Tumors have developed several systems to evade or overwhelm the host’s immune system and exogenous stimulation of the immune system could be utilized to lyse tumor cells. Tumor-associated macrophages have a significant role in controlling the tumor microenvironment, and these cells could be activated by inhalation of granulocyte macrophage colony-stimulating factor (GM-CSF). In humans, inhaled GM-CSF (500 pg/day in 2 divided doses) has modest effects in patients with pulmonary metastasis (Anderson et al. 1999). In patients with metastatic melanoma, aerosol delivery of GM-CSF may induce melanoma-specific immunity, similar to an in vivo dendritic cell vaccination (Markovic et al. 2008). In experimental and human studies, alveolar macrophages can be induced to destroy tumor cells and prolong survival.

In experimental animals, the anticancer activity of inhaled interleukin 2 (IL-2) is enhanced by liposomal encapsulation compared to free IL-2. Two or three times a day inhalation of 1 x 106 units of IL-2 was found to be effective for the treatment of canine osteosarcoma lung metastases. In metastatic renal carcinoma in humans, high-dose inhaled IL-2 in combination with low-dose subcutaneous IL-2 and subcutaneous interferon (IFN)-a improved median survival. However, inhaled IL-2 alone did not achieve significant efficacy in the treatment of patients with renal cancer and NSCLC. Inhaled IL-2 also had only modest effects against human metastatic melanoma and sarcoma.

IFNs are important mediators of immunity against tumors, and at low doses, cIFNs stimulate the immune system against cancer cells. IFN-y is the most potent, and its effects are augmented by coadministration of tumor necrosis factor-a. Inhaled IFN-y could achieve high lung levels and stimulate the local immune system, but it had limited efficacy in treating diffuse or locally advanced bron- choalveolar carcinoma.

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