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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2436-2442.
Prepublished online as a Blood First Edition Paper on November 9, 2004; DOI 10.1182/blood-2004-07-2556.
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IMMUNOBIOLOGY
Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor–reactive cytotoxic T lymphocytes
Ettore Biagi,
Gianpietro Dotti,
Eric Yvon,
Edward Lee,
Martin Pule,
Stephane Vigouroux,
Stephen Gottschalk,
Uday Popat,
Raphael Rousseau, and
Malcolm Brenner
From the Center for Cell and Gene Therapy, Baylor College of Medicine, Methodist Hospital and Texas Children's Hospital, Houston.
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- (IFN-) 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.
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