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.
Highlights
Glioblastoma is the most common and most malignant form of primary brain cancer in humans
We simultaneously tested single-walled carbon nanotubes (SWCNTs) dispersed with this heterogenous mixture composed primarily of RSS-CpG and Lipid-PEG-NH2 and revised our synthesis to produce SWCNTs coated in pure Lipid-PEG-CpG (SWCNT/LipidPEG-CpG) (S2A Fig)
No cytotoxicity was observed in vitro at the concentrations used (Fig 1D). Because of these promising in vitro results, SWCNT/CpG-2 was subjected to further testing in animals
Summary
Glioblastoma is the most common and most malignant form of primary brain cancer in humans. One strategy to overcome these barriers is through tumor-localized activation of pattern-recognition receptors that are expressed by innate immune cells. Agonists, such as CpG oligodeoxynucleotides (CpG) that bind to Toll Like Receptor 9 (TLR9), have been evaluated as therapeutic adjuvants in cancer vaccine strategies and have shown efficacy in inducing antigen-specific adaptive antitumor immune responses in animal models [4]. Early-stage clinical trials evaluating direct injection of CpG into gliomas have been less promising [5,6,7]. It is unclear what factors are responsible for the unsatisfactory response in clinical trials: some possibilities are the sequence of the CpG oligonucleotide tested, rapid degradation of the CpG, or rapid diffusion of the CpG away from the injection site
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