title: Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model.
abstract: 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.
authors.affiliation: Department of Cardiology, Third Xiangya Hospital, Central South University, Changsha Hunan, P.R. China.
authors.forename: Mao
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Irell & Manella Graduate School of Biological Sciences at City of Hope, Duarte, California, 91010, United States of America.|Department of Molecular Medicine, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Ethan E
authors.initials: EE
authors.lastname: White
authors.affiliation: Department of General Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha Hunan, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Zhang
authors.affiliation: Department of Bone and Joint Surgery, No.1 Hospital of Jilin University, Changchun, Jilin Province, P.R. China.
authors.forename: Hang
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Nephrology, The Second Hospital of Jilin University, Changchun, Jilin Province, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Yanyan
authors.affiliation: Department of General Surgery, China Japan Union Hospital of Jilin University, Changchun, Jilin Province, P.R. China.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Molecular Medicine, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Weng
authors.affiliation: Laboratório de Morfogênese Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Anna
authors.initials: A
authors.lastname: Da Fonseca
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Sunny
authors.initials: S
authors.lastname: Shah
authors.affiliation: Division of Translational Vaccine Research, Department of Virology, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Manuel
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Leying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Comparative Medicine, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Vonderfecht
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Darya
authors.initials: D
authors.lastname: Alizadeh
authors.affiliation: Irell & Manella Graduate School of Biological Sciences at City of Hope, Duarte, California, 91010, United States of America.|Department of Molecular Medicine, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Berlin
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.|Department of Cancer Immunotherapeutics & Tumor Immunology City of Hope Beckman Research Institute, Duarte, California, 91010, United States of America.
authors.forename: Behnam
authors.initials: B
authors.lastname: Badie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D007167:Immunotherapy; D007249:Inflammation / Q000473:pathology; D008055:Lipids / Q000737:chemistry; D008810:Mice, Inbred C57BL; D037742:Nanotubes, Carbon / Q000737:chemistry*; D009361:Neoplasm Invasiveness; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry; D013154:Spleen / Q000473:pathology; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D008055:Lipids; D037742:Nanotubes, Carbon; D009838:Oligodeoxyribonucleotides; D011092:Polyethylene Glycols; D003606:Dacarbazine; D000077204:Temozolomide
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