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Frankfurt am Main, Germany

Meier R.,TU Munich | Golovko D.,University of Massachusetts Medical School | Tavri S.,University of California at San Diego | Henning T.D.,TU Munich | And 6 more authors.
Magnetic Resonance in Medicine | Year: 2011

Genetically modified natural killer (NK) cells that recognize tumor-associated surface antigens have recently shown promise as a novel approach for cancer immunotherapy. To determine NK cell therapy response early, a real-time, noninvasive method to quantify NK cell homing to the tumor is desirable. The purpose of this study was to evaluate if MR imaging could provide a noninvasive, in vivo diagnosis of NK cell accumulation in epithelial cell adhesion molecule (EpCAM)-positive prostate cancers in a rat xenograft model. Genetically engineered NK-92-scFv(MOC31)-Χ cells, which express a chimeric antigen receptor specific to the tumor-associated EpCAM antigen, and nontargeted NK-92 cells were labeled with superparamagnetic particles of iron-oxides (SPIO) ferumoxides. Twelve athymic rats with implanted EpCAM positive DU145 prostate cancers received intravenous injections of 1.5 × 107 SPIO labeled NK-92 and NK-92-scFv(MOC31)-Χ cells. EpCAM-positive prostate cancers demonstrated a progressive and a significant decline in contrast-to-noise-ratio data at 1 and 24 h after injection of SPIO-labeled NK-92-scFv(MOC31)-Χ cells. Conversely, tumor contrast-to-noise-ratio data did not change significantly after injection of SPIO-labeled parental NK-92 cells. Histopathology confirmed an accumulation of the genetically engineered NK-92-scFv(MOC31)-Χ cells in prostate cancers. Thus, the presence or absence of a tumor accumulation of therapeutic NK cells can be monitored with cellular MR imaging. EpCAM-directed, SPIO labeled NK-92-scFv(MOC31)-Χ cells accumulate in EpCAM-positive prostate cancers. Copyright © 2011 Wiley-Liss, Inc. Source

Rettinger E.,Goethe University Frankfurt | Meyer V.,Goethe University Frankfurt | Kreyenberg H.,Goethe University Frankfurt | Volk A.,Chemotherapeutisches Forschungsinstitut | And 8 more authors.
Frontiers in Oncology | Year: 2012

Allogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients' relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc-, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity against AML and RMS cells without causing GvHD. © 2012 Rettinger, Meyer, Kreyenberg, Volk, Kuçi, Willasch, Koscielniak, Fulda, Wels, Boenig, Klingebiel and Bader. Source

Hartmann C.,Chemotherapeutisches Forschungsinstitut | Muller N.,Chemotherapeutisches Forschungsinstitut | Blaukat A.,Merck KGaA | Koch J.,Chemotherapeutisches Forschungsinstitut | And 2 more authors.
Oncogene | Year: 2010

Aberrant activation of the epidermal growth factor receptor (EGFR) has been found in human cancers of various origins, and has been implicated in cancer pathogenesis. The therapeutic anti-EGFR antibodies cetuximab and matuzumab inhibit both ligand-induced receptor activation and growth of EGFR-expressing tumor cells. The efficacy of such EGFR-targeted therapies may be further enhanced by induction of functionally equivalent endogenous antibody responses. Here we describe novel peptide sequences selected from random peptide libraries for binding to single-chain antibody fragments of cetuximab or matuzumab. Two of these peptides characterized by KTL and YPLG motifs are recognized equally well by cetuximab and matuzumab, although nonoverlapping epitopes were previously reported for these antibodies. Immunization of experimental animals with synthetic KTL-and YPLG-containing peptides led to induction of antibodies that cross-react with human EGFR, and prevent binding of natural EGFR ligands, ligand-induced receptor activation and tumor cell growth in a manner similar to cetuximab and matuzumab. Our findings show that these peptide mimotopes can induce anti-EGFR antibodies with antitumoral activity, which may have implications for EGFR-specific cancer immunotherapy. © 2010 Macmillan Publishers Limited All rights reserved. Source

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