Metronomic Chemo-Immunotherapy: Schedule-Dependent Activation of Immune-Induced Tumor Regression

Clinical strategies that target cancer cells for destruction are frequently confounded by responses of tumor-associated stromal cells, which can lead to increased tumor growth, angiogenesis, invasion and metastasis, and confer an immune suppressive environment. Chemotherapy given as a single dose can stimulate anti-tumor immune responses, but this finding has not translated well to the clinic, where many conventional cancer chemotherapy regimens are toxic to immune cells, leading to immunosuppression. Using preclinical models of glioma, we identified a novel approach that combines direct tumor cell cytotoxicity with repeated disruption of the tumor microenvironment. Cyclophosphamide (CPA) treatment on an intermittent, 6-day repeating metronomic schedule (‘metro-CPA’) activates potent anti-tumor immune responses that induce major regression of large, implanted gliomas, with functional contributions from both the innate and the adaptive immune systems and the activation of long-term anti-tumor immunity. These immune responses require drug-free breaks for recovery of drug-sensitive immune cells from drug-induced cytotoxicity, suggesting a need to optimize current, daily clinical metronomic treatment schedules in order to maximize anti-tumor immune responses. We also characterized several tumor models that are intrinsically sensitive to CPA cytotoxicity but do not exhibit drug-induced immune responses, and we identified genes and upstream regulators associated with this tumor-differential responsiveness to metro-CPA treatment. The genes and regulators identified may include diagnostic and prognostic markers that facilitate translation to the clinic. The high potency of these immune-based responses to metro-CPA treatment may result from synergistic actions on tumor cells, by increasing tumor cell antigenicity and/or tumor cell susceptibility to immune attack, and on the immune system, by activation of both innate and adaptive immune effectors, and by inactivation of immune suppressors. Grant support: NIH-R01CA049248 (to DJW).