Treatment of Hepatocellular Carcinoma with Adeno-Associated Virus Encoding Interleukin-15 Superagonist

Chang, Chia‐Ming; Lo, Chia-Hui; Shih, Yao-Ming; Chen, Yin; Wu, Ping-Yi; Tsuneyama, Koichi; Roffler, Steve R.; Tao, Mi‐Hua

doi:10.1089/hum.2009.187

Cited by 35 publications

(41 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, loss of the NKG2D ligand ULBP-1 in HCC cells was associated with shorter recurrence-free survival (34). In mice, injection of a hepatotropic adeno-associated virus that delivered IL15 and its receptor expanded the number of NK cells in the liver and prolonged survival in a liver metastatic murine HCC model, whereas depletion of NK cells eliminated the therapeutic effect (35). These data suggest that NK cells are an important component of the HCC microenvironment and might contribute to the control tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

Kamiya

Chang

Campana

2016

Cancer Immunology Research

View full text Add to dashboard Cite

Viral infection of the liver is a major risk factor for hepatocellular carcinoma (HCC). Natural killer (NK) cells recognize virally infected and oncogenically transformed cells, suggesting a therapeutic role for NK-cell infusions in HCC. Using the K562-mb15-41BBL cell line as a stimulus, we obtained large numbers of activated NK cells from the peripheral blood of healthy donors. Expanded NK cells exerted remarkably high cytotoxicity against HCC cell lines, which was generally much higher than that of unstimulated or IL2-activated NK cells. In immunodeficient NOD/scid IL2RGnull mice engrafted with Hep3B, treatment with expanded NK cells markedly reduced tumor growth and improved overall survival. HCC cells exposed for 48 hours to 5 mmol/L of sorafenib, a kinase inhibitor currently used for HCC treatment, remained highly sensitive to expanded NK cells. HCC cell reductions of 39.2% to 53.8% caused by sorafenib in three cell lines further increased to 80.5% to 87.6% after 4 hours of culture with NK cells at a 1:1 effector-to-target ratio. NK-cell cytotoxicity persisted even in the presence of sorafenib. We found that NKG2D, an NK-cell-activating receptor, was an important mediator of anti-HCC activity. We therefore enhanced its signaling capacity with a chimeric NKG2D-CD3z-DAP10 receptor. This considerably increased the anti-HCC cytotoxicity of expanded NK cells in vitro and in immunodeficient mice. The NK expansion and activation method applied in this study has been adapted to clinical-grade conditions. Hence, these results warrant clinical testing of expanded NK-cell infusions in patients with HCC, possibly after genetic modification with NKG2D-CD3z-DAP10.

show abstract

Section: Discussionmentioning

confidence: 99%

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

Kamiya

Chang

Campana

2016

Cancer Immunology Research

View full text Add to dashboard Cite

show abstract

“…IL-15 is an attractive drug candidate because of its selective actions on NK and mCD8 + T cells, both of which mediate anticancer and antiviral immunity (7,9). Several papers have demonstrated the efficacy of IL-15 in experimental models of melanoma, pancreatic cancer, and multiple myeloma (29,34). The recent paper by Conlon et al (19) reported clearance of pulmonary lesions in patients with malignant melanoma that were treated with IL-15.…”

Section: Discussionmentioning

confidence: 99%

“…Recent preclinical studies showed that IL-15 SA is more effective than IL-15 in causing regression of established melanoma and pancreatic cancer in mice (26,27). IL-15/IL-15Ra fusion proteins and IL-15 SA-expressing adenovirus expression systems have also been efficacious in experimental tumor models (28)(29)(30). These promising preclinical studies have generated robust interest in the application of IL-15 SA as an anticancer agent.…”

mentioning

confidence: 99%

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

Guo

Luan

Rabacal

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8+ T (mCD8+ T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8+ T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8+ T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA–induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA–mediated immunotoxicity.

show abstract

“…53 A multicolor flow cytometric analysis and the gating strategy were developed for phenotyping tumor-infiltrating immune cells as shown in Supplementary Figure. S1.…”

Section: Methodsmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

Self Cite

View full text Add to dashboard Cite

Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8+ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

show abstract

Treatment of Hepatocellular Carcinoma with Adeno-Associated Virus Encoding Interleukin-15 Superagonist

Cited by 35 publications

References 53 publications

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Contact Info

Product

Resources

About