In metronomic
chemotherapy, frequent drug administration at lower than maximally tolerated doses can improve activity while reducing the dose-limiting toxicity of conventional dosing schedules. Although the antitumor activity produced by metronomic
chemotherapy is attributed widely to antiangiogenesis, the significance of this mechanism remains somewhat unclear. In this study, we show that a 6-day repeating metronomic schedule of
cyclophosphamide administration activates a potent antitumor immune response associated with
brain tumor recruitment of natural killer (NK) cells, macrophages, and dendritic cells that leads to marked
tumor regression.
Tumor regression was blocked in nonobese diabetic/severe combined immunodeficient (NOD/SCID-γ) mice, which are deficient or dysfunctional in all these immune cell types. Furthermore, regression was blunted by NK cell depletion in immunocompetent syngeneic mice or in
perforin-deficient mice, which are compromised for NK, NKT, and T-cell cytolytic functions. Unexpectedly, we found that
VEGF receptor inhibitors blocked both innate immune cell recruitment and the associated
tumor regression response.
Cyclophosphamide administered at a maximum tolerated dose activated a transient, weak innate immune response, arguing that persistent drug-induced cytotoxic damage or associated
cytokine and
chemokine responses are required for effective innate immunity-based
tumor regression. Together, our results reveal an innate immunity-based mechanism of
tumor regression that can be activated by a traditional cytotoxic
chemotherapy administered on a metronomic schedule. These findings suggest the need to carefully evaluate the clinical effects of
combination chemotherapies that incorporate antiangiogenesis drugs targeting
VEGF receptor.