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Rimke Oostvogels

Thursday 26 November 2015

Minor histocompatibility antigens: from identification to vaccination

Promotor: Prof. dr. H.M. Lokhorst
Defence: 26 November 2015, 12.45 h

Over the past years, important steps have been made to turn the conceptual idea of mHag-directed immunotherapy into actual clinical applications for patients with a hematological malignancy. In the current stage the need for the identification of more therapeutic mHags however proceeds, whereas on the other hand the first evaluation of mHag-based therapies in the clinic can be carried out.
In this thesis these questions are addressed by (1) identifying new mHags using ameliorated identification strategies [chapters 2, 3 and 4], (2) evaluating the feasibility, safety and efficacy of mHag-loaded and –unloaded DC vaccination therapy [chapter 5] and (3) evaluating the possibility of improving the immunogenicity of mHags to induce optimal T cell responses in future applications [chapter 6]. Specifically, Chapter 2 demonstrates the identification of mHag UTA2-1 using our efficient genome-wide zygosity-genotype correlation analysis. UTA2-1 is presented by the common HLA-molecule HLA-A*02:01, has a balanced population frequency and is strictly hematopoietic restricted. Therefore this new mHag is highly interesting for clinical application in immunotherapy. In Chapter 3 a further improvement of the
genetic association analysis by the implementation of the comprehensive data set of the 1000 Genomes Project is described. With this approach we were able to reidentify all known mHags and moreover we could identify the HLA class II mHag UTDP4-1, which in spite of extensive attempts could not be identified before with any of the previously developed techniques. Chapter 4 once again utilizes the powerful databases of the 1000 Genomes Project to identify mHag LB-TTK-1D using an ‘inferred correlation’ method. Remarkably, this new mHag is encoded by an alternative transcript containing a premature stop codon. Such abnormal transcripts are targeted by a mRNA surveillance pathway called nonsense mediated decay (NMD), resulting in rapid mRNA degradation. The identification of mHag LB-TTK-1D provides the first proof that an endogenous NMD transcript can generate antigenic peptides despite rapid mRNA degradation. Chapter 5 shows the results of our clinical trial of host DC vaccination combined with DLI in patients with multiple myeloma. Eleven patients were treated in total, of which 4 received DCs that were exogenously loaded with a mismatched mHag peptide. This therapy appeared feasible and safe, as no new GvHD occurred and toxicity was limited. Moreover objective host- and mHag-specific T cell responses were observed, which were in 2 cases associated with a clinical response. The possibility to enhance the immunogenicity of mHags is analyzed in Chapter 6. With the incorporation of nonproteogenic amino acids at anchoring positions we generated chemically enhanced altered peptide ligands for mHag UTA2-1 and other model epitopes, that showed enhanced HLA-affinity and –stability and prolonged recognition by specific T cells compared to the wildtype epitope. Most importantly the modified UTA2-1 epitope induced increased frequency UTA2-1 specific cytotoxic T cell responses in both in vitro stimulation assays and in vivo immunizations. Finally, in Chapter 7 the results and implications from the aforementioned studies are summarized and discussed.