Natural killer cell therapy and aerosol interleukin‐2 for the treatment of osteosarcoma lung metastasis

Abstract

PURPOSE Survival of patients with osteosarcoma lung metastases has not improved in 20 years. We evaluated the efficacy of combining natural killer [NK] cells with aerosol interleukin-2 [IL-2] to achieve organ-specific NK cell migration and expansion in the metastatic organ, and to decrease toxicity associated with systemic IL-2. EXPERIMENTAL DESIGN Five human osteosarcoma cell lines and 103 patient samples (47 primary and 56 metastatic) were analyzed for NKG2D ligand [NKG2DL] expression. Therapeutic efficacy of aerosol IL-2 + NK cells was evaluated in vivo compared with aerosol IL-2 alone and NK cells without aerosol IL-2. RESULTS Osteosarcoma cell lines and patient samples expressed various levels of NKG2DL. NK-mediated killing was NKG2DL-dependent and correlated with expression levels. Aerosol IL-2 increased NK cell numbers in the lung and within metastatic nodules but not in other organs. Therapeutic efficacy, as judged by tumor number, size, and quantification of apoptosis, was also increased compared with NK cells or aerosol IL-2 alone. There were no IL-2-associated systemic toxicities. CONCLUSION Aerosol IL-2 augmented the efficacy of NK cell therapy against osteosarcoma lung metastasis, without inducing systemic toxicity. Our data suggest that lung-targeted IL-2 delivery circumvents toxicities induced by systemic administration. Combining aerosol IL-2 with NK cell infusions, may be a potential new therapeutic approach for patients with osteosarcoma lung metastasis.

Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D–NKG2DL dependent manner

“…As several of the currently used chemotherapeutic drugs, as well as ionizing irradiation act via the DNA damage response pathway, a mild preconditioning using these drugs and/or local ionizing irradiation might sensitize tumor cells to immune recognition, leading to synergistic antitumor effects. These observations are in agreement with one previous report [27] but are in contrast with one that showed that DNAM-1 receptor also had a main role in NK cells' cytotoxicity against OS [28]. In vivo, OS primary and metastatic tumors have been shown to lose or downregulate HLA class I expression, thus becoming more susceptible to NK cell killing [29].…”

MicroRNA-126 enhances the sensitivity of osteosarcoma cells to cisplatin and methotrexate

“…Osteosarcoma is a progressive and fatal malignant bone tumor with a nearly unchanged case fatality rate (23). At present, the majority of studies advocate the comprehensive treatment of osteosarcoma, including the use of surgery, radiotherapy, chemotherapy and immune therapy (24)(25)(26).…”

Strategies and developments of immunotherapies in osteosarcoma

“…Guma et al (34) demonstrated that aerosol IL-2 treatment may increase lung NK cell numbers via stimulation of local NK cell proliferation, and this proliferation was observed to be organ specific, without IL-2-associated systemic toxicities. In addition, the therapeutic efficacy of aerosol treatment with IL-2+NK cells in inducing metastatic regression and increasing overall survival was observed to be higher, compared with aerosol IL-2 treatment alone or treatment with NK cells without aerosol IL-2 (34,35). In a murine OS transplantation model, an intraperitoneal injection of IL-2 monoclonal antibody was administered (S4B6) into mice that had received transplanted LM8 osteosarcoma cells, and it was identified that the number of pulmonary metastatic colonies and tumor size were significantly reduced (36).…”