Normalizing tumor microenvironment with nanomedicine and metronomic therapy to improve immunotherapy.

Nanomedicine offered hope for improving the treatment of cancer but the survival benefits of the clinically approved nanomedicines are modest in many cases when compared to conventional chemotherapy. Metronomic therapy, defined as the frequent, low dose administration of chemotherapeutics - is being tested in clinical trials as an alternative to the conventional maximum tolerated dose (MTD) chemotherapy schedule. Although metronomic chemotherapy has not been clinically approved yet, it has shown better survival than MTD in many preclinical studies. When beneficial, metronomic therapy seems to be associated with normalization of the tumor microenvironment including improvements in tumor perfusion, tissue oxygenation and drug delivery as well as activation of the immune system. Recent preclinical studies suggest that nanomedicines can cause similar changes in the tumor microenvironment. Here, by employing a mathematical framework, we show that both approaches can serve as normalization strategies to enhance treatment. Furthermore, employing murine breast and fibrosarcoma tumor models as well as ultrasound shear wave elastography and contrast-enhanced ultrasound, we provide evidence that the approved nanomedicine Doxil can induce normalization in a dose-dependent manner by improving tumor perfusion as a result of tissue softening. Finally, we show that pretreatment with a normalizing dose of Doxil can improve the efficacy of immune checkpoint inhibition.