CMV-specific TCR-transgenic T cells for immunotherapy.
Reactivation of CMV can cause severe disease after allogeneic hemopoietic stem cell transplantation. Adoptive T cell therapy was successfully used for patients who had received transplants from CMV-positive donors. However, patients with transplants from CMV-negative donors are at highest risk, and an adoptive therapy is missing because CMV-specific T cells are not available from such donors. To address this problem, we used retroviral transfer of CMV-specific TCR genes. We generated CMV-specific T cell clones of several HLA restrictions recognizing the endogenously processed Ag pp65. The genes of four TCRs were cloned and transferred to primary T cells from CMV-negative donors. These CMV-TCR-transgenic T cells displayed a broad spectrum of important effector functions (secretion of IFN-gamma and IL-2, cytotoxicity, proliferation) in response to endogenously processed pp65 and could be enriched and expanded by strictly Ag-specific stimulation. Expansion of engineered T cells was accompanied by an increase in specific effector functions, indicating that the transferred specificity is stable and fully functional. Hence, we expect these CMV-TCR-transgenic T cells to be effective in controlling acute CMV disease and establishing an antiviral memory.
Department of Gene Vectors, Helmholtz Zentrum München, Munich, Germany.
Andrea
A
Schub
Ingrid G
IG
Schuster
Wolfgang
W
Hammerschmidt
Andreas
A
Moosmann
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D014161:Transduction, Genetic; D019076:Transgenes; D014763:Viral Matrix Proteins / Q000276:immunology* / Q000378:metabolism
D007376:Interleukin-2; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma