UTRECHT: MYELOMA IMMUNOTHERAPY

Immunotherapy of Myeloma and other haematological tumors printPrint Laat de tekst voorlezen met ReadSpeakerLees voor Immunotherapy of Myeloma and other haematological tumors Myeloma and several other haematological cancers can be treated by cellular immunotherapy, as illustrated by the success of allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) to induce long term remissions in a fraction of patients. This donor T-cell-mediated therapeutic Graft-vs-Tumor effect (GvT) is, however, frequently inefficiently developed, compromised by several tumor microenvironment-related immune escape mechanisms and is furthermore associated with severe complications such as Graft-vs-Host Disease (GvHD). Set out to improve the efficacy and safety of immune therapies of myeloma and other haematological malignancies, the research in the haemato-oncology group is focused on three important areas: 1. Separating GvT and GvHD by: a) Identification of GvT-associated Tumor antigens and minor Histocompatibility antigens (mHag) by Genome wide genetic association analyses (GWAS) and by reverse immunology. b) Development and clinical application therapeutic dendritic cell vaccines loaded with GvT associated mHags. c) Development and clinical application adoptive immunotherapy strategies based on GvT associated mHags. d) Defining the appropriate conditions to separate GvT from GvHD using regulatory T cells. e) Development of effective cancer vaccines by protein misfolding. 2. Understanding and eliminating tumor microenvironment-related immune escape mechanisms. a) Identification, in vitro and in vivo modulation of (intra) cellular mechanisms of immune suppression and immune resistance within the bone marrow, the natural microenvironment of myeloma microenvironment. Specific attention is given to p53, Notch and WNT signalling pathways. b) identification and modulation of (intra) cellular immune suppressive/resistance mechanisms leading to extramedullar Myeloma outgrowth. 3. Development of efficient targeted antibody therapy for MM by combining novel therapeutic antibodies with immune stimulatory agents like lenalidomide, pomalidomide, bortezomib and others. The research mission of Haemato-oncology lab is strongly linked to the clinical goals of the Department of Haematology, which is one of the largest SCT centres in the Netherlands and functions as a reference centre for Multiple Myeloma (MM) patients. The preclinical research is carried out in advanced in vitro models as well as in humanized in vivo murine models that are developed with a longstanding collaboration with Dr. A.C.M. Martens. Faculty Dr. Tuna Mutis Prof. dr. Henk Lokhorst Recent publications - Groen, R.W., W.A. Noort, R.A. Raymakers, H.J. Prins, L. Aalders, F.M. Hofhuis, P. Moerer, J.F. van Velzen, A.C. Bloem, B. van Kessel, H. Rozemuller, E. van Binsbergen, A. Buijs, H. Yuan, J.D. de Bruijn, M. de Weers, P.W. Parren, J.J. Schuringa, H.M. Lokhorst, T. Mutis, and A.C. Martens (2012). Reconstructing the human hematopoietic niche in immunodeficient mice: opportunities for studying primary multiple myeloma. Blood 120, e9-e16. - Kneppers, E. B. van der Holt, M.J. Kersten, S. Zweegman, E. Meijer, G. Huls, J.J. Cornelissen, J.J. Janssen, C. Huisman, P.B. Cornelisse, C.P. Bruijnen, M. Emmelot, P. Sonneveld, H.M. Lokhorst, T. Mutis, M.C. Minnema –(2011) Lenalidomide maintenance following non-myeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 trial. Blood 118, 2413-2419 - Veer, M. van der, M. de Weers, B. van Kessel, J.M. Bakker, S. Wittebol, P.W.H.I. Parren, H.M. Lokhorst, T. Mutis (2011) Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica 96, 284-290