Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts

Blood. 2007 Dec 1;110(12):4037-46. doi: 10.1182/blood-2007-02-076075. Epub 2007 Aug 27.

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

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Murine-Derived
  • Antibody Formation / drug effects
  • Antineoplastic Agents / agonists
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Complement System Proteins / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Female
  • Humans
  • Killer Cells, Natural / metabolism
  • Lymphocyte Depletion
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / metabolism
  • Mice
  • Mice, Inbred ICR
  • Mice, SCID
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / metabolism
  • Recombinant Proteins / agonists
  • Recombinant Proteins / pharmacology*
  • Recombinant Proteins / therapeutic use
  • Rituximab
  • TNF-Related Apoptosis-Inducing Ligand / agonists
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand / therapeutic use
  • Transplantation, Heterologous
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antineoplastic Agents
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFSF10 protein, human
  • Rituximab
  • Complement System Proteins