Abstract A63: Normalizing the microenvironment with metronomic nanomedicine potentiates immune checkpoint inhibition in preclincial tumor models
Authors: Mpekris Fotios , Voutouri Chrysovalantis , Panagi Myrofora , Baish James W , Jain Rakesh K , Stylianopoulos Triantafyllos 
Published: December 2022

Abstract
IntroductionNanomedicines have been developed to preferentially delivery drugs to cancer cells or improve the drug pharmacokinetic properties for the treatment of solid tumors. Recent preclinical studies have shown that nanomedicines cannot only simply deliver drugs but also to normalize the tumor microenvironment, improving blood vessel functionality, tumor oxygenation and immunostimulation. Metronomic therapy is a different approach to substitute conventional chemotherapy, which is based on the low and more frequent administration of the therapeutic agent compared to the maximum tolerated dose (MTD) schedule of conventional treatment. When beneficial metronomic strategy can also induce normalization. We hypothesize that these two approaches can be viewed using the same unified framework as strategies that normalize the tumor microenvironment to potentiate immune checkpoint inhibition(ICI) in resistant to ICI murine models of breast cancer and sarcoma. MethodologyTo test our hypothesis, we performed in vivo experiments in murine breast and fibrosarcoma tumor models, and employed the clinically approved nanoparticle formulation Doxil(PEGylated liposomal doxorubicin). Doxil has an elimination half-life 20-30 hours and thus, we hypothesized that to produce similar to metronomic therapy effects, effective drug levels should be maintained. To this end, we employed three different dose schedules providing the same amount of Doxil on a weekly basis: every day(1mg/kg), every other day(2mg/kg) and every 6 days(6mg/kg). At the second week of Doxil treatment, we added to the treatment regimen an immune checkpoint inhibitor aPDL1(10 mg/kg) every 3 days (totally 3 doses) alone or in combination with Doxil. Given the increasing interest in nano-immunotherapy, our purpose was to investigate whether pretreatment with a normalizing dose of nanomedicine can optimize nano-immunotherapy. ResultsWe found that low and more frequent doses of Doxil (either 1mg/kg or 2mg/kg) -compared to high and less frequent doses- decrease tumor stiffness, improve perfusion and exhibit enhanced anti-tumor effects either alone or in combination with immunotherapy. Use of appropriately-sized nanoparticles to normalize the tumor microenvironment could be advantageous over MTD chemotherapy because preferential targeting of tumor tissue could ameliorate adverse effects of MTD chemotherapy, whereas improved vascular function could increase the effectiveness of the immune system and importantly the intratumoral delivery of nanoparticles, which is the main barrier for the effective use of nanomedicines today. Importantly, to account for heterogeneity among different tumors types, we employed two tumor models, the 4T1 breast cancer and the MCA205 fibrosarcoma and found similar normalization and anti-tumor effects.ConclusionPretreatment with a normalizing dose of Doxil can improve the efficacy of immune checkpoint inhibition in murine models of breast cancer and sarcoma.
Citation Format: Fotios Mpekris, Chrysovalantis Voutouri, Myrofora Panagi, James W Baish, Rakesh K Jain, Triantafyllos Stylianopoulos. Normalizing the microenvironment with metronomic nanomedicine potentiates immune checkpoint inhibition in preclincial tumor models [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A63.