Remodeling the Lung Tumor Microenvironment with Locally Administered Nano-Immunochemotherapies for Osteosarcoma Lung Metastases

Abstract

Osteosarcoma (OS) is the most common type of primary bone cancer and is primarily metastasized to the lungs. With lung metastasis (OSLM), the curability of disease and the overall survival rate diminish drastically. The standard of care has failed to improve the therapeutic outcomes of OSLM. The interplay between tumor cells and immune infiltrates in the tumor microenvironment (TME) is a critical determinant of metastasis growth. Gemcitabine (GMT) chemotherapy is used to treat OSLM. The combination therapy with colony-stimulating factor-1 receptor inhibitors (CSF-1Ris) to treat solid tumors has shown benefits in manipulating TME away from tolerance and is now in the clinic (PLX). A potential limitation of both therapies is the poor biodistribution and the off-target toxicity. Thus, there is an opportunity to develop novel combination therapies and delivery strategies to improve the therapeutic potential and decrease off-target toxicity of currently available therapeutics. In this work, we explain developing a reproducible, robust in vivo model of OSLM that enables screening of various therapeutics via local administration to the lungs and their influence on tumor foci. Then we evaluate the tolerability and efficacy of the local lung delivery of PLX in combination with GMT and their effect in tuning TME to prevent the growth of gross metastases. As lung tissue retention limit treatment potentials, sustained-release nanoformulation is a possible strategy to increase drugs\u27 retention and enhance their efficacy. Thus, we describe the optimization of GMT liposomal formulation. Combining these strategies can have translation potential to improve OSLM patients’ outcomes and survival