The purpose of this study is to test aerosol delivery of Interkeukin-2 (IL-2) in patients > 12 yrs. with lung metastases to establish feasibility and safety in the pediatric population and determine the maximum tolerated dose (MTD) for potential combination therapies in patients with Osteosarcoma (OS) lung metastases.

Organ-specific delivery of agents by the aerosol route offers many advantages for the treatment of OS since it targets the organ where metastases are and provides significantly less toxic effects. OS survival has remained at 65-70% for the last 20 years. Our pre-clinical data using a human OS mouse model demonstrated therapeutic efficacy of aerosol IL-2 in OS lung metastases (p = 0.03) and increase apoptosis measured by TUNEL (p= 0.003). In addition, aerosol IL-2 increased local immune cell proliferation as demonstrated by an increase in CD4+ T cells and NK cells with no evidence of T regulatory cells. Most recently, IL-2 was shown to induce 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. Immunohistochemistry staining of OS lung tumors from mice treated with aerosol IL-2 showed an increase in Beclin expression as evidence of autophagy induction.

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.

Results: 5 patients have been enrolled, ages 18, 35, 66, 20 and 15; all male, 3 with Ewing's Sarcoma and 2 with Osteosarcoma. No side effects had been detected and serum levels of IL-2 were only detected in the fourth patient but were very low.

Conclusion: Aerosol IL-2 seems so far feasibly and safe. Completion of the Phase I will provide information on the maximum tolerated dose (MTD) to use on the Phase II where only patients with OS lung metastases will be enrolled. Culmination of this trial will provide the basis for future combination therapy trials.

Citation Format: Nancy Beatriz Gordon, Najat Daw Bitar, Peter Anderson, Sergei Guma, Hsuan-Chu Chien, Lacey M. McQuinn, Joshua P. Hein, Ralph Zinner, Eugenie S. Kleinerman, Aung Naing. Aerosol interleukin-2 for the treatment of patients ≥ 12 years old with osteosarcoma lung disease: A phase I/II study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT406. doi:10.1158/1538-7445.AM2014-CT406