Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor-reactive cytotoxic T lymphocytes.
Clinical benefits from monoclonal antibody therapy for B-chronic lymphocytic leukemia (B-CLL) have increased interest in developing additional immunotherapies for the disease. CD40 ligand is an accessory signal for T-cell activation and can overcome T-cell anergy. The OX40-OX40 ligand pathway is involved in the subsequent expansion of memory antigen-specific T cells. We expressed both CD40L and OX40L on B-CLL cells by exploiting the phenomenon of molecular transfer from fibroblasts overexpressing these ligands. We analyzed the effects of the modified B-CLL cells on the number, phenotype, and cytotoxic function of autologous T cells in 7 B-CLL patients. Transfer of CD40L and OX40L was observed in all and was followed by the up-regulation of B7-1 and B7-2. The culture of CD40L/OX40L-expressing B-CLL cells with autologous T cells generated CD4+/CD8+ cytotoxic T-cell lines, which secreted interferon-gamma (IFN-gamma) and granzyme-B/perforin in response to autologous, but not to allogeneic, B-CLL cells or to autologous T-cell blasts. CD40L or OX40L alone was insufficient to expand tumor-reactive T cells. The combination of CD40L and OX40L on B-CLL cells may allow the generation of therapeutic immune responses to B-CLL, either by active immunization with modified tumor cells or by adoptive immunotherapy with tumor-reactive autologous T cells.
Biagi
Ettore
E
Center for Cell and Gene Therapy, Baylor College of Medicine, Methodist Hospital, Suite 750.01, 1102 Bates St, Houston, TX 77030, USA. exbiagi@txccc.org
Dotti
Gianpietro
G
Yvon
Eric
E
Lee
Edward
E
Pule
Martin
M
Vigouroux
Stephane
S
Gottschalk
Stephen
S
Popat
Uday
U
Rousseau
Raphael
R
Brenner
Malcolm
M
D019264:Adoptive Transfer; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D023201:CD40 Ligand / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D049109:Cell Proliferation; D018920:Coculture Techniques; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020014:K562 Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology*; D053278:OX40 Ligand; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C089251:TNFSF4 protein, human; D048069:Tumor Necrosis Factors; D023201:CD40 Ligand; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases