1d-restricted T-cells is an important regulatory step in the initiation of adaptive immune responses. It is well known that DC play a crucial role in the induction of contact hypersensitivity (CHS), a frequently studied form of in vivo T-cell-mediated immunity. In this study, we show that CD1d-restricted T-cells are also necessary for CHS, because both wild-type mice treated systemically or topically with CD1d glycolipid antagonists and CD1d-restricted T-cell-null mice have markedly diminished CHS responses. Thus, pharmacologic antagonists of CD1d can be used as effective inhibitors of CHS, a prototype for a variety of delayed-type tissue hypersensitivity responses.

Administration, Topical↗

PubMed2005

Von Hippel-Lindau disease--a rare disease important to recognize.

INTRODUCTION: Von Hippel-Lindau disease (VHL) is an autosomal dominant multisystemic cancer syndrome due to a mutation of the VHL tumor suppressor gene on chromosome 3, region p25-26, with an incidence of 1/36,000 in newborns. Patients are at risk of developing cerebellar, spinal and retinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, pancreatic neuroendocrine tumors, pancreatic and renal cysts, and epididymal cystadenoma. The most common causes of death from VHL are metastases from renal cell carcinoma and neurological complications from cerebellar hemangioblastomas. Molecular analysis of the VHL gene is clinically available and indicated in patients with known or suspected VHL. CASE REPORT: A 19-year-old woman was surgically treated for cerebellar hemangioblastoma in 1998 and for renal cell carcinoma of the right side in 2002. Familial VHL was subsequently diagnosed as the patient's mother was found to be affected with bilateral polycystic kidney disease with chronic renal failure as well as hemangioblastoma of the retina and medulla oblongata. The mother underwent surgery for bilateral renal cell carcinoma in 2003. CONCLUSION: The multitude of VHL-associated tumors and intra-familial variability in clinical expressivity render early diagnosis of VHL difficult. We therefore shortly illustrate the spectrum of clinical phenotypes and the VHL screening and surveillance guidelines.

Adult↗

PubMed2004

Phenotype and functional analysis of human monocyte-derived dendritic cells loaded with biodegradable poly(lactide-co-glycolide) microspheres for immunotherapy.

Dendritic cells (DC) are increasingly explored as cellular vaccines for tumor immunotherapy. In most reported DC-based cancer vaccine trials, DC have been pulsed with soluble tumor antigen-derived peptide ligands of MHC molecules. Considering that the half-life of peptide/MHC complexes on the cell surface is relatively short and that soluble exogenous protein antigens cannot be efficiently processed via the MHC class I-processing pathway, the current vaccination procedure is not optimal for the induction of strong T cell responses aiming at tumor rejection. Recently, we have shown that antigen presentation can be prolonged when synthetic peptides were encapsulated in biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microspheres (MS) for uptake by DC. In the present study, we investigated the phenotypic and functional consequences of MS uptake by human monocyte-derived dendritic cells (MoDC) in vitro. We found that immature MoDC that were prepared in serum free media suitable for clinical application were able to phagocytose high numbers of MS, while matured MoDC showed a reduced capacity for phagocytosis of MS. The ingestion of MS did not change the cell surface expression of CD80, CD83, CD86 and HLA-DR of immature and mature DC, suggesting that MS uptake did not induce DC maturation but that maturation by cytokines or LPS was unaltered in the presence of MS. Furthermore, MS-loaded mature MoDC expressed normal levels of the chemokine receptor CCR7 and migrated as efficiently towards CCL19 or CCL21 as unloaded MoDC. DC viability and the secretion of TNF-alpha and IL-12 was not significantly changed by MS loading. Taken together, our data indicate that PLGA-MS loading has no negative effects on the pivotal properties of MoDC in vitro. It should therefore be feasible to further develop this antigen loading strategy for clinical use in immunotherapy against viral infections and tumors.

Absorbable Implants↗

PubMed2003

CCL19/CCL21-triggered signal transduction and migration of dendritic cells requires prostaglandin E2.

The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.

Blotting, Western↗

PubMed2003

Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

PURPOSE: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer. PATIENTS AND METHODS: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 x 10(6), 4 x 10(6), or 1 x 10(7) tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106 cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease. CONCLUSION: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

Adenoviridae↗

PubMed2003

CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion.

CD1d-restricted T cells contribute to tumor protection, but their precise roles remain unclear. Here we show that tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor induce the expansion of CD1d-restricted T cells through a mechanism that involves CD1d and macrophage inflammatory protein 2 expression by CD8 alpha-, CD11c+ dendritic cells (DCs). The antitumor immunity stimulated by vaccination with irradiated, granulocyte-macrophage colony-stimulating factor-secreting tumor cells was abrogated in CD1d- and J alpha 281-deficient mice, revealing a critical role for CD1d-restricted T cells in this response. The loss of antitumor immunity was associated with impaired tumor-induced T helper 2 cytokine production, although IFN-gamma secretion and cytotoxicity were preserved. DCs from immunized CD1d-deficient mice showed compromised maturation and function. Together, these results delineate a role for CD1d-restricted T cell-DC cross talk in the shaping of antitumor immunity.

Animals↗

PubMed2003

Deficiencies of GM-CSF and interferon gamma link inflammation and cancer.

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-gamma attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.

Animals↗

PubMed2003

Thalidomide: from tragedy to promise.

Thalidomide is an immunomodulatory and antiangiogenic drug. Although the exact mechanism of action is not fully understood, it has been shown to be active in a variety of diseases. There are multiple trials going on to evaluate the optimal dose of thalidomide and the importance of combining thalidomide with other drugs. This review introduces the properties and putative mechanism of action of thalidomide and summarizes the most important clinical trials with this biological modifier.

Angiogenesis Inhibitors↗

PubMed2002

Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells.

Dendritic cells (DCs) are potent antigen-presenting cells that are able to initiate and modulate immune responses and are hence exploited as cellular vaccines for immunotherapy. Their capacity to migrate from peripheral tissues to the T-cell areas of draining lymph nodes is crucial for the priming of T lymphocytes. In this study, we investigated how the maturation of human monocyte-derived DCs (MoDCs) by several different stimuli under serum-free conditions affected their T-cell stimulatory function, cytokine secretion, and migratory behavior. Surprisingly, we found that for all maturation stimuli tested, the addition of prostaglandin E2 (PGE2) was required for effective migration of MoDCs toward the lymph node-derived chemokines CCL19 (EBI1 ligand chemokine/macrophage inflammatory protein--3beta) and CCL21 (secondary lymphoid tissue chemokine [SLC]/6Ckine). Costimulation with PGE2 enhanced the expression of the CCL19/CCL21 receptor CCR7 on the cell surface of MoDCs when they were matured with soluble CD40 ligand or proinflammatory cytokines, but did not affect CCR7 expression of polyI:C-stimulated MoDCs. The effects of PGE2 on MoDCs were mediated through increased cyclic adenosine monophosphate by 2 of the known PGE2 receptors, EP2 and EP4, which are expressed and down-regulated after PGE2 binding in these cells. In conclusion, our results suggest that signals provided by the proinflammatory mediator PGE2 are crucial for MoDCs to acquire potent T-helper cell stimulatory capacity and substantial chemotactic responsiveness to lymph node-derived chemokines. This is a new and important parameter for the preparation of MoDCs as cellular vaccines in tumor immunotherapy. (Blood. 2002;100:1354-1361)

Chemokine CCL19↗