M. von Bergwelt-Baildon

Rare naturally occurring immune responses to three epitopes from the widely expressed tumour antigens hTERT and CYP1B1 in multiple myeloma patients

The widely expressed tumour antigens hTERT and CYP1B1 are commonly expressed in multiple myeloma (MM) cells. Several trials targeting these antigens by immunotherapy have been initiated. The aim of this study was to explore whether patients with MM have an endogenous pre‐existing immune response against recently identified epitopes from hTERT and CYP1B1. Peripheral blood T cells from 27 HLA‐A*0201+ multiple myeloma patients at different stages of disease and 20 healthy HLA‐A*0201+ donors were enriched and studied for the presence of hTERT‐ and CYP1B1‐specific cytotoxic T cells using MHC tetramer detection and short‐term ex vivo expansion. No significant expansion of tetramer‐positive cells was detected in the peripheral blood of either MM patients or healthy controls when cells were stained with tetramers containing the dominant hTERT‐derived epitope or two peptides derived from CYP1B1. A single ex vivo peptide stimulation led to the detection of a small population (0·3–0·5%) of hTERT‐specific cells in two of 27 patients with MM. None of the patients or controls showed significant expansion of CYP1B1‐specific cells after a single peptide stimulation. Thus, endogenous in vivo priming of T cells against hTERT and CYP1B1 is a rare event in MM patients. These results suggest that strategies targeting hTERT and CYP1B1 may have to utilize techniques to induce T cell responses from a naive precursor frequency.

CD40-activated B cells can be generated in high number and purity in cancer patients: analysis of immunogenicity and homing potential

Cellular adjuvants such as dendritic cells (DC) are in the focus of tumour immunotherapy. In DC‐vaccine trials, induction of tumour antigen‐specific immunity is observed frequently and well‐documented clinical responses have been reported. However, the overall response rate is less than 3%, therefore alternative strategies are being investigated. CD40‐activated B cells (CD40‐B) have been characterized previously as an interesting alternative because they present antigen efficiently and can be expanded by several logs from small amounts of peripheral blood. To determine the central technical challenges of cell‐based vaccines we performed a single‐patient analysis of 502 patients from DC‐based tumour vaccine trials and identified at least three factors contributing to their limited efficiency: (1) lack of cell numbers; (2) lack of documented purity thus high contamination of bystander cells; and (3) lack of quality control and thus heterogeneous or unknown expression of important surface molecules such as major histocompatibility complex (MHC) and chemokine receptors. Based on these findings we re‐evaluated the CD40‐B approach in cancer patients. Here, we show that proliferation of B cells from cancer patients is equivalent to that observed in healthy donors. Purity is always > 90% after 2 weeks and remains stable for several weeks. They have comparable antigen‐presenting capability determined phenotypically and by allogeneic mixed lymphocyte reaction. Expression of CCR7 and CD62L was detected in all samples and B cells migrated towards the relevant homing chemokines. Taken together, CD40‐B cells from cancer patients can be expanded in virtually unlimited numbers at high purity and full function concerning antigen‐presentation and migratory properties.

Tumour immunotherapy: new tools, new treatment modalities and new T-cell antigens.

Tumour immunology has seen many exciting developments in the last few years. In addition to tumour antigens that are defined by antitumour T‐ and B‐cell responses in patients, the human telomerase reverse transcriptase has been identified by ‘reverse immunology’ as the first truly universal tumour antigen. Molecular remission has been associated with a cancer vaccine that targets the clonal idiotype of B‐cell malignancies, and sophisticated cellular vaccines (including fusions of tumour cells and antigen‐presenting cells) have demonstrated promising results. Moreover, our capabilities of measuring immunity have been significantly enhanced by novel technology, such as major histocompatibility complex (MHC)–peptide tetramers and ELISPOT analysis. We are now capable of tracking antigen‐specific T cells at a single cell level. This review will analyse recent developments and highlight some important issues that need to be addressed in the future.

Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

The bi-specific CD3 x NCAM antibody: a model to preactivate T cells prior to tumour cell lysis.

To target the neural cell adhesion molecule (NCAM, CD56) on neuroblastoma by T cell‐based immunotherapy we have generated a bi‐specific CD3 × NCAM antibody (OE‐1). This antibody can be used to redirect T cells to NCAM+ cells. Expectedly, the antibody binds specifically to NCAM+ neuroblastoma cells and CD3+ T cells. OE‐1 induces T cell activation, expansion and effector function in peripheral blood mononuclear cell (PBMC)‐derived CD4+ and CD8+ T cells. T cell activation was shown to depend on the presence of normal natural killer (NK) cells in the culture. Interestingly, while PBMC‐ derived T cells were activated by OE‐1, NK cells were almost completely depleted, suggesting that T cells activated by OE‐1 deleted the NK cells. Activated CD4+ and CD8+ T cells differentiate into a larger CCR7+ central memory and a smaller CCR7– effector memory cell population. Most importantly, preactivated T cells were highly cytotoxic for neuroblastoma cells. In eight of 11 experiments tumour‐directed cytotoxicity was enhanced when NK cells were present during preactivation with OE‐1. These data strongly support a bi‐phasic therapeutic concept of primarily stimulating T cells with the bi‐specific antibody in the presence of normal NCAM+ cells to induce T cell activation, migratory capacity and finally tumour cell lysis.

Donor lymphocyte infusions combined with systemic PUVA/bexarotene as an effective bimodal immunologic approach in a patient with relapsed cutaneous T cell lymphoma after allogeneic stem cell transplantation.

One central challenge of allogeneic stem cell transplantation is the positive correlation between graft versus lymphoma effect (GvL) and graft-versus-host disease (GvHD). To date, specific targeting of GvL antigens with effector T cells and of GvHD antigens with specific regulatory T cells remains the subject of experimental research. In clinical reality, negative modulation of GvHD, e.g. by immunosuppression, reduces GvL and positive modulation of GvL, e.g. by donor lymphocyte infusions, often amplifies GvHD. Clinically feasible strategies to induce GvL while simultaneously reducing GvHD are urgently needed. Here, we report the case of an early relapsed primary cutaneous T cell lymphoma in tumor stage after allogeneic stem cell transplantation which was successfully treated with a parallel administration of donor lymphocyte infusions (DLI) and systemic PUVA and bexarotene which led to sustained complete remission without onset of acute GvHD. After termination of the treatment with PUVA/bexarotene subacute chronic GvHD occurred but was subsequently brought under control by extracorporeal photopheresis. We suggest that the combination of DLI and PUVA/bexarotene might be an interesting immunologic bimodal treatment option which warrants further investigation.

Personalbedarf einer Intensivstation unter Berücksichtigung geltender Hygienerichtlinien

The patient burden in intensive care units (ICU) has continually increased worldwide over the past decades. Age, co-morbidities and an increasing complexity of conditions and treatments increase the number of patients who are either colonized or infected with antibiotic-resistant pathogens. To prevent nosocomial infections, hygiene guidelines play an important role. In this paper, we investigate the time needed for nursing of five hypothetical critically ill patients in the intensive care unit. The results show that current staffing is not sufficient under the given hygiene guidelines and that a nurse to patient ratio of one will be necessary to meet the requirements. In a national survey of university hospitals, however, we found that the current nurse to patient ratio is 1: 2.47 in German intensive care units. The apparent staffing shortage is compensated by an extraordinary personal commitment of nurses caring for patients in the ICU.

Prospective Analyses of Circulating B Cell Subsets in ABO-Compatible and ABO-Incompatible Kidney Transplant Recipients.

Immunosuppressive strategies applied in renal transplantation traditionally focus on T cell inhibition. B cells were mainly examined in the context of antibody‐mediated rejection, whereas the impact of antibody‐independent B cell functions has only recently entered the field of transplantation. Similar to T cells, distinct B cell subsets can enhance or inhibit immune responses. In this study, we prospectively analyzed the evolution of B cell subsets in the peripheral blood of ABO‐compatible (n = 27) and ABO‐incompatible (n = 10) renal transplant recipients. Activated B cells were transiently decreased and plasmablasts were permanently decreased in patients without signs of rejection throughout the first year. In patients with histologically confirmed renal allograft rejection, activated B cells and plasmablasts were significantly elevated on day 365. Rituximab treatment in ABO‐incompatible patients resulted in long‐lasting B cell depletion and in a naïve phenotype of repopulating B cells 1 year following transplantation. Acute allograft rejection was correlated with an increase of activated B cells and plasmablasts and with a significant reduction of regulatory B cell subsets. Our study demonstrates the remarkable effects of standard immunosuppression on circulating B cell subsets. Furthermore, the B cell compartment was significantly altered in rejecting patients. A specific targeting of deleterious B cell subsets could be of clinical benefit in renal transplantation.

Hämatologische und onkologische Notfälle

The rapid development of novel, targeted drugs in cancer medicine has led to an increase in chronically ill cancer patients and hematology patients, who are being treated aggressively despite significant comorbidities and higher age. This development will lead to an increase in the number of hematologic and oncologic emergencies, and these patients will be seen by various specialties. This review article, therefore, aims at providing clinical management algorithms for the most frequent emergencies.ZusammenfassungDie rasante Entwicklung neuer, spezifischer Medikamente in der Krebsmedizin führt zu einer Zunahme sowohl chronisch kranker onkologischer Patienten als auch hämatologischer Patienten, die trotz signifikanter Komorbiditäten und höheren Alters zunehmend aggressiv behandelt werden. Deshalb wird es mittelfristig zu einer Zunahme an hämatolgischen und onkologischen Notfallpatienten kommen, die multidisziplinär und kompetent versorgt werden müssen. Der Übersichtsartikel stellt einen Leitfaden für das Management einiger häufiger Krankheitsbildern dar.AbstractThe rapid development of novel, targeted drugs in cancer medicine has led to an increase in chronically ill cancer patients and hematology patients, who are being treated aggressively despite significant comorbidities and higher age. This development will lead to an increase in the number of hematologic and oncologic emergencies, and these patients will be seen by various specialties. This review article, therefore, aims at providing clinical management algorithms for the most frequent emergencies.

Identification of native, immunogenic peptides from Cyclin D1

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