Abstract
Several chemotherapeutic drugs are now considered to exert anti-tumour effects, by inducing an immune-promoting inflammatory response. Cisplatin is a potent chemotherapeutic agent used in standard medulloblastoma but not glioblastoma protocols. There is no clear explanation for the differences in clinical efficacy of cisplatin between medulloblastomas and glioblastomas, despite the fact that cisplatin is effective in vitro against the latter. Systemic toxicity is often dose limiting but could tentatively be reduced by intratumoral administration. We found that intratumoral cisplatin can cure GL261 glioma-bearing C57BL/6 mice and this effect was abolished in GL261-bearing NOD-scid IL2rγnull (NSG) mice. Contrary to previous results with intratumoral temozolomide cisplatin had no additive or synergistic effect with whole cell either GL261 wild-type or GM-CSF-transfected GL261 cells whole cell vaccine-based immunotherapy. While whole tumour cell immunizations increased CD8+ T-cells and decreased F4/80+ macrophages intratumorally, cisplatin had no effect on these cell populations. Taken together, our results demonstrate that intratumoral cisplatin treatment was effective with a narrow therapeutic window and may be an efficient approach for glioma or other brain tumour treatment.
Highlights
Platinum-based drugs, such as cisplatin, are among the most widely used chemotherapeutic agents and have shown efficacy against various solid neoplasms outside the central nervous system as testicular, ovarian, breast, colorectal, lung, head and neck tumours[1]
We have previously reported that glioma-bearing mice could be cured by peripheral whole cell immunizations using granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced tumour cells in the GL261 mouse glioma model, and that the therapeutic effect was mediated by both CD4+ and CD8+ T cells[27,28]
Since major histocompatibility complex (MHC) expression affects the immunogenicity of cells, we investigated the expression of MHC, as well as other surface proteins linked to antigen presentation, on the cell surface after cisplatin exposure in vitro for 3 days
Summary
Platinum-based drugs, such as cisplatin (cis-diamminedichloroplatinum-II), are among the most widely used chemotherapeutic agents and have shown efficacy against various solid neoplasms outside the central nervous system as testicular, ovarian, breast, colorectal, lung, head and neck tumours[1]. Cisplatin has been shown to have cytotoxic effects on human glioblastoma cells in vitro[2,3], the response in clinical treatment is weak and has not improved the overall survival of patients with brain tumours as a single agent[4,5] or in combinations with radiotherapy[6,7] and chemotherapeutic drugs such as carmustine (BCNU)[8,9,10] and temozolomide (TMZ)[11]. In the present study we aimed to investigate the therapeutic efficacy of intratumorally delivered cisplatin as a single agent or in combination with whole cell vaccine-based immunotherapy as peripheral immunizations using GL261 wild type (GL-wt) and GM-CSF-producing GL261 cells (GL-GM) in the mouse glioma GL261 model
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