Shifting the immune infiltrates in osteosarcoma lung metastases with locally targeted CSF-1Ris for combination therapies

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PROJECT SUMMARY/ABSTRACT Osteosarcoma (OS) is the most common type of primary malignancy of the bone. OS metastasizes primarily to the lungs, with pulmonary disease being the leading cause of death in those cases. Standard of care therapy has done little to improve the low rates of survival of patients with OS lung metastases (OSLM) in the past three decades, as they are not curative, nor able keep metastases in check. We will address the need for more effective treatments by establishing adjuvant immunotherapies that shift the equilibrium of the tumor immune microenvironment (TIME) in OSLM away from tumor tolerance, thus helping overcome limitations of standard of care chemotherapies. Our central hypothesis is that small molecule colony stimulating factor 1 receptor inhibitors (CSF-1Ris) will safely exert their action upon pulmonary administration (P.A.). CSF-1Ris impact the balance of immune infiltrates in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs), which are their primary target and the most abundant immune cells in the TME of OSLM. Infiltrating immune cells in the TME play a critical role in tumor formation, progression and response to therapy. Several CSF-1Ris are under clinical trials, with pexidartnib (PLX) approved in 2019. The P.A. of CSF-1Ris to the lungs will allow for local tumor targeting, reducing off-target effects in the liver, which can be life threatening. We will demonstrate that (aim #01) CSF-1Ris delivered via P.A. overcome lung and tumor barriers and safely reach their intracellular targets, the CSF-1 receptors, which are highly expressed in TAMs, shifting the balance away from the tumorigenic phenotype, and that (aim #02) such inhibitors are efficient adjuvants to chemotherapy (gemcitabine, GMT), decreasing tumor burden and improving survival. Our pilot studies indicate that CSF-1Ris can safely reach their molecular target in the TME upon P.A., leading to a reduction in tumor burden that correlates with a decrease in TAMs and in abundance of the anti-tumorigenic TAM phenotype. In combination with GMT, pilot studies indicate that CSF-1Ris are safe and reduce the number of large metastases compared to GMT alone. We expect to demonstrate that potent and selective CSF-1Ris inhibitors will lead to benefits as adjuvant therapy, and based on the new knowledge of the TIME, devise combinations with GMT that will lead to significant increase in survival. This work is scientifically relevant as for the first time we will understand the impact of CSF-1Ris on immune infiltrates in OSLM upon P.A., and translationally relevant because we will devise combination therapies with CSF-1Ris locally administered to the lungs that will improve outcomes in OLSM.