Genetically Modified T-cell Therapy for the Treatment of Osteosarcoma: An Update.
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ABSTRACT:
SUBMITTER: DeRenzo C
PROVIDER: S-EPMC4904842 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
Publications
Genetically Modified T-cell Therapy for the Treatment of Osteosarcoma: An Update.
DeRenzo Christopher C Gottschalk Stephen S
Journal of clinical & cellular immunology 20160429 2
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Project description:T-cell immunotherapy may offer an approach to improve outcomes for patients with osteosarcoma who fail current therapies. In addition, it has the potential to reduce treatment-related complications for all patients. Generating tumor-specific T cells with conventional antigen-presenting cells ex vivo is time-consuming and often results in T-cell products with a low frequency of tumor-specific T cells. Furthermore, the generated T cells remain sensitive to the immunosuppressive tumor microenvironment. Genetic modification of T cells is one strategy to overcome these limitations. For example, T cells can be genetically modified to render them antigen specific, resistant to inhibitory factors, or increase their ability to home to tumor sites. Most genetic modification strategies have only been evaluated in preclinical models; however, early clinical phase trials are in progress. In this chapter, we will review the current status of gene-modified T-cell therapy with special focus on osteosarcoma, highlighting potential antigenic targets, preclinical and clinical studies, and strategies to improve current T-cell therapy approaches.
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Project description:BackgroundChimeric antigen receptor (CAR)-engineered T cells have displayed outstanding performance in the treatment of patients with hematological malignancies. However, their efficacy against solid tumors has been largely limited.MethodsIn this study, human osteosarcoma cell lines were prepared, flow cytometry using antibodies against CD166 was performed on different cell samples. CD166-specific T cells were obtained by viral gene transfer of corresponding DNA plasmids and selectively expanded using IL-2 and IL-15. The ability of CD166.BBζ CAR-T cells to kill CD166+ osteosarcoma cells was evaluated in vitro and in vivo.ResultsCD166 was selectively expressed on four different human osteosarcoma cell lines, indicating its role as the novel target for CAR-T cell therapy. CD166.BBζ CAR-T cells killed osteosarcoma cell lines in vitro; the cytotoxicity correlated with the level of CD166 expression on the tumor cells. Intravenous injection of CD166.BBζ CAR-T cells into mice resulted in the regression of the tumor with no obvious toxicity.ConclusionsTogether, the data suggest that CD166.BBζ CAR-T cells may serve as a new therapeutic strategy in the future clinical practice for the treatment of osteosarcoma.
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Project description:BackgroundSurvival 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.ProcedureFive 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.ResultsOsteosarcoma 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.ConclusionAerosol 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.
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