Biomedical subjects

Roland Schnell

Publications and source records attributed to Roland Schnell.

13 recordsLinked to original sources

PubMed2006

SGN-30 (Seattle genetics).

Seattle Genetics is developing SGN-30, an intravenously administered recombinant anti-CD30 monoclonal antibody for the potential treatment of Hodgkin's disease, certain non-Hodgkin's lymphomas, specific leukemia, and immunological diseases such as multiple sclerosis and systemic lupus erythematosus. Phase II trials in patients with Hodgkin's disease, anaplastic large cell lymphoma, and cutaneous lymphoma have been conducted in the U.S. and Europe.

Antibodies, Monoclonal↗

PubMed2005

A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo.

The inability of the immune system to recognize and kill malignant plasma cells in patients with multiple myeloma (MM) has been attributed in part to the ineffective activation of natural killer (NK) cells. In order to activate and target NK cells to the malignant cells in MM we designed a novel recombinant bispecific protein (ULBP2-BB4). While ULBP2 binds the activating NK receptor NKG2D, the BB4 moiety binds to CD138, which is overexpressed on a variety of malignancies, including MM. ULBP2-BB4 strongly activated primary NK cells as demonstrated by a significant increase in interferon-gamma (IFN-gamma) secretion. In vitro, ULBP2-BB4 enhanced the NK-mediated lysis of 2 CD138+ human MM cell lines, U-266 and RPMI-8226, and of primary malignant plasma cells in the allogenic and autologous setting. Moreover, in a nude mouse model with subcutaneously growing RPMI-8226 cells, the cotherapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth. These data suggest potential clinical use of this novel construct in patients with MM. The use of recombinant NK receptor ligands that target NK cells to tumor cells might offer new approaches for other malignancies provided a tumor antigen-specific antibody is available.

Animals↗

PubMed2005

Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial.

PURPOSE: To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). PATIENTS AND METHODS: A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment. RESULTS: The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred. CONCLUSION: The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.

Adult↗

PubMed2005

Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody.

PURPOSE: Hodgkin's lymphoma (HL) has been demonstrated to be a good target for immunotherapy since lymphocyte activation markers such as CD30 are expressed in high numbers on the malignant cells. Thus, we developed a new radioimmunoconjugate consisting of the murine anti-CD30 monoclonal antibody (MAb) Ki-4 labeled with iodine-131 ((131)I). PATIENTS AND METHODS: The biodistribution of (131)I-Ki-4 was assessed via dosimetry after preinfusion of 5 mg native Ki-4 followed by 250 to 300 MBq (131)I-labeled Ki-4. Whole-body scintigraphy was performed 1 hour, 24 hours, 48 hours, 72 hours, and 6 days after the infusion. Dosimetry was calculated using the programs NucliDose ICON-IDL (version 5.0.2; Siemens, Erlanger, Germany) and MIRDOSE (version 3.1; Oak Ridge National Laboratories; Oak Ridge, TN). The therapeutic dose was given on day 8 after preinfusion of unlabeled Ki-4. RESULTS: We treated 22 patients with relapsed or refractory CD30-positive HL. Preinfusion of 5 mg native Ki-4 was sufficient to bind the soluble CD30. Imaging demonstrated localization of involved areas measuring 5 cm in diameter or more in four patients and 2.5 cm in one patient. Patients received total body doses of 0.035 Gy to 0.99 Gy. Acute toxicity was mild with grade 1 fatigue in 19 of 22 assessable patients. Seven patients experienced grade 4 degrees hematotoxicity 4 to 8 weeks after treatment. Response included one complete remission, five partial remissions, and three minor responses. CONCLUSION: Treatment with (131)I-Ki-4 is effective but can be associated with severe hematotoxicity.

Adolescent↗

PubMed2005

Imaging of central nervous system lymphomas with iodine-123 labeled rituximab.

Most patients with primary central nervous system (CNS) lymphoma (PCNSL) relapse after initial response to chemotherapy or the combination of chemotherapy and irradiation. Thus, novel treatment regimens for relapsed PCNSL are needed. As the majority of PCNSL are B-cell neoplasms expressing the CD20 antigen, treatment with the chimeric monoclonal antibody (MAb) rituximab might be reasonable. Nevertheless, the potential efficacy of intravenous rituximab in PCNSL seems to be limited as MAbs are high molecular weight proteins, which might be unable to pass the blood brain barrier. Thus, we performed dosimetric measurements with iodine-123 (123I)-rituximab to evaluate rituximab uptake in PCNSL after systemic intravenous administration. We analyzed four patients with PCNSL receiving a preinfusion of 250 mg/m2 rituximab followed by 200-500 MBq of the gamma-emitter 123I-rituximab. Single photon emission computed tomography (SPECT) was performed 1, 24 and 48 h after administration of the radio-immunoconstruct. Only one patient showed a very weak or questionable uptake of 123I-rituximab into tumor tissue which was ninefold lower compared with the blood-pool accumulation. These data suggest that systemic MAb-based radio-immunotherapy is not feasible in patients with PCNSL because a sufficient activity in the tumor will be associated with severe hematotoxicity. If an uptake of therapeutic rituximab doses into PCNSL can be achieved remains questionable.

Adult↗

PubMed2005

The role of pixantrone in the treatment of non-Hodgkin's lymphoma.

Pixantrone is an anthraquinone-based inhibitor of topoisomerase II. It is similar to both the anthracycline doxorubicin and the anthracenedione mitoxantrone, but lacks the 5,8-dihydroxy substitution pattern of mitoxantrone, and has a tricyclic system unlike the tetracyclic structure seen with anthracyclines. Anthracyclines are the most active drugs in lymphoma therapy, but their use is limited by their cumulative and irreversible cardiotoxicity. Pixantrone was developed to improve the toxicity profile of the current anthracyclines and anthracenediones while maintaining their activity. Interestingly, pixantrone showed no measurable cardiotoxicity compared with its parent compound mitoxantrone or other anthracyclines at equi-effective doses in several animal models. Together with its superior cytotoxic activity in leukaemia and lymphoma models, these features render the drug a promising candidate for clinical development in indolent and aggressive non-Hodgkin's lymphoma. In this review, the latest results of the use of pixantrone in indolen-t and aggressive non-Hodgkin's lymphomas are summarised.

Animals↗

PubMed2005

Current treatment and immunotherapy of Hodgkin's lymphoma.

The treatment of Hodgkin's lymphoma has changed significantly over the last decades, rendering this entity one of the most curable human cancers. To date, about 80% of patients achieve long-term disease-free survival. Current strategies in first-line treatment aim at further improving outcome and thereby preventing therapy-induced complications, such as infertility, cardiopulmonary toxicity, and secondary malignancies. Ongoing trials for patients in early stages are investigating lower radiation doses and smaller radiation fields and possible reductions in the doses or number of cycles of chemotherapy given. For patients in advanced stages, new drug combinations with higher dose density and intensity have been developed, and are currently being evaluated in clinical trials. Approaches for relapsed Hodgkin's lymphoma comprise salvage radiotherapy, salvage chemotherapy and high-dose chemotherapy followed by autologous stem cell transplantation. In recent years, the introduction of effective salvage high-dose therapy and a better understanding of prognostic factors have remarkably improved the management of relapsed Hodgkin's lymphoma. For multiple pretreated patients antibody-based agents that showed promising results in experimental models are being investigated in clinical trials. Radioimmunoconjugates and monoclonal antibodies have demonstrated some clinical efficacy. Here, we review new aspects in the treatment of primary and relapsed Hodgkin's lymphoma as well as recent immunotherapeutic approaches.

Adult↗

PubMed2004

Metalloproteinase inhibition augments antitumor efficacy of the anti-CD30 immunotoxin Ki-3(scFv)-ETA' against human lymphomas in vivo.

There is increasing evidence that the shedding of extracellular antigen domains impedes selective immunotherapy. One example is CD30, which is overexpressed on the surface of malignant lymphoma cells and has been identified as a promising target for antibody-based immunotherapy. However, CD30 is cleaved from the surface of target cells and the resulting soluble ectodomain (sCD30) is protecting the cells from antibody binding. Shedding can be inhibited by hydroxamate inhibitors of metalloproteinases such as BB-3644. We thus evaluated the influence of BB-3644 on the efficacy of the anti-CD30 single-chain immunotoxin Ki-3(scFv)-ETA'. In vitro, the addition of BB-3644 augmented the antitumor effect of Ki-3(scFv)-ETA' against Hodgkin-derived L540Cy cells by a factor of 2.75. Severe combined immunodeficiency (SCID) mice challenged with CD30-positive L540Cy cells were treated with the immunotoxin. One single nontoxic dose of BB-3644 increased the mean survival time of animals treated concomitantly with Ki-3(scFv)-ETA' to 93 days as compared with 35 days in the control (p = 0.0017). When BB-3644 was continuously delivered using subcutaneously implanted pumps, this effect was even more pronounced with no observed tumor growth in the animals within 200 days. Thus, concomitant application of metalloproteinase inhibitors might become clinically relevant in antibody-based immunotherapy against targets known to be shed from tumor cells.

Aminopyridines↗

PubMed2004

Monoclonal antibody-based immunotherapy of Hodgkin's lymphoma.

Many new approaches involving the use of antibody-based agents have produced promising results in experimental Hodgkin's lymphoma (HL) models. Early clinical trials using immunotoxins, radioimmunotherapy (RIT), bispecific molecules and monoclonal antibodies (mAbs), have demonstrated some clinical efficacy in patients with advanced refractory HL. Although it seems unlikely that these approaches alone will cure chemotherapy-resistant patients with larger tumor masses, combination with conventional chemotherapy may help to overcome resistance of Hodgkin-Reed/Sternberg (H-RS) cells or to eliminate residual disease. Since H-RS cells are extremely sensitive to irradiation, RIT may be a potential approach. A murine mAb (Ki-4)-based 131I conjugate showed efficacy in refractory HL patients, however, toxicity was a problem and less toxic constructs using alternate mAbs or isotopes need to be designed. A humanized and a fully human anti-CD30 mAb are currently being evaluated in phase I/II clinical trials. These mAbs could engage the human immune system against the HL and are capable of directly inducing apoptosis of H-RS cells. In addition, these mAbs could be combined with conventional chemotherapy and are thus promising candidates for further development for the therapy of HL.

Animals↗

PubMed2003

The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma.

CD30 is a promising target for antibody-based immunotherapy of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma. To overcome the limitations from currently available murine anti-CD30 monoclonal antibodies (mAbs), a new fully human anti-CD30 antibody was generated. Binding properties were evaluated by recombinant CD30 capture enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell-sorter (FACS) flow cytometry. Activity of this new mAb was assessed in vitro using growth inhibition and antibody-dependent cellular cytotoxicity (ADCC) assays on several cell lines. In vivo activity was determined in a solid as well as in a disseminated xenografted model of HL in severe combined immunodeficiency (SCID) mice. The mAb 5F11 showed specific binding to CD30 (cluster A). The ADCC assays indicated dose-dependent lysis of L540 cells when 5F11 was combined with human effector cells. Upon cross-linking in vitro, 5F11 inhibited the growth of CD30-expressing cell lines. In vivo, treatment with 5F11 induced a marked growth delay or even a complete regression of established xenografted HL in SCID mice. In the disseminated HL model, a high proportion of 5F11-treated mice experienced long-term survival. The new human anti-CD30 monoclonal antibody 5F11 shows promise as a means of CD30-targeted immunotherapy of malignant lymphomas. Based on these results, a clinical phase 1 study in patients with refractory CD30+ lymphoma has been initiated.

Animals↗

PubMed2003

Phase-II study of the new aza-anthracenedione, BBR 2778, in patients with relapsed aggressive non-Hodgkin's lymphomas.

BACKGROUND AND OBJECTIVES: BBR 2778 is a new aza-anthracenedione. Its activity against hematologic neoplasias in a mouse model is greater than that of doxorubicin or mitoxantrone. A phase-I study in patients with non-Hodgkin's lymphoma (NHL) showed that the drug has promising anti-tumor activity. Therefore, a phase-II study in patients with relapsed aggressive NHL was initiated. DESIGN AND METHODS: The primary objective was to determine the efficacy of 85 mg/m2 BBR 2278 for a q1w x3 treatment schedule (repeat day 29). Secondary objectives included the evaluation of response duration and safety in this open-label, non-randomized, multicenter trial. Patients with relapsed aggressive NHL according to the REAL-classification were included. RESULTS: Eight centers enrolled a total of 33 patients. The median age of these patients was 66 years (range 24-81). The majority of patients had diffuse large B-cell lymphoma (n=24) or mantle-cell lymphoma (n=7), pretreated with a median of 2 regimens. Confirmed responses included 5 complete and 4 partial remissions, with the period between the first appearance of response and any signs or symptoms of progression being up to 17+ months. The main toxicity was neutropenia. INTERPRETATIONS AND CONCLUSIONS: These results indicate that 85 mg/m2 BBR 2778 in a q1w x 3 schedule is active in elderly and pretreated patients with relapsed aggressive NHL and was generally well tolerated. Thus, we recommend further clinical evaluation of this new compound in phase-III studies for the treatment of NHL.

Adult↗

PubMed2002

Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma.

CD30 is an excellent target for immunotherapy of Hodgkin lymphoma (HL) because it is overexpressed on Hodgkin and Reed-Sternberg cells. We developed a novel bispecific molecule (BSM) consisting of F(ab') fragments derived from the murine anti-CD30 monoclonal antibody (MoAb) Ki-4 and the humanized CD64-specific MoAb H22. In vitro experiments of H22xKi-4 demonstrated specific phagocytosis of HL-derived cell lines. Patients (pts) with refractory CD30(+) HL were treated with escalating doses of H22xKi-4 at doses of 1, 2.5, 5, 10, and 20 mg/m(2)/d, respectively (administered intravenously on days 1, 3, 5, and 7). The main study objectives were to determine the maximum tolerated dose and the dose-limiting toxicities of H22xKi-4, to define its pharmacokinetic profile, and to document clinical response. Ten pts were enrolled and are evaluable for toxicity and response. Side effects were transient and mild with hypotension (4 of 10), tachycardia (6 of 10), fatigue (10 of 10), and fever (2 of 10 grade I, 3 of 10 grade II). Pharmacokinetic (PK) data revealed an elimination half-life of 11.1 hours, resulting in a significant accumulation of H22xKi-4. The BSM was shown to bind to both monocytes and malignant cells. Response to H22xKi-4 included 1 complete remission (CR), 3 partial remissions (PR), and 4 pts with stable disease. The new BSM H22xKi-4 can be given safely to pts with refractory CD30(+) HL in doses up to 80 mg/m(2) per cycle. Although this dose is not the maximum tolerated dose (MTD) as defined by toxicity criteria, surrogate parameters suggest a biologic effective regimen. H22xKi-4 shows activity in heavily pretreated HL patients warranting further clinical evaluation.

Adult↗

PubMed2002

A Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin's and non-Hodgkin's lymphoma.

Ki-4.dgA is an anti-CD30 immunotoxin (IT) constructed by coupling the monoclonal antibody Ki-4 via a sterically hindered disulfide linker to deglycosylated ricin A-chain. This IT was efficacious in vitro and in SCID mice with disseminated human Hodgkin's lymphoma. Accordingly, a Phase I trial in patients (pts) with Hodgkin's lymphoma was designed. The objectives of this Phase I trial were to determine the maximum tolerated dose, the dose-limiting toxicities, pharmacokinetics, and antitumor activity. Seventeen pts with relapsed CD30+ lymphoma were treated with escalating doses (5, 7.5, or 10 mg/m(2)/cycle) of the IT as four bolus infusions on days 1, 3, 5, and 7 for one to three cycles. All of the pts had progressive disease and were heavily pretreated. Nine had primary progressive disease and 14 had advanced disease with massive tumor burdens. The mean age was 35 years (24-52 years). Peak serum concentrations of the intact IT varied from 0.23 to 1.1 microg/ml. Side effects and dose-limiting toxicities were related to vascular leak syndrome, i.e., decreases in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. The maximum tolerated dose was 5 mg/m(2). Seven of 17 (40%) pts made human antiricin antibodies (> or =1.0 microg/ml), and 1 pt developed human antimouse antibodies (> or =1.0 microg/ml). Clinical response in the 15 evaluable pts included 1 partial remission, 1 minor response, and 2 stable diseases. In conclusion, the IT was less well tolerated than other ITs of this type. This might be because of the low number of CD30+ peripheral blood mononuclear cells, and in part because of binding of the IT to soluble CD30 antigen and the resulting circulation of IT/sCD30 complexes.

Adult↗