Friday 26 February 2010
Novel strategies for identification and therapeutic application of minor histocompatibility antigens
Promotor: Prof.dr H.M. Lokhorst
Defence: 26 February 2010
T cells recognizing the highly immunogenic minor histocompatibility antigens (mHags) expressed by hematopoietic and tumor cells may be powerful tools in the battle against hematological malignancies. However, mHag-specific immunotherapy is still in its infancy, since currently only few clinically useful mHags are identified, and since the exploration of T cell based immunotherapy for the treatment of cancer was initiated only a decade ago. The scope of thesis is to tackle these issues by 1) identifying and facilitating the identification of novel clinically relevant mHags and 2) investigating the immunotherapeutic potential of mHag-specific CD4+ T cells in vitro as well as in a preclinical murine model.
Chapter 2 describes the identification of the first HLA class II-restricted mHag with a truly hematopoietic tissue expression. The mHag is encoded by the CD19 gene, which is not only highly expressed on B cells, but also on their malignant derivatives. The identification of the CD19-derived mHag is performed using a novel genetic fine-mapping strategy, called zygosity-genotype correlation analysis. The genome-wide application of this strategy is easy and rapid as we demonstrate in Chapter 3 with the molecular characterization of the novel SLC19A1-derived mHag. Here we also outline a directed strategy to make significant progress toward wide scale application of mHag-specific immunotherapy. In Chapter 4, we utilize the rationale behind this directed strategy towards the identification of new mHags using a reverse identification approach. We describe the advantages of reverse identification and provide an extensive list of putative mHags that are predicted using reliable antigen-processing and HLA-binding algorithms combined with databases containing all currently known genes and genotyped SNPs.
Chapter 5 shows the feasibility of transferring a TCR derived from mHag-specific CD4+ human T cells into recall antigen (tetanus toxoid; TT)-specific CD4+ T cells. The TCR-transgenic cells acquire mHag specificity, and expand efficiently in vitro via stimulation of their intrinsic TT-specific TCR. In Chapter 6, similar dual-specific T cells as well as the parent mHag-specific T cells are used as sole treatment for established multiple myeloma tumors in immunodeficient mice. This adoptive immunotherapy with sole mHag-specific CD4+ T cells is very effective against tumor in the bone marrow. However, the mice suffer from extramedullary tumor relapses, which are in vitro but not in vivo susceptible to further T cell therapy. These results seem also relevant for the clinic, since the relapse of multiple myeloma at extramedullary sites is a known complication in patients treated with DLI.
Finally, the general discussion describes how the current findings may contribute to the improvement of immunotherapeutic strategies based on mHag-specific (CD4+) T cells.