Enhancement of glioma radiotherapy and chemotherapy response with targeted antibody therapy against death receptor 5.
OBJECTIVE
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
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.
Fiveash
John B
JB
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35249, USA. dbmccurdy@uabmc.edu
Gillespie
G Yancey
GY
Oliver
Patsy G
PG
Zhou
Tong
T
Belenky
Michael L
ML
Buchsbaum
Donald J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D003606:Dacarbazine; D000077204:Temozolomide