Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia
Acute myeloid leukaemia (AML) is an aggressive blood cancer that can be treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Although allo-HSCT reduces the chance of relapse because of the Graft-versus-leukaemia (GvL) effect, it is also associated with the Graft-versus-Host...
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| Format: | Thesis |
| Language: | English |
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2023
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| _version_ | 1826311954755485696 |
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| author | Mickute, G |
| author2 | Vyas, P |
| author_facet | Vyas, P Mickute, G |
| author_sort | Mickute, G |
| collection | OXFORD |
| description | Acute myeloid leukaemia (AML) is an aggressive blood cancer that can be treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Although allo-HSCT reduces the chance of relapse because of the Graft-versus-leukaemia (GvL) effect, it is also associated with the Graft-versus-Host Disease (GvHD). This and other treatment or disease related complications mean that only around half of transplanted AML patients survive at 3-years[1]. To harness the GvL effect, on-going research is trying to identify novel GvL-specific allogeneic peptide antigens presented by the major histocompatability complex (MHC), called minor histocompatability antigens (miHA). However, it remains unclear which miHAs mediate a successful GvL effect and what GvL-specific T cell functions are associated with it. This work describes a novel HLA-DP-restricted PADI4 miHA response identified as part of a previous allogeneic antigen screen in a cohort of AML patients with long-term remission post-transplant. Antigen-specific allogeneic T cells were successfully isolated and their T cell receptor (TCR) transferred to third-party primary T cells. PADI4 TCR T cell activation was seen to cancer cell lines, where it could also exert a growth inhibitory effect. Although this work did not show evidence of direct T cell activation to primary leukaemia samples, leukaemia-derived antigen was successfully presented by primary monocyte-derived dendritic cells. PADI4 miHA expression is haematopoietically restricted, suggesting no reactivity to the GvHD target tissues. However, PADI4 TCR T cell activation, without target cell killing, was seen to healthy monocytes. Overall, this data supports the idea that the PADI4 miHA response could exert an anti-leukaemic or a broader anti-haematopoietic effect. This work provides an important starting point to further investigate the PADI4 TCR for its anti-leukaemic effect and the importance of the PADI4 miHA response in other AML patients. It also highlights the role of CD4+ MHC class II-restricted T cell responses in GvL. |
| first_indexed | 2024-03-07T08:20:23Z |
| format | Thesis |
| id | oxford-uuid:902faf9f-0bf4-4798-877d-7ee36f86b510 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:20:23Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:902faf9f-0bf4-4798-877d-7ee36f86b5102024-01-23T10:42:23ZDescription of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemiaThesishttp://purl.org/coar/resource_type/c_db06uuid:902faf9f-0bf4-4798-877d-7ee36f86b510EnglishHyrax Deposit2023Mickute, GVyas, PBorrow, PChakraverty, RMcMichael, AAcute myeloid leukaemia (AML) is an aggressive blood cancer that can be treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT). Although allo-HSCT reduces the chance of relapse because of the Graft-versus-leukaemia (GvL) effect, it is also associated with the Graft-versus-Host Disease (GvHD). This and other treatment or disease related complications mean that only around half of transplanted AML patients survive at 3-years[1]. To harness the GvL effect, on-going research is trying to identify novel GvL-specific allogeneic peptide antigens presented by the major histocompatability complex (MHC), called minor histocompatability antigens (miHA). However, it remains unclear which miHAs mediate a successful GvL effect and what GvL-specific T cell functions are associated with it. This work describes a novel HLA-DP-restricted PADI4 miHA response identified as part of a previous allogeneic antigen screen in a cohort of AML patients with long-term remission post-transplant. Antigen-specific allogeneic T cells were successfully isolated and their T cell receptor (TCR) transferred to third-party primary T cells. PADI4 TCR T cell activation was seen to cancer cell lines, where it could also exert a growth inhibitory effect. Although this work did not show evidence of direct T cell activation to primary leukaemia samples, leukaemia-derived antigen was successfully presented by primary monocyte-derived dendritic cells. PADI4 miHA expression is haematopoietically restricted, suggesting no reactivity to the GvHD target tissues. However, PADI4 TCR T cell activation, without target cell killing, was seen to healthy monocytes. Overall, this data supports the idea that the PADI4 miHA response could exert an anti-leukaemic or a broader anti-haematopoietic effect. This work provides an important starting point to further investigate the PADI4 TCR for its anti-leukaemic effect and the importance of the PADI4 miHA response in other AML patients. It also highlights the role of CD4+ MHC class II-restricted T cell responses in GvL. |
| spellingShingle | Mickute, G Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia |
| title | Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia |
| title_full | Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia |
| title_fullStr | Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia |
| title_full_unstemmed | Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia |
| title_short | Description of a novel MHC class II restricted allogeneic TCR T cell therapy for acute myeloid leukaemia |
| title_sort | description of a novel mhc class ii restricted allogeneic tcr t cell therapy for acute myeloid leukaemia |
| work_keys_str_mv | AT mickuteg descriptionofanovelmhcclassiirestrictedallogeneictcrtcelltherapyforacutemyeloidleukaemia |