TY  - JOUR
A1  - Rasche, Leo
A1  - Duell, Johannes
A1  - Morgner, Charlotte
A1  - Chatterjee, Manik
A1  - Hensel, Frank
A1  - Rosenwald, Andreas
A1  - Einsele, Hermann
A1  - Topp, Max S.
A1  - Brändlein, Stephanie
T1  - The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78
JF  - PLoS ONE
N2  - In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM.
KW  - cytotoxicity
KW  - apoptosis
KW  - immunohistochemistry techniques
KW  - enzyme-linked immunoassays
KW  - multiple myeloma
KW  - cell staining
KW  - cell binding
KW  - complement system
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130125
VL  - 8
IS  - 5
ER  - 
TY  - JOUR
A1  - Chopra, Martin
A1  - Lang, Isabell
A1  - Salzmann, Steffen
A1  - Pachel, Christina
A1  - Kraus, Sabrina
A1  - Bäuerlein, Carina A.
A1  - Brede, Christian
A1  - Jordán Garrote, Ana-Laura
A1  - Mattenheimer, Katharina
A1  - Ritz, Miriam
A1  - Schwinn, Stefanie
A1  - Graf, Carolin
A1  - Schäfer, Viktoria
A1  - Frantz, Stefan
A1  - Einsele, Hermann
A1  - Wajant, Harald
A1  - Beilhack, Andreas
T1  - Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1
JF  - PLoS ONE
N2  - Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
KW  - Bioluminescence
KW  - cancer treatment
KW  - cell staining
KW  - cytokines
KW  - immune cells
KW  - metastasis
KW  - regulatory T cells
KW  - T cells
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97246
ER  -