Cellular immunotherapy of hematological tumors after allogeneic stem cell transplantation
Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusions (DLI) can induce long term remissions of hematological malignancies. These treatments are associated with a potent Graft versus Tumor effect (GvT) mediated by donor T cells that recognize recipient’s (host’s) minor Histocompatibility antigens (mHags) presented by malignant cells. Recent studies suggest that Tumor Associated Antigens (TAAs) also play a role in GvT. For the initiation of these anti-tumor responses potent antigen presentation to donor T cells is required. Hence, host’s dendritic cells (DCs) are also crucial for an effective GvT. Currently, the success of allo-SCT and DLI is hampered by two important obstacles: i) high rates of transplant related mortality due to Graft versus Host Disease (GvHD) ii) relatively low rates of sustained remissions, especially in acute Leukemia and Multiple Myeloma patients.
The research mission of the Hemato-Oncology Section, lead by Dr. T. Mutis and Dr. H.M. Lokhorst from the Department of Haematology is the development and clinical translation of novel cellular immunotherapeutic strategies to improve GvT and control GvHD.
This mission is strongly linked to the clinical goals of the Department of Haematology, which is the largest SCT center of the Netherlands and functions as a reference center for Multiple Myeloma (MM) patients. Consequently, Multiple Myeloma-related SCT research is a main theme in the research activities of the Hemato-Oncology Laboratory. Next to this, a strong collaboration has been recently established with Dr. M.F.B.G. Gebbink to develop improved cancer vaccines based on protein modifications.
Towards accomplishing our mission our research currently focus on the following topics:
1. Identification of GvT-associated minor Histocompatibility antigens (mHag)
2. Exploring the impact of TAAs in the Graft versus Myeloma (GvM) effect.
3. Exploring Human Foxp3+ regulatory T cells as cellular tools to separate GvT from GvHD.
4. Improvement of GvM after DLI by (antigen-loaded) host DC-vaccinations in clinical trials.
5. Exploring the impact of novel anti-myeloma agents, lenalidomide and Bortezomib on GvT/GvHD in vitro and in clinical trials.
6. Development of novel Myeloma therapies based on combination of SCT, novel agents and novel anti-CD38 antibodies.
7. Exploring the immunostimulatory capacities of misfolded proteins as candidates for novel cancer vaccines.
The participants of these projects are:
Andries Bloem, PhD (Department of Immunology)
Monique Minnema, MD, PhD (Department of Haematology)
Teun Guichelaar, Post-Doc
Anton Bussink, Post-Doc
Julie Huang, Post-Doc
Robbert M. Spaapen, Ph.D. student
Ellen van der Spek, MD, Ph.D. student
Michael van der Veer, Ph.D. student
Evelien Kneppers, MD, PhD student
Tineke Aarts-Riemens, technician
Maureen van Elk, technician
Maarten E. Emmelot, technician
Berris van Kessel, technician
Kelly van den Oudenalder , technician
Thomasz Poplonski, technician
Mark Ruitenbeek, Internship Student
Tamara Martinovic, Internship Student
Ron de Korte, Internship Student
Sanne de Haart, Internship Student
The preclinical research also benefits from a longstanding collaboration with:
Dr. A.C.M. Martens, PhD, Department of Immunology
The translational research is realized in collaboration with:
Dr. I. Slaper-Cortenbach and K. Westinga, Gene and Cell Therapy Facility, UMC Utrecht.
Other national and international collaborators are:
Dr. C. Kesmir , University U trecht
Prof.dr. E. Goulmy, Leiden University Medical Center
Dr. J-W. Drijfhout, Leiden University Medical Center
Dr. R. Rijniers, University Medical Center Nijmegen
Dr. H. Dolstra, University Medical Center Nijmegen
Dr. S. Shota, University of Southampton, United Kingdom
Recent publications:
Spaapen, R.M., H.M. Lokhorst, K . van den Oudenalder, B.E. Otterud, H. Dolstra, M.F. Leppert, M.C. Minnema, A.C. Bloem and T. Mutis.
Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis.
J. Exp. Med. (2008) E-pub ahead of print
Minnema, M.C., M. van der Veer, T. Aarts, M.E. Emmelot, T. Mutis and H.M. Lokhorst.
Lenalidomide alone or in combination with dexamethasone is highly effective in patients with relapsed multiple myeloma following allogeneic stem cell transplantation and increases the frequency of CD4(+)Foxp3(+) T cells.
Leukemia (2008) E-pub ahead of print
Rozemuller, H., E van der Spek, L.H. Bogers-Boer, M.C. Zwart, V. Verweij, M.E. Emmelot, R.W. Groen, R.M. Spaapen, A.C. Bloem, H.M. Lokhorst, T. Mutis and A.C.Martens.
A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect.
Haematologica 93 (2008) pp. 1049-1057.
Aarts-Riemens, T., M.E. Emmelot, L.F. Verdonck and T. Mutis.
Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4(+)CD25(-) cells.
Eur. J. Immunol. 38 (2008) pp. 1381-1390.
Spaapen, R.M., K. van den Oudenalder, R. Ivanov, A.C. Bloem, H.M. Lokhorst and T. Mutis.
Rebuilding human leukocyte antigen class II-restricted minor histocompatibility antigen specificity in recall antigen-specific T cells by adoptive T cell receptor transfer: implications for adoptive immunotherapy.
Clin. Cancer Res. 13 (2007) pp. 4009-4015.