LOCAL DELIVERY OF TUMOR ASSOCIATED MACROPHAGE IMMUNOTHERAPY FOR THE TREATMENT OF METASTASES TO THE LUNGS

Abstract

Metastases are the leading cause of cancer-related deaths, and the lungs are one of the primary sites of metastases from several malignancies, including breast cancer and osteosarcoma. Existing therapies fail to entirely eradicate tumors that disseminate and reside in lungs; therefore, patient prognosis significantly worsens, and the overall survival decreases drastically. Conventional therapies utilized to treat lung tumors such as chemotherapy and targeted therapies are administered systemically and typically exhibit poor lung biodistribution profiles, leading to many undesirable off target effects and suboptimal drug concentration in the tumor, which may promote resistance, further compromising the quality of life of secondary lung cancer patients. Immune cells that infiltrate the tumor microenvironment (TME) play a central role in cancer development, prognosis, and response to therapy, with tumor associated macrophages (TAMs) being one of the most abundant immunosuppressive cells in the TME of many malignancies. Several therapeutic strategies that target TAMs have been proposed. They aim to reduce immune tolerance and to help overcome limitations associated with standard of care therapy. TAM immunotherapy has been correlated with positive clinical outcomes, including increase in survival in patients bearing lung cancers. However, such therapeutics are given systemically and present similar challenges as standard of care chemotherapy and other treatments. In this work, we investigate the potential of an alternative strategy to treat lung metastases, in which we target TAMs by local lung administration of colony stimulating factor 1 receptor inhibitors (CSF-1Ris). We sought to enhance the selectivity and reduce off-target toxicity associated with such therapeutic strategies, particularly that observed in the liver of patients that receive systemic CSF-1Ri. In our breast cancer lung metastasis (BCLM) model, we combine pulmonary administered (p.a.) TAM immunotherapy with standard of care chemotherapy (first line treatment in lung metastases). In our osteosarcoma lung metastasis (OSLM) model, the efficacy of free and liposomal CSF-1Ris is evaluated upon p.a. Liposomal formulation of highly hydrophobic CSF-1Ris is critical for the development of translational strategies for local lung administration. We report the effects of locally administered CSF-1Ris in i) shifting the balance of TAMs away from the tumorigenic (M2-like) phenotype, ii) modulating the T cell profile and thus repurposing the immune response, and iii) as monotherapy or in combination with chemotherapy, in reducing lung tumor burden. The scientific relevance of this work is based on the fact that for the first time the effects of CSF1-Ris are being investigated in the treatment of lung tumors upon local lung administration. This work has translational relevance as this knowledge is allowing us to devise combination therapies to address unmet clinical needs in the treatment of metastatic tumors to the lungs, including the development, for the first time, of a lipid-based formulation for CSF-1Ris.