Abstract
INTRODUCTION: Glioblastoma is the most malignant brain tumor and is characterized by resistance to current therapies. Multi-modal treatment holds potential for complete tumor eradication, however the combination of chemotherapy and immunotherapy has been avoided due to concerns over possible mutually excluding effects. Localized chemotherapy (LC) consisting of biodegradable polymers as the delivery system for the BCNU (BCNU-LC) is FDA approved while treatment with the anti-PD-1 monoclonal antibody (anti-PD-1-mAb) has shown promising early results in clinical trials. Here we report evidence of superior survival and a positive immunological profile resulting from the combination of BCNU-LC + anti-PD-1-mAb in an established murine glioblastoma model. RESULTS: Mice were treated with the following regimens: BCNU-LC + anti-PD-1-mAb, systemic-BCNU + anti-PD-1-mAb, BCNU-LC, systemic-BCNU, anti-PD-1-mAb, untreated. BCNU-LC + anti-PD-1-mAb treated mice showed improved survival compared to mice treated with monotherapies and exhibited enhanced tumor-specific immunity: flow-cytometric analysis of the lymphocytic, myeloid, and microglial compartments in the tumor microenvironment as well as the lymphocytic and myeloid compartments in the periphery showed activation of immune molecules, whereas the mice treated with systemic-BCNU or systemic-BCNU + anti-PD-1-mAb exhibited severe immunosuppression in addition to poor survival. 70% of the BCNU-LC + anti-PD-1-mAb group exhibited long-term survival while the anti-PD-1-mAb, systemic-BCNU and systemic-BCNU + anti-PD-1-mAb groups also produced lower percentages of long-term survivors. Upon tumor re-challenge in the flank or the contralateral brain hemisphere, long-term survivors in the BCNU-LC + anti-PD-1-mAb and anti-PD-1-mAb groups were able to prevent formation of recurrence whereas long-term survivors from the systemic-BCNU and systemic-BCNU + anti-PD-1-mAb groups succumbed to Glioblastoma and were unable to form an immune memory response. CONCLUSIONS: Our results suggest that we rethink our chemotherapy strategies in the setting of immunotherapy. We found that systemic chemotherapy has a cytoreductive effect, and that LC could possibly augment an immunological response and survival benefit.