Augmentation of virus-specific immunity after hematopoietic stem cell transplantation by adoptive T-cell therapy.
Adoptive transfer of virus-specific T cells offers the potential for accelerating reconstitution of antigen-specific immunity after allogeneic hematopoietic stem cell transplantation. However, the logistics of producing virus-specific T cells and the risk of inducing graft-versus-host disease has limited their application. We developed a relatively simple system employing cytomegalovirus lysate-pulsed, monocyte-derived dendritic cells as stimulator cells, requiring only a single blood draw from the donor. We treated 16 patients with these T-cell lines, administered after the detection of human cytomegalovirus (HCMV) DNA by polymerase chain reaction. Massive in vivo expansions of HCMV-specific cytotoxic T lymphocytes (3-5 log) were observed within days of adoptive transfer. In eight cases viral titers were decreasing within 5 days and antiviral drug therapy was not required. The T-cell receptor CDR3 lengths of HCMV-specific cytotoxic T lymphocytes expanding in vivo were identical to those of the transferred cells. A low incidence of late CMV reactivation was seen (2/14 assessable patients compared with 45/72 historical controls, p = 0.001) and no significant toxicities were observed. Our findings indicate that application of cell lines generated in relatively short-term in vitro cultures is both feasible and effective in a clinical environment. This simple in vitro methodology should allow widespread application of adoptive transfer of virus-specific T cells.
Peggs
Karl S
KS
Department of Haematology, Royal Free and University College London Medical School, London, United Kingdom.
Mackinnon
Stephen
S
D019264:Adoptive Transfer; D000328:Adult; D000956:Antigens, Viral / Q000276:immunology / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000628:therapy*; D003601:Cytotoxicity Tests, Immunologic; D004279:DNA, Viral / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000175:diagnosis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006680:HLA Antigens / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D018579:Patient Selection; D010750:Phosphoproteins / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D014763:Viral Matrix Proteins / Q000276:immunology
D000956:Antigens, Viral; D000998:Antiviral Agents; D022801:Complementarity Determining Regions; D004279:DNA, Viral; D006680:HLA Antigens; D010750:Phosphoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine