The purpose of this study is to determine safety of aerosol IL-2 in patients ≥12 yrs. with lung metastases to establish the maximum tolerated dose (MTD) to use for combination therapy with infused natural killer (NK) cells in patients with osteosarcoma (OS) lung metastases. OS survival has remained at 65-70% for the last 20 years. One recent therapeutic approach has been to use adoptive cell-therapy to non-specifically augment immune function in vivo. However, therapeutic efficacy of immune cells depends upon proliferation and persistence in the tumor area. Organ-specific delivery of interleukin-2 (IL-2) offers that benefit. 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. Patients only 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. Each patient is educated on treatment administration the first time in the hospital. Further treatments are administered at home and remote spirometry and pulse oximetry are recorded before each treatment. Data is downloaded on a web portal and captured into the patient's medical record. We anticipated the maximum tolerated dose (MTD) to be at dose level 5. From dose levels 1-4 only 1 patient/dose level was enrolled. From dose level 5 on, 3 patients will be enrolled and the 3 x 3 model will be followed. Once MTD is reached an additional 14 patients will be treated at the MTD. 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. So far, 4 patients have been enrolled, ages 18, 35, 66, and 20; all male, 3 with Ewing's Sarcoma and 1 with osteosarcoma. Side effects were grade 1 fatigue (n= 1), grade 1 cough (n= 2), and grade 1 wheezing (n=1). None of these adverse events have been attributed to the IL-2 therapy since symptoms resolved without intervention while on therapy. Serum levels of IL-2 in the first three patients were undetectable and they had progressive disease. The fourth patient is on treatment. Supporting this clinical study is pre-clinical data from our lab. Immunocompetent mice treated with aerosol IL-2 had significant increase in the number of local NK cells in the lung when compared with aerosol phosphate buffer saline (PBS) group. Using a human OS mouse model we demonstrated therapeutic efficacy of aerosol IL-2 in OS lung metastases when compared with aerosol PBS group (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 when compared with aerosol PBS group (p= 0.03 and p=0.007 at 24 and 72 hours respectively) with no proliferation demonstrated in other organs including bone marrow. In conclusion, clinical evaluation of aerosol IL-2 therapy will potentially benefit patients with OS who succumb almost always due to lung disease and allow future combination therapy with infused NK cells.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C64.

Citation Format: Nancy B. Gordon, Peter Anderson, Sergei R. Guma, Hsuan-Chu Chien, Lacey M. McQuinn, Joshua P. Hein, Ralph G. Zinner, Eugenie S. Kleinerman, Aung Naing. Clinical evaluation of aerosol IL-2 in patients with lung metastases to test feasibility and safety for future combination therapy using infused natural killer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C64.