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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.

Original publication

DOI

10.3324/haematol.2015.132712

Type

Journal article

Journal

Haematologica

Publication Date

04/2016

Volume

101

Pages

482 - 490

Keywords

Animals, Bone Marrow Transplantation, Cell Line, Tumor, Female, Gene Expression, Genes, Dominant, Genetic Vectors, Graft vs Host Disease, Humans, Immunotherapy, Adoptive, Lymphocyte Depletion, Mammary Tumor Virus, Mouse, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Receptors, Antigen, T-Cell, Survival Analysis, T-Lymphocytes, Transgenes, Transplantation, Homologous, Whole-Body Irradiation