Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model

• Published in: PloS one Vol. 11; no. 2; p. e0148139
• Main Authors: Ouyang, Mao, White, Ethan E., Ren, Hui, Guo, Qin, Zhang, Ian, Gao, Hang, Yanyan, Song, Chen, Xuebo, Weng, Yiming, Da Fonseca, Anna, Shah, Sunny, Manuel, Edwin R., Zhang, Leying, Vonderfecht, Steven L., Alizadeh, Darya, Berlin, Jacob M., Badie, Behnam
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Anticancer properties; Antigens; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biology and Life Sciences; Blood-brain barrier; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Brain research; Brain tumors; Cancer therapies; Carbon; Cell Death - drug effects; Cell Line, Tumor; Chemotherapy; Clinical trials; Complications and side effects; CpG islands; Cytotoxicity; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; Disease Models, Animal; Dosage and administration; Dose-Response Relationship, Drug; Drug dosages; Drug therapy; Effectiveness; Engineering and Technology; Female; Glioblastoma; Glioma; Glioma - drug therapy; Glioma - pathology; Gliomas; Health aspects; Immunotherapy; Implantation; Inflammation - pathology; Joint surgery; Lipids - chemistry; Medical research; Medicine; Medicine and Health Sciences; Melanoma; Mice, Inbred C57BL; Nanotechnology; Nanotubes; Nanotubes, Carbon - chemistry; Neoplasm Invasiveness; Neurosurgery; Oligodeoxyribonucleotides - therapeutic use; Oligonucleotides; Patients; Polyethylene Glycols - chemistry; Research and Analysis Methods; Single wall carbon nanotubes; Spleen - pathology; Splenocytes; Surgery; Temozolomide; Toxicology; Treatment Outcome; Tumors; United States; Brazil; Rio de Janeiro Brazil; California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0148139

Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG.