title: Expression of a dominant T-cell receptor can reduce toxicity and enhance tumor protection of allogeneic T-cell therapy.
abstract: Due to the lack of specificity for tumor antigens, allogeneic T-cell therapy is associated with graft-versus-host disease. Enhancing the anti-tumor specificity while reducing the graft-versus-host disease risk of allogeneic T cells has remained a research focus. In this study, we demonstrate that the introduction of 'dominant' T-cell receptors into primary murine T cells can suppress the expression of endogenous T-cell receptors in a large proportion of the gene-modified T cells. Adoptive transfer of allogeneic T cells expressing a 'dominant' T-cell receptor significantly reduced the graft-versus-host toxicity in recipient mice. Using two bone marrow transplant models, enhanced anti-tumor activity was observed in the presence of reduced graft-versus-host disease. However, although transfer of T-cell receptor gene-modified allogeneic T cells resulted in the elimination of antigen-positive tumor cells and improved the survival of treated mice, it was associated with accumulation of T cells expressing endogenous T-cell receptors and the development of delayed graft-versus-host disease. The in-vivo deletion of the engineered T cells, mediated by endogenous mouse mammary tumor virus MTV8 and MTV9, abolished graft-versus-host disease while retaining significant anti-tumor activity of adoptively transferred T cells. Together, this study shows that the in-vitro selection of allogeneic T cells expressing high levels of a 'dominant' T-cell receptor can lower acute graft-versus-host disease and enhance anti-tumor activity of adoptive cell therapy, while the in-vivo outgrowth of T cells expressing endogenous T-cell receptors remains a risk factor for the delayed onset of graft-versus-host disease.
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Angelika
authors.initials: A
authors.lastname: Holler
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Mathias
authors.initials: M
authors.lastname: Zech
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Sara
authors.initials: S
authors.lastname: Ghorashian
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pike
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Alastair
authors.initials: A
authors.lastname: Hotblack
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Pedro
authors.initials: P
authors.lastname: Veliça
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London Department of Haematology, Cancer Institute, University College London, UK.
authors.forename: Ronjon
authors.initials: R
authors.lastname: Chakraverty
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Morris
authors.affiliation: Institute of Immunity and Transplantation, UCL Division of Infection and Immunity, University College London, Royal Free Hospital London h.stauss@ucl.ac.uk.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stauss
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D005822:Genetic Vectors / Q000276:immunology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008212:Lymphocyte Depletion / Q000379:methods; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D019076:Transgenes; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D011948:Receptors, Antigen, T-Cell