Abstract A87: Metronomic chemotherapy activates innate immunity-induced tumor regression.
Authors: Waxman David J. , Chen Chong-Sheng , Wu Junjie , Doloff Joshua C. 
Published: August 2014

Abstract
Metronomic chemotherapy involves frequent drug administration at a lower than maximally tolerated dose to reduce the severe, dose-limiting toxicities of conventional drug schedules. Some metronomic regimens are anti-angiogenic, reflecting the high chemosensitivity of tumor endothelial cells to metronomic schedules of cytotoxic drugs. However, the significance of the anti-angiogenic activity of metronomic chemotherapy is unclear, as VEGF receptor inhibitors induce substantially greater anti-angiogenesis than metronomic chemotherapy, yet often show less anti-tumor activity. Recently, we reported that cyclophosphamide, when given on a 6-day repeating metronomic schedule to mice bearing brain tumor xenografts, activates potent anti-tumor innate immunity, with tumor recruitment of macrophages, dendritic cells and natural killer cells leading to major tumor regression. Immune cell recruitment and tumor regression were both blocked in mice where innate immune cells are either deficient or dysfunctional. Furthermore, VEGF receptor-selective inhibitors blocked these responses, suggesting that their use in the clinic may interfere with anti-tumor immunity (Doloff JC and Waxman DJ, Cancer Research (2012) 72:1103-1115). We now report that this interference by VEGF receptor-selective inhibitors is not due to anti-angiogenesis per se, and that it can be avoided by using anti-angiogenic drugs that do not act primarily by VEGF receptor inhibition. Furthermore, traditional high-dose (MTD) chemotherapy induced an innate immune response that was transient, and weak, suggesting that sustained drug-induced cytotoxic damage and their associated cytokine responses are required for immune-based tumor regression. Indeed, several innate-immune recruiting chemokines showed sustained up regulation following metronomic cyclophosphamide treatment but were only transiently up regulated by traditional MTD drug treatment. Metronomic cyclophosphamide was cytotoxic to the tumor infiltrating immune cells, especially to natural killer cells and dendritic cells. Consistently, we found that both the dose and the timing of metronomic drug treatment are critical, with innate immune responses and tumor regression both lost when the frequency of metronomic cyclophosphamide administration was increased from once/6 days to once/3 days without a change in total dose, or to a daily metronomic regimen commonly used in the clinic. Thus, both the dose and the frequency of metronomic drug administration must be sufficiently high to activate tumor damage and immune anti-tumor response pathways, but also sufficiently well-spaced so as to not kill off the infiltrating anti-tumor immune populations, which are sensitive to chemotherapy. These findings suggest that current clinical metronomic treatment schedules can be optimized to enhance anti-tumor immunity; furthermore, they highlight the potential for negative interactions between innate immune anti-tumor responses and VEGF pathway-targeted anti-angiogenic drugs. Supported in part by NIH grant CA49248 (to DJW).
Citation Format: David J. Waxman, Chong-Sheng Chen, Junjie Wu, Joshua C. Doloff. Metronomic chemotherapy activates innate immunity-induced tumor regression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A87.