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Rack B.,Ludwig Maximilians University of Munich | Juckstock J.,Ludwig Maximilians University of Munich | Gunthner-Biller M.,Ludwig Maximilians University of Munich | Andergassen U.,Ludwig Maximilians University of Munich | And 8 more authors.
Archives of Gynecology and Obstetrics | Year: 2012

Purpose Isolated tumor cells (ITC) in the bone marrow of breast cancer patients increase the risk of recurrence and decrease survival, both at primary diagnosis and during follow-up. We tested the eYcacy of trastuzumab in clearing HER2/neu-positive ITC from the marrow of patients completing primary treatment. Methods Ten recurrence-free patients with persistent HER2/neu-positive ITC after routine adjuvant treatment received trastuzumab 6 mg/kg q3w for 12 months in a non-randomized pilot phase II interventional study. Bone marrow ITC HER2/neu status was evaluated at baseline, after treatment for 3, 6 and 12 months, and yearly thereafter, in combination with clinical follow-up. Median follow-up was 23 (15-64) months after baseline bone marrow aspiration. Results Trastuzumab for 12 months eradicated HER2/neu-positive ITC from bone marrow in all patients (P = 0.002) and signiWcantly reduced the number of ITCpositive patients (P = 0.031). However, HER2/neu-nega-tive ITC persisted in three patients immediately after treatment and were detected at yearly bone marrow aspiration in Wve patients. Two patients with ITC counts ≥5 at yearly follow-up developed metastases and one died. Conclusion This is the Wrst evidence that trastuzumab is eVective in clearing HER2/neu-positive cells from bone marrow during recurrence-free follow-up in breast cancer patients. It also suggests, thanks to the antigen shift phenomenon, an important prognostic role for HER2/neu expression on marrow ITC as a real-time biopsy. However, treatment was mainly eVective in patients with HER2/neu-positive ITC. Given the heterogeneity of minimal residual disease, these patients might beneWt from a combination of targeted treatment approaches. © 2011 Springer-Verlag.

Buhmann R.,Ludwig Maximilians University of Munich | Buhmann R.,Helmholtz Center Munich | Michael S.,TRION Pharma GmbH | Juergen H.,TRION Pharma GmbH | And 4 more authors.
Journal of Translational Medicine | Year: 2013

Background: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD.Methods/Design: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab- and/or alemtuzumab-refractory, CD20-positive low- or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial.Discussion: Promising data (e.g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse.Trial registration: NCT01138579. © 2013 Buhmann et al.; licensee BioMed Central Ltd.

The present invention refers to a pharmaceutical composition containing trifunctional bispecific and/or trispecific antibodies being capable of binding to a specific target antigen(s) for use in a method of immunizing mammals against diseases in which said target antigen(s) is (are) involved, and further to a pharmaceutical composition containing trifunctional bispecific and/or trispecific antibodies being capable of binding to (a) specific target antigen (s) which is (are) involved in a disease of a mammal, specifically a human.

Ruf P.,TRION Research GmbH | Kluge M.,Fresenius Biotech GmbH | Jager M.,TRION Research GmbH | Burges A.,Ludwig Maximilians University of Munich | And 7 more authors.
British Journal of Clinical Pharmacology | Year: 2010

AIMS Catumaxomab is the first EMEA approved trifunctional anti-EpCAM×anti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development. METHODS Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 mg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored. RESULTS Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml -1 range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (Cmax) of 403 pg ml-1. The mean elimination half-life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter-individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model. CONCLUSIONS Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate. © 2010 The British Pharmacological Society.

Schuster F.R.,Heinrich Heine University Dusseldorf | Stanglmaier M.,TRION Research GmbH | Woessmann W.,Justus Liebig University | Winkler B.,University of Wurzburg | And 9 more authors.
British Journal of Haematology | Year: 2015

Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow-up of ten patients diagnosed with relapsed or refractory mature B-cell Non Hodgkin Lymphoma (B-NHL), Burkitt leukaemia (B-AL) or pre B-acute lymphoblastic leukaemia (pre B-ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti-CD3 x anti-CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo-SCT, n = 6) to induce sustained long-term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo-SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow-up. The other patients still maintain CR with a current overall survival of 874-1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients. © 2014 John Wiley & Sons Ltd.

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