Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1.
Donor T cells directed at hematopoietic system-specific minor histocompatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8(+) cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA)-matched sibling. UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag(+) hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus, with the capacity to induce relevant immunotherapeutic CTLs, it's HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based immunotherapy.
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
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Minnema
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van Elk
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Giovannone
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Buijs
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van Baarle
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Kater
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Griffioen
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Lokhorst
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D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous
D014408:Biomarkers, Tumor; D006680:HLA Antigens; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger