Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia
<p>Allogeneic haematopoietic stem cell transplantation (allo-SCT) is the best established cellular immunotherapy and is a common treatment for acute myeloid leukaemia (AML). Allo-SCT relies on donor T cells identifying AML cells as foreign and eradicating them, which is known as graft-versus-l...
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| Format: | Thesis |
| Language: | English |
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2021
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| _version_ | 1797112173986578432 |
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| author | Sweeney, C |
| author2 | Vyas, P |
| author_facet | Vyas, P Sweeney, C |
| author_sort | Sweeney, C |
| collection | OXFORD |
| description | <p>Allogeneic haematopoietic stem cell transplantation (allo-SCT) is the best established cellular immunotherapy and is a common treatment for acute myeloid leukaemia (AML). Allo-SCT relies on donor T cells identifying AML cells as foreign and eradicating them, which is known as graft-versus-leukaemia (GvL). Donor T cells recognise AML through interactions between their T cell receptor (TCR) and peptide antigens bound by human leukocyte antigen (HLA) on the surface of AML cells. Despite being administered for over 50 years, our understanding of the AML antigens that elicit a donor T cell response after allo-SCT is very limited.</p>
<p>Identification of antigens that mediate GvL may directly lead to improvements in selection of allo-SCT donors for treating AML patients. A donor whose cells can produce a specific alloimmune response against the recipient’s AML cells would reduce relapse. Furthermore, antigens represent potential targets for immunotherapy.</p>
<p>This study establishes a novel workflow to identify and characterise GvL antigens and the donor-derived T cells that respond to them. GvL antigens are likely to result from germline DNA variants that are present in a patient but absent in their allo-SCT donor. Exome and RNA sequencing were used to identify mismatched DNA variants between patient and donor that are expressed in AML. Candidate GvL antigens were identified using: (1) in silico HLA-binding prediction, and (2) mass spectrometry of peptides eluted from HLA on AML cells.</p>
<p>Predicted GvL peptide antigens were functionally screened, which led to the identification of 24 validated antigens from 9 patients. Of the antigen-specific T cell responses characterised, 86% stimulate CD4+ donor T cells. For a GvL antigen derived from the PADI4 gene, responses are HLA-DP restricted and donor T cells are CD4+ with a cytotoxic T helper 1 phenotype.</p>
<p>As a proof of concept, a T cell therapy was developed targeting the PADI4 antigen. Antigen-specific TCR sequences were identified and inserted into human T cells. These were then used to assess T cell-mediated killing of AML cells in vitro and in vivo, and also to investigate the mechanism of PADI4 antigen presentation by HLA.</p> |
| first_indexed | 2024-03-07T08:20:25Z |
| format | Thesis |
| id | oxford-uuid:9613cd9e-ea61-4bf8-ab00-3e5afa012c10 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:20:25Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:9613cd9e-ea61-4bf8-ab00-3e5afa012c102024-01-25T07:37:28ZHarnessing the graft-versus-leukaemia effect in acute myeloid leukaemiaThesishttp://purl.org/coar/resource_type/c_db06uuid:9613cd9e-ea61-4bf8-ab00-3e5afa012c10Acute leukemiaCellular therapyMyeloid leukemiaHematopoietic stem cells--TransplantationHematologyEnglishHyrax Deposit2021Sweeney, CVyas, P<p>Allogeneic haematopoietic stem cell transplantation (allo-SCT) is the best established cellular immunotherapy and is a common treatment for acute myeloid leukaemia (AML). Allo-SCT relies on donor T cells identifying AML cells as foreign and eradicating them, which is known as graft-versus-leukaemia (GvL). Donor T cells recognise AML through interactions between their T cell receptor (TCR) and peptide antigens bound by human leukocyte antigen (HLA) on the surface of AML cells. Despite being administered for over 50 years, our understanding of the AML antigens that elicit a donor T cell response after allo-SCT is very limited.</p> <p>Identification of antigens that mediate GvL may directly lead to improvements in selection of allo-SCT donors for treating AML patients. A donor whose cells can produce a specific alloimmune response against the recipient’s AML cells would reduce relapse. Furthermore, antigens represent potential targets for immunotherapy.</p> <p>This study establishes a novel workflow to identify and characterise GvL antigens and the donor-derived T cells that respond to them. GvL antigens are likely to result from germline DNA variants that are present in a patient but absent in their allo-SCT donor. Exome and RNA sequencing were used to identify mismatched DNA variants between patient and donor that are expressed in AML. Candidate GvL antigens were identified using: (1) in silico HLA-binding prediction, and (2) mass spectrometry of peptides eluted from HLA on AML cells.</p> <p>Predicted GvL peptide antigens were functionally screened, which led to the identification of 24 validated antigens from 9 patients. Of the antigen-specific T cell responses characterised, 86% stimulate CD4+ donor T cells. For a GvL antigen derived from the PADI4 gene, responses are HLA-DP restricted and donor T cells are CD4+ with a cytotoxic T helper 1 phenotype.</p> <p>As a proof of concept, a T cell therapy was developed targeting the PADI4 antigen. Antigen-specific TCR sequences were identified and inserted into human T cells. These were then used to assess T cell-mediated killing of AML cells in vitro and in vivo, and also to investigate the mechanism of PADI4 antigen presentation by HLA.</p> |
| spellingShingle | Acute leukemia Cellular therapy Myeloid leukemia Hematopoietic stem cells--Transplantation Hematology Sweeney, C Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia |
| title | Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia |
| title_full | Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia |
| title_fullStr | Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia |
| title_full_unstemmed | Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia |
| title_short | Harnessing the graft-versus-leukaemia effect in acute myeloid leukaemia |
| title_sort | harnessing the graft versus leukaemia effect in acute myeloid leukaemia |
| topic | Acute leukemia Cellular therapy Myeloid leukemia Hematopoietic stem cells--Transplantation Hematology |
| work_keys_str_mv | AT sweeneyc harnessingthegraftversusleukaemiaeffectinacutemyeloidleukaemia |