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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4750-4757
Immunotherapy of B-Cell Lymphoma With CD3x19 Bispecific Antibodies:
Costimulation via CD28 Prevents "Veto" Apoptosis of
Antibody-Targeted Cytotoxic T Cells
Peter T. Daniel,
Arne Kroidl,
Joachim Kopp,
Isrid Sturm,
Gerhard Moldenhauer,
Bernd Dörken, and
Antonio Pezzutto
From the Max Delbrück Center for Molecular Medicine,
Berlin-Buch, Germany; Department of Hematology, Oncology, and Tumor
Immunology, Charité-Campus Berlin-Buch, Humboldt University,
Berlin-Buch, Germany; Tumorimmunology Program, German Cancer Research
Center, Heidelberg, Germany.
Bispecific antibodies (CD3x19) against the CD3 -chain of the
T-cell-receptor/CD3 complex and the CD19 antigen on B cells can target
polyclonal, nontumor-specific T cells to B lymphoma cells. This induces
T-cell activation, and generation of cytotoxic T cells (CTLs). These
polyclonal CTLs, targeted by the CD3x19 bispecific antibodies, can lyse
CD19+ B-lymphoma cells. In a xenotransplant model in
severe combined immunodeficiency deficient (SCID) mice, we
and others observed that CD28 triggering is required for efficient
elimination of B-lymphoma cells and cure from the tumor in addition to
CD3x19 administration. We also showed that the activation and targeting of CTLs to the target cell by signal one alone, ie, the CD3x19 mab,
induces T-cell death by apoptosis. In blocking experiments we showed
that this "veto" apoptosis is mediated by the CD95/Fas ligand.
Addition of anti-CD28 (signal 2) renders the T cells resistant for veto
apoptosis both in vitro and in vivo. We therefore conclude that the
role of costimulation in immunotherapy with bispecific antibodies or
other T-cell-based immune strategies is not only to facilitate T-cell
activation but also to prevent T-cell deletion by apoptosis.
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