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The lungs are major sites of metastases for several cancer types, including breast cancer (BC). Prognosis and quality of life of BC patients that develop pulmonary metastases are negatively impacted. The development of strategies to slow the growth and relieve the symptoms of BC lung metastases (BCLM) is thus an important goal in the management of BC. However, systemically administered first line small molecule chemotherapeutics have poor pharmacokinetic profiles and biodistribution to the lungs and significant off-target toxicity, severely compromising their effectiveness. In this work, we propose the local delivery of add-on immunotherapy to the lungs to support first line chemotherapy treatment of advanced BC. In a syngeneic murine model of BCLM, we show that local pulmonary administration (p.a.) of PLX-3397 (PLX), a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri), is capable of overcoming physiological barriers of the lung epithelium, penetrating the tumor microenvironment (TME), and decreasing phosphorylation of CSF-1 receptors, as shown by the Western blot of lung tumor nodules. That inhibition is accompanied by an overall decrease in the abundance of protumorigenic (M2-like) macrophages in the TME, with a concomitant increase in the amount of antitumor (M1-like) macrophages when compared to the vehicle-treated control. These effects with PLX (p.a.) were achieved using a much smaller dose (1 mg/kg, every other day) compared to the systemic doses typically used in preclinical studies (40–800 mg/kg/day). As an additive in combination with intravenous (i.v.) administration of paclitaxel (PTX), PLX (p.a.) leads to a decrease in tumor burden without additional toxicity. These results suggested that the proposed immunochemotherapy, with regional pulmonary delivery of PLX along with the i.v. standard of care chemotherapy, may lead to new opportunities to improve treatment, quality of life, and survival of patients with BCLM.

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Osteosarcoma (OS) metastasizes primarily and almost exclusively to the lungs. The survival rate decreases significantly for patients who develop OS lung metastasis (OSLM). Purpose: To assess the safety and efficacy of colony-stimulating factor-1 receptor inhibitor (CSF-1Ri) (Pexidartinib; PLX) in shifting the OSLM tumor microenvironment (TME) to an anti-tumorigenic state upon local delivery to lungs of a syngeneic mouse model of OSLM. Methods: The safety of PLX upon repeated pulmonary administration (9 doses, every other day at 2 mg/kg) in healthy BALB/c mice was assessed using health scoring, pulmonary mechanics, molecular and cellular composition of bronchoalveolar lavage fluid (BALF), blood count and plasma biochemistry, and H&E of lungs and liver. To establish the OSLM model, murine OS cells, expressing bioluminescent and fluorescent genes (K7M2-Luc-tdT), were used. Mice bearing OSLM were randomized into two groups (vehicle and PLX) and treated over 3 weeks. Tumor burden was evaluated using bioluminescent imaging (BLI) and lung weight. The treatment impact on the abundance and phenotype of tumor-associated macrophages (TAMs) and their CSF-1R expression as well as on the abundance of tumor-infiltrating lymphocytes and their expression to PD-1 were investigated using immunofluorescence, flow cytometry, and western blot. Results: PLX is well tolerated upon local lung administration with all safety markers indicating no alteration compared to naïve and vehicle controls. Treatment did not affect health scores. We did not detect any functional or mechanical alteration on the lungs or systemically (including liver); no marked differences in pulmonary function parameters, proinflammatory cytokines, nor infiltrating differential cell count obtained from BALF were observed. Both total blood count and liver enzymes were within normal range. As a measure of efficacy, treatment with PLX via local lung administration reduced tumor burden, indicated by the in vivo BLI and lung weight. Notably, PLX significantly decreased the abundance of total TAMs, with a more pronounced effect on pro-tumorigenic alternatively-activated (M2-like) TAMs phenotype, thus leading to a 22-fold increase in M1/M2 ratio. PLX further led to a marked decrease in tumor-promoting T regulatory cells (Treg), increase in the CD8/Treg ratio, and decrease in PD-1+ percentage in CD8 T cells in the TME, indicating a shift to a more immunogenic tumor phenotype. Conclusions: We demonstrated that repeated doses of PLX is safe upon local delivery to the lungs of murine model of OSLM, with no alternations in lungs or liver tissue. We further showed that PLX reduces tumor burden, which correlates with a change in the immune phenotype of the OSLM toward a more anti-tumorigenic profile. These results are clinically relevant as PLX has been approved by the FDA, thus opening opportunities for its repurposing to support standard of care therapy in OSLM. Citation Format: Fatemah S. Sunbul, Sulaiman S. Alhudaithi, Rashed M. Almuqbil, Hanming Zhang, Raneem R. Aldaqqa, Shane Albin, Rebecca L. Heise, Valentina Robila, Matthew S. Halquist, Sarah W. Gordon, Paula D. Bos, Sandro R. da Rocha. Remodeling the microenvironment of osteosarcoma lung metastases with inhaled CSF-1Ri immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1991.