Combination Therapy With Aerosol Il-2 And Nk Cells For The Treatment Of Osteosarcoma Lung Metastasis
Date of Graduation
5-2014
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Eugenie S. Kleinerman
Committee Member
Dr. Russell R. Broaddus
Committee Member
Dr. Gary E. Gallick
Committee Member
Dr. Shulin Li
Committee Member
Dr. Laurence J. N. Cooper
Abstract
The survival of patients with osteosarcoma lung metastases has not improved in the last 20 years. Novel alternative therapies are needed. The purpose of this investigation was to evaluate the efficacy of combining natural killer [NK] cell therapy with aerosol interleukin-2 [IL-2] for the treatment of osteosarcoma lung metastasis. The expression of NKG2D ligands was analyzed in five different human osteosarcoma cell lines and 103 patient samples (47 from primary tumors and 56 from lung metastases). We discovered that osteosarcoma expresses the ligands for the NKG2D. In vitro studies demonstrated that NK-mediated killing of osteosarcoma cells is dependent on the NKG2D-NKG2D ligand interaction and that cytotoxicity correlates with the level of NKG2D ligand expression. Aerosol IL-2 increased NK cell numbers in the lung but not in other organs. This increase in NK numbers was due to an aerosol IL-2-induced increase in NK proliferation that occurs almost exclusively in the lung. Aerosol IL-2 also increased the NK cell infiltration within the lung metastatic nodules. Compared to control, NK cell treatment alone and aerosol IL-2 treatment alone, aerosol IL-2 + NK cell therapy had a higher therapeutic efficacy, as judged by a greater decrease in the number and sizes of tumors nodules, as well as by a greater increase in tumor apoptosis. Furthermore, aerosol IL-2 + NK cell therapy significantly improved the survival of mice with osteosarcoma lung metastasis. In addition, there was no evidence of IL-2-associated systemic toxicities.
In conclusion, combining NK cell therapy with aerosol IL-2 achieved organ-specific NK cell migration and proliferation in the lung and reduced pulmonary metastatic burden, while at the same time avoided the systemic toxicities associated with IL-2. We believe that a combination therapy consisting of aerosol IL-2 with NK cell infusions can be a new and effective therapeutic approach for the treatment of patients with osteosarcoma lung metastasis.
Keywords
osteosarcoma, natural killer cells, interleukin-2, immunotherapy