Enhancement of glioma radiotherapy and chemotherapy response with targeted antibody therapy against death receptor 5.

Abstract

PURPOSE:

TRA-8 is an agonistic mouse monoclonal antibody that binds to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5, which induces apoptosis in cancer cells through a caspase-8-dependent mechanism. We investigated the ability of TRA-8 to augment the radiotherapy (RT) and chemotherapy response of human glioma cells in vitro and in vivo.

METHODS AND MATERIALS:

The in vitro cytotoxicity of TRA-8 and temozolomide (Tmz) or RT was examined using adenosine triphosphate-dependent viability and clonogenic survival assays with five glioma cell lines. Death receptor 5 expression was determined by flow cytometry. In vivo studies included subcutaneous and intracranial xenograft models testing various combination treatments, including RT, Tmz, and TRA-8.

RESULTS:

TRA-8, combined with Tmz or RT, produced enhanced cytotoxicity against five glioma cell lines compared with the use of the individual agents alone. Death receptor 5 upregulation occurred in response to RT. Complete tumor regression in the subcutaneous experiments was the most common in animals that received combination therapy with TRA-8/Tmz/RT. TRA-8 enhanced tumor growth delay in combination with RT or Tmz. TRA-8 alone had limited activity against intracranial tumors. In contrast, the median survival of mice treated with TRA-8/Tmz/RT was significantly greater than the control or TRA-8-alone-treated mice. The median survival of the mice treated with TRA-8/Tmz/RT or chemoradiotherapy only was significantly greater than the control or TRA-8-treated mice. A trend toward improved survival was observed between TRA-8/Tmz/RT-treated and Tmz/RT-treated mice.

CONCLUSIONS:

These preliminary findings support the hypothesis that TRA-8 will augment the RT and chemotherapy response in gliomas. A humanized version of TRA-8 is being evaluated in a Phase II clinical trial.

• Authors: John B Fiveash, G Yancey Gillespie, Patsy G Oliver, Tong Zhou, Michael L Belenky, Donald J Buchsbaum
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 71 Issue 2 Pg. 507-16 (Jun 01 2008) ISSN: 0360-3016 [Print] United States
• PMID: 18474311 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents, Alkylating
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Dacarbazine
• Temozolomide

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Agents, Alkylating (therapeutic use)
• Apoptosis (physiology)
• Brain Neoplasms (drug therapy, radiotherapy)
• Cell Line, Tumor
• Combined Modality Therapy (methods)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Glioma (drug therapy, radiotherapy)
• Humans
• Mice
• Mice, Nude
• Random Allocation
• Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists)
• Temozolomide
• Xenograft Model Antitumor Assays (methods)