Abstract
Recombinant human rhApo2L/TRAIL selectively stimulates apoptosis in various cancer cells through its receptors DR4 and DR5, and is currently in clinical trials. Preclinical studies have established antitumor activity of rhApo2L/TRAIL in models of epithelial cancers; however, efficacy in non-Hodgkin lymphoma (NHL) models is not well studied. Of 7 NHL cell lines tested in vitro, rhApo2L/TRAIL stimulated apoptosis in BJAB, Ramos RA1, and DoHH-2 cells. Rituximab, a CD20 antibody used to treat certain types of NHL, augmented rhApo2L/TRAIL-induced caspase activation in Ramos RA1 and DoHH2 but not BJAB or SC-1 cells, through modulation of intrinsic rather than extrinsic apoptosis signaling. In vivo, rhApo2L/TRAIL and rituximab cooperated to attenuate or reverse growth of tumor xenografts of all 4 of these cell lines. Depletion of natural killer (NK) cells or serum complement substantially reduced combined efficacy against Ramos RA1 tumors, suggesting involvement of antibody-dependent cell- and complement-mediated cytotoxicity. Both agents exhibited greater activity against disseminated than subcutaneous BJAB xenografts, and worked together to inhibit or abolish disseminated tumors and increase survival. Moreover, rhApo2L/TRAIL helped circumvent acquired rituximab resistance of a Ramos variant. These findings provide a strong rationale for clinical investigation of rhApo2L/TRAIL in combination with rituximab as a novel strategy for NHL therapy.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Murine-Derived
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Antibody Formation / drug effects
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Antineoplastic Agents / agonists
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects*
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Cell Line, Tumor
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Complement System Proteins / metabolism
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Drug Resistance, Neoplasm / drug effects
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Drug Synergism
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Female
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Humans
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Killer Cells, Natural / metabolism
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Lymphocyte Depletion
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Lymphoma, Non-Hodgkin / drug therapy*
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Lymphoma, Non-Hodgkin / metabolism
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Mice
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Mice, Inbred ICR
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Mice, SCID
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Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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Receptors, Tumor Necrosis Factor / antagonists & inhibitors
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Receptors, Tumor Necrosis Factor / metabolism
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Recombinant Proteins / agonists
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Recombinant Proteins / pharmacology*
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Recombinant Proteins / therapeutic use
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Rituximab
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TNF-Related Apoptosis-Inducing Ligand / agonists
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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TNF-Related Apoptosis-Inducing Ligand / therapeutic use
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Transplantation, Heterologous
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Murine-Derived
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Antineoplastic Agents
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10A protein, human
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TNFSF10 protein, human
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Rituximab
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Complement System Proteins