- Associate professor
Mirjam H.M. Heemskerk performed her Ph.D. research from 1990-1994 at the Department of Immunology at the Veterinary Faculty in Utrecht where she studied the T cell immunity against murine coronaviruses. After this she joined the group of Hergen Spits at the Department of Immunology of the Netherlands Cancer Institute. During this post-doctoral training she developed the retroviral introduction of dominant negative transcription factors for studying thymic development and of tumor associated antigens for the generation of tumor specific cellular immunity. She joined the Department of Hematology at the LUMC as an Assistant Professor in 1998 to pioneer the retroviral introduction of antigen specific T cell receptors as a means to engineer leukemia specific immunity. Mirjam Heemskerk is currently Associate Professor and Head of the Laboratory of Experimental Hematology at the Department of Hematology.
- Characterisation of alloimmune responses and occurrence of delayed immune reconstitution after HLA mismatched stem cell transplantation (SCT). In this line of research we want to identify high avidity T cells directed against tumor associated antigens, relevant for immunotherapeutic strategies of cancer patients. In addition, we will investigate the cause of delayed immune reconstitution after HLA-mismatched stem cell transplantation.
- T cell epitope identification of hematopoiesis-restricted minor histocompatibility antigens and tumor associated antigens by reverse immunology approaches. In collaboration with the group of P. van Veelen (IHB, LUMC) an in-depth identification of the HLA-ligandome, including 16.000 HLA ligands, presented on EBV-transformed lymphoblastic cell lines was established. This large set of peptides formed the basis for a reversed immunology approach to identify potential therapeutic T cell responses, not based on in silico predictions, but based on the bona fide eluted HLA-ligandome. In addition, we established in collaboration with the group of T. Schumacher (NKI, Amsterdam) the parallel detection of antigen-specific T cells by multidimensional encoding of multimers. MHC tetramer staining in combination with magnetic bead enrichment was used for the isolation of antigen specific T cells derived from the naïve repertoire. Results demonstrate that by using a selection of peptides from this large set of HLA ligands clinical relevant immune responses could be identified specific for minor histocompatibility antigens (MiHA) as well as tumor associated antigens (TAA).
- TCR gene therapy of hematological malignancies and solid tumors. We have demonstrated that anti-leukemic T cells can be engineered by retroviral introduction of minor histocompatibility antigen specific T cell receptors (TCR). A clinical HA-1-TCR gene therapy trial will start in 2012 to treat patients with hematological malignancies after allogeneic stem cell transplantation with these MiHA specific TCR engineered T cells. In addition, we investigate the physiological properties of TCR redirected T cells. Since we recently demonstrated that mispaired TCRab dimers exhibit harmful neoreactivities, strategies to prevent the formation of these mispaired TCRab dimers are under investigation. Recently, we have started to set up a clinical gene therapy study in which patients with solid tumors for which no adequate treatment is available will be treated with TAA specific TCRs.
Amir, A.L., D.M. van der Steen, R.S. Hagedoorn, M.G. Kester, C.A. van Bergen, A.H. de Ru, J.H. Falkenburg, P.A. van Veelen, M.H. Heemskerk. 2011. Allo-HLA reactive T-cells isolated from a patient with graft versus host disease are single peptide specific. Blood, 118 : 6733.
Amir, A.L., D.M. van der Steen, M.M. van Loenen, R.S. Hagedoorn, R. de Boer, M.G. Kester, A.H. de Ru, G.J. Lugthart, C. van Kooten, P.S. Hiemstra, I. Jedema, M. Griffioen, P.A. van Veelen, J.H. Falkenburg, and M.H. Heemskerk. 2011. PRAME specific allo-HLA restricted T-cells with potent antitumor reactivity useful for therapeutic T cell receptor gene transfer. Clin. Cancer Res. 17: 5615.
van Loenen, M.M., R. de Boer, R.S. Hagedoorn, E.H. van Egmond, J.H. Falkenburg, and M.H. Heemskerk. 2011. Optimization of the HA-1-specific T-cell receptor for gene therapy of hematological malignancies. Haematologica. 96 : 477.
van Loenen, M.M., R. de Boer, A.L. Amir, R.S. Hagedoorn, G.L. Volbeda, R. Willemze, J.J. van Rood, J.H. Falkenburg, and M.H. Heemskerk. 2010. Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc. Natl. Acad. Sci. U. S. A. 107:10972.
Amir, A.L., L.J. D'Orsogna, D.L. Roelen, M.M. van Loenen, R.S. Hagedoorn, R. de Boer, M.A. van der Hoorn, M.G. Kester, I.I. Doxiadis, J.H. Falkenburg, F.H. Claas, and M.H. Heemskerk. 2010. Allo-HLA reactivity of virus-specific memory T-cells is common. Blood 115 : 3146.
Leids Universitair Medisch Centrum
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