Current status of granulocyte (neutrophil) transfusion therapy for infectious diseases.

The transfusion of neutrophils, or granulocyte transfusion therapy, has long been considered as a logical approach to the treatment of severe bacterial and fungal infections in patients with prolonged neutropenia or intrinsic defects in neutrophil function. However, despite numerous clinical trials, the efficacy and safety of granulocyte transfusion therapy remain controversial. Efficacy has been compromised largely by the inability to transfuse sufficient quantities of functionally active neutrophils to patients.

Use of G-CSF for granulocyte transfusion therapy.

Patients with neutropenia, especially neutropenia following aggressive myeloablative therapy, are at high risk for developing infectious complications caused by bacteria and opportunistic fungi. Infections remain one of the leading causes of treatment failure in patients with cancer. Thus, new and innovative therapeutic strategies are needed for management of neutropenic patients with infection.

Increase of anti-inflammatory cytokines in patients with esophageal cancer after perioperative treatment with G-CSF.

Granulocyte colony-stimulating factor (G-CSF) has been shown to effectively stimulate granulopoiesis, in both neutropenic and in non-neutropenic patients. Recently, other effects of G-CSF on the immune system have attracted interest in treating non-neutropenic patients with a high risk of severe infection. In this phase II trial, we measured the effects of G-CSF on the serum cytokine levels in patients with esophageal cancer undergoing esophagectomy.

IDEC-C2B8 (Rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group.

Purpose: The current study was initiated to assess the clinical efficacy and side effects of rituximab in patients with relapsed advanced stage follicular lymphoma.

Patients And Methods: The study was performed as an open-label non-randomized multicenter phase-II trial and included patients older than 18 years of age with relapsed advanced-stage follicular lymphomas (FL) grades I and II, according to the REAL classification, or with centroblastic/centrocytic (CB/CC lymphomas according to the Kiel classification. Four weekly doses of 375 mg/m2 rituximab were applied.

Recombinant immunotoxins for the treatment of Hodgkin's disease (Review).

In recent years, substantial experience has been accumulated with tumor-specific immunotherapeutics which seem to be effective against minimal residual disease. The coupling of toxins to monoclonal antibodies has indicated promising results in early clinical trials. Recombinant DNA technology makes it possible to genetically fuse coding regions of V genes or cytokines to modified toxin domains.

Combining phage display and screening of cDNA expression libraries: a new approach for identifying the target antigen of an scFv preselected by phage display.

A potential method for identifying new tumor-specific antibody structures as well as tumor-associated antigens is by selecting scFv phage libraries on tumor cells. This phage display technique involves multiple rounds of phage binding to target cells, washing to remove non-specific phage and elution to retrieve specific binding phage. Although the binding properties of an isolated tumor-specific scFv can be evaluated by ELISA, FACS and immunohistochemistry, it still remains a challenge to define the corresponding antigen.

Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group.

To determine prognostic factors and treatment outcome, patients with primary progressive Hodgkin lymphoma (HD) registered in the database of the German Hodgkin Lymphoma Study Group (GHSG) were analyzed retrospectively. Detailed records from randomized prospective multicenter trials performed between 1988 and 1998 of 3807 patients recruited in these trials were reviewed. The median age of the 206 patients available was 34 years (range, 16-71).

Treatment of patients with malignant lymphomas with monoclonal antibodies.

Malignant lymphomas represent a heterogenous group of B and T cell-derived malignancies. Most lymphomas are sensitive to chemo- and radiotherapy, however many patients will eventually relapse. Immunotherapeutic approaches including monoclonal antibodies, cytokines or vaccination approaches may offer an alternative treatment of chemotherapy-resistant residual cells especially in cases with low tumor burden or residual disease following chemo- or radiotherapy.

Human anti-CD30 recombinant antibodies by guided phage antibody selection using cell panning.

In various clinical studies, Hodgkin's patients have been treated with anti-CD30 immunotherapeutic agents and have shown promising responses. One of the problems that appeared from these studies is the development of an immune response against the nonhuman therapeutics, which limits repeated administration and reduces efficacy. We have set out to make a recombinant, human anti-CD30 single-chain variable fragment (scFv) antibody, which may serve as a targeting moiety with reduced immunogenicity and more rapid tumour penetration in similar clinical applications.

Ki-4(scFv)-ETA', a new recombinant anti-CD30 immunotoxin with highly specific cytotoxic activity against disseminated Hodgkin tumors in SCID mice.

The human lymphocyte activation marker CD30 is highly overexpressed on Hodgkin/Reed-Sternberg cells and represents an ideal target for selective immunotherapy. We used the murine anti-CD30 hybridoma Ki-4 to construct a new recombinant immunotoxin (rIT) for possible clinical use in patients with CD30(+) lymphoma. Hybridoma V genes were polymerase chain reaction-amplified, assembled, cloned, and expressed as a mini-library for display on filamentous phage.

Perioperative treatment with filgrastim stimulates granulocyte function and reduces infectious complications after esophagectomy.

We investigated the effects of recombinant G-CSF (Filgrastim) on the function of neutrophils and the rate of infectious complications in an open-label, nonrandomized study of patients with esophageal cancer undergoing esophagectomy. In this single-center phase-II trial 20 sequential patients (19 evaluable) received Filgrastim at standard doses (300 microg or 480 microg) subcutaneously for 2 days prior to and up to 7 days after surgery. The phagocytotic activity of neutrophils and the oxidative burst in the study group and in an experimental control group (n=27) were measured on days -2, 2, and 10.

Recombinant anti-CD25 immunotoxin RFT5(SCFV)-ETA' demonstrates successful elimination of disseminated human Hodgkin lymphoma in SCID mice.

Since clinical phase-I/II trials in patients with resistant Hodgkin's lymphoma treated with the chemically linked anti-CD25 ricin-A-chain immunotoxin RFT5-SMPT-dgA indicate promising results for patients with minimal residual disease, we constructed a new immunotoxin by fusing the RFT5 single-chain variable fragment to a deletion mutant of Pseudomonas exotoxin A (ETA'). The recombinant protein was directed into the periplasmic space of E. coli by means of the pET-derived expression vector pBM1.

A real-time PCR assay for the quantification of residual malignant cells in B cell chronic lymphatic leukemia.

Several new therapeutic approaches for the treatment of monoclonal B cell lymphomas are currently being investigated. In parallel with new therapeutic modalities, more sensitive diagnostic methods are needed. These methods should be highly sensitive in detecting very low amounts of malignant cells and should be specific for the malignant clone.

Compatible-solute-supported periplasmic expression of functional recombinant proteins under stress conditions.

The standard method of producing recombinant proteins such as immunotoxins (rITs) in large quantities is to transform gram-negative bacteria and subsequently recover the desired protein from inclusion bodies by intensive de- and renaturing procedures. The major disadvantage of this technique is the low yield of active protein. Here we report the development of a novel strategy for the expression of functional rIT directed to the periplasmic space of Escherichia coli.

Dexa-BEAM: an effective regimen for cytoreduction prior to high-dose chemotherapy with autologous stem cell support for patients with relapsed/refractory mantle-cell lymphoma.

Mantle-cell lymphoma (MCL) is not a curable disease using conventional chemotherapy. Patients with MCL have the shortest median time to progression and the shortest median survival of all lymphoma subtypes after first-line treatment. In the present study we determined the efficacy of maximal cytoreductive therapy with up to four cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell support (ASCT) for patients with advanced relapsed or refractory MCL.

Dexamethasone, carmustine, etoposide, cytarabine, and melphalan (dexa-BEAM) followed by high-dose chemotherapy and stem cell rescue--a highly effective regimen for patients with refractory or relapsed indolent lymphoma.

We performed a phase II study to determine the efficacy of maximal cytoreductive therapy with up to five cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) for patients with advanced relapsed or refractory indolent lymphoma. Thirty-two patients with primary refractory or relapsed indolent lymphoma were treated with the Dexa-BEAM regimen. Thirteen patients had primary refractory disease, 4 patients partial remission, and 15 patients first or subsequent relapse.

Treatment of Hodgkin's disease: results and current concepts of the German Hodgkin's Lymphoma Study Group.

Background: Treatment strategies in Hodgkin's disease (HD) are changing fundamentally over the last decades. Both radiotherapy and combination chemotherapy are effective treatment modalities. However, the optimal choice of treatment or combinations of treatment is still debated for different prognostic groups.

Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin.

The anti-CD25 immunotoxin RFT5.dgA was constructed by coupling the monoclonal antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin A-chain and was administered to patients with relapsed Hodgkin's lymphoma in four bolus infusions over 7 days (day 1, 3, 5 and 7). The maximum tolerated dose in these patients as defined in a previous phase I study was 15 mg/m2.

Treatment of primary progressive Hodgkin's and aggressive non-Hodgkin's lymphoma: is there a chance for cure?

Purpose: To determine differences in prognosis between primary progressive Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL), we retrospectively analyzed patients with progressive lymphoma who were treated with different salvage chemotherapy regimens including high-dose chemotherapy (HDCT) followed by autologous stem-cell support (ASCT).

Patients And Methods: One hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n = 64) were enrolled. Primary progressive disease was defined as disease progression during first-line chemotherapy or only transient response (complete or partial response lasting View Article and Find Full Text PDF

Prognostic factors for subdiaphragmatic involvement in clinical stage I-II supradiaphragmatic Hodgkin's disease: a retrospective analysis of the GHSG.

Background: Staging laparotomy and splenectomy were routinely performed in patients with early-stage Hodgkin's disease (HD) qualifying for radiotherapy alone to determine the exact extent of disease. However, staging laparotomy is associated with a considerable number of side effects, warranting more sophisticated diagnostic procedures and new therapy strategies. We retrospectively analyzed patients undergoing staging laparotomy to identify pretherapy risk factors predicting the probability of abdominal disease and to define high-risk groups that might benefit from staging laparotomy and subsequent stage-adjusted treatment.

[Anti-angiogenesis: a new approach to tumor therapy?].

Background: The overall mortality due to metastatic cancer has not or only minimally been reduced in spite of intensive research and many innovations in the field of conventional antineoplastic therapy in the past decade. In the last years it has become a fact that tumor growth is angiogenesis-dependent. Therefore, inhibitors of angiogenesis are a new class of antineoplastic substances with a novel mechanism of action that might be a powerful complement to conventional cytostatic therapy.

CD30L-ETA': a new recombinant immunotoxin based on the CD30 ligand for possible use against human lymphoma.

Recombinant DNA technology makes it possible to genetically fuse V genes or cytokines to toxin domains, resulting in immunotherapeutics for selective destruction of tumor cells. Since recombinant immunotoxins can be easily manipulated in terms of affinity or cytotoxic potency and produced in large quantities, we have developed a new CD30 ligand-based fusion toxin (CD30L-ETA'). Human CD30L cDNA was ligated into a pET-based expression plasmid and thereby fused to a modified Pseudomonas aeruginosa exotoxin A (ETA') lacking its cell-binding domain I.

Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8).

Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin's lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.

[Role of high-dose chemotherapy in hematology and internal medicine/ oncology].

Background: High-dose chemotherapy (HDCT) with stem cell rescue is increasingly being used as a salvage or consolidation therapy for patients with a variety of malignant diseases. The authors give an overview of the current role of HDCT in lympho-hematopoietic malignancies and solid tumors.

Methods: The use of allogenic or autologous hematopoietic stem cells allows an increase of the dose of chemotherapeutic drugs by a factor of between 4- and 30-fold compared to conventional chemotherapy protocols.