Organ-specific delivery of agents by the aerosol route offers many advantages since it targets the organ where metastases are and provides significantly less toxic effects. The purpose of this study is to evaluate safety of aerosol IL-2 in patients > 12 yrs. with lung metastases to establish the maximum tolerated dose (MTD) to use for combination therapies with infused natural killer cells and/or autophagy inhibitors in patients with Osteosarcoma (OS) lung metastases.

Lung metastases constitute the main cause of death in patients with OS. Survival has remained the same in the past 15 years. Using a human OS mouse model we demonstrated therapeutic efficacy of aerosol IL-2 in OS lung metastases (p = 0.03) and there was significant increase in apoptosis measured by TUNEL (p= 0.003). In addition, aerosol IL-2 significantly increased proliferation of local infused NK cells in the lungs (p= 0.03 and p=0.007 at 24 and 72 hours respectively) with no proliferation demonstrated in other organs including bone marrow. Moreover, immunocompetent mice treated with aerosol IL-2 had significant increase in the number of local NK cells in the lung and there was no evidence of T regulatory cells, a group of cells known to abrogate immune response. Additionally, there is recent evidence to suggest that IL-2 induces autophagy, an evolutionary, conserved, intracellular self-defense mechanism, in CD4+ T cells and NK cells and contributes to growth factor withdrawal cell death. Inhibition of autophagy augments immune cell function allowing a better anti-tumor effect. We initiated a Phase I/II clinical trial of aerosol IL-2 to include patients > 12 years with lung metastases. The primary objective is to determine feasibility and safety of aerosol IL-2. The secondary objective is to determine local effects of aerosol IL-2 by analyzing pre and post-treatment surgical samples for evidence of increase NK cell number, function and autophagy induction. Patients received aerosolized IL-2 for 3 consecutive weeks (21 day cycle) for 2 cycles with 1-week rest between cycles providing no drug limiting toxicities (DLTs) occur. The first treatment is delivered in the hospital. Subsequent treatments are given at home providing patients had been educated. From dose levels 1-4 only 1 patient/dose level was enrolled. From dose level 5 on, 3 patients will be enrolled. Once MTD is reached an additional 14 patients will be treated. 34 to 56 patients may be enrolled. Clinical response will be assessed by chest CT and determined using modified Response Evaluation Criteria in Solid Tumor (RECIST) after 2nd cycle. We have reached dose level 4 and the only side effects were grade 1 fatigue (n= 1), grade 1 cough (n= 2), and grade 1 wheezing (n=1) Adverse events were not attributed to the IL-2 therapy since symptoms resolved without intervention. Serum levels of IL-2 were undetectable in the first three patients. The fourth patient has detectable but low serum levels of IL-2. All patients had progressive disease. In conclusion, feasibility and safety of aerosol IL-2 therapy will set the ground for future combination therapies with NK cells and/or autophagy inhibitors as potential therapeutic options for patients with recurrent and resistant OS lung disease.

Citation Format: Nancy B. Gordon, Peter Anderson, Sergei Guma, Hsuan-Chu Chien, Lacey M. McQuinn, Joshua P. Hein, Ralph Zinner, Eugenie S. Kleinerman, Aung Naing. Feasibility and safety of aerosol IL-2 in patients with lung metastases for future combination therapies for the treatment of osteosarcoma lung metastases. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A82.