Cytotoxicity of Activated Natural Killer Cells against Pediatric Solid Tumors

Cho, Duck; Shook, David; Shimasaki, Noriko; Chang, Yu-Hsiang; Fujisaki, Hiroyuki; Campana, Dario

doi:10.1158/1078-0432.ccr-10-0735

Cited by 202 publications

(193 citation statements)

References 45 publications

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“…The range of cytotoxicity approached that observed in assays with K562, a leukemia cell line regarded as the gold-standard target for NK-cell cytotoxicity testing. As we previously observed in studies with other tumor types (25,31), expanded NK cells were more powerful than nonstimulated and IL2-stimulated cells from the same donors, and were effective even at low E:T ratios. HCC killing was also measurable in immunodeficient mice engrafted with HCC cells; treatment with expanded NK cells reduced tumor expansion and lengthened overall survival.…”

Section: Discussionsupporting

confidence: 76%

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

Kamiya

Chang

Campana

2016

Cancer Immunology Research

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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.

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Section: Discussionsupporting

confidence: 76%

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

Kamiya

Chang

Campana

2016

Cancer Immunology Research

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“…Indeed, previous attempts at using autologous activated NK cells have failed to prevent relapse after autologous stem cell transplantation. 55 We show here that even optimized stimulatory and cytokine conditions that induce NK cells with potent cytolytic responses to both AML 56 and solid tumors 57 could by themselves not overcome the functional NK-cell defects in CML. More refined strategies to improve the functionality of autologous NK cells in CML are required.…”

Section: Discussionmentioning

confidence: 92%

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

et al. 2011

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Although BCR-ABL þ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1 þ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL þ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.

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“…Immune therapy may offer such an approach because RMS cells are potentially susceptible to cytolysis by redirected T cells, 14 antigen-independent cytokine-induced killer cells, 29 and activated natural killer cells, 30 although with disappointing low efficacy. Herein, we show that this may be due to, at least in part, inefficient effector cell activation as the result of lack of costimulation.…”

Section: Discussionmentioning

confidence: 99%

Survivin Blockade Sensitizes Rhabdomyosarcoma Cells for Lysis by Fetal Acetylcholine Receptor–Redirected T Cells

Simon-Keller

Paschen

Hombach

et al. 2013

The American Journal of Pathology

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Cellular immunotherapy may provide a strategy to overcome the poor prognosis of metastatic and recurrent rhabdomyosarcoma (RMS) under the current regimen of polychemotherapy. Because little is known about resistance mechanisms of RMS to cytotoxic T cells, we investigated RMS cell lines and biopsy specimens for expression and function of immune costimulatory receptors and anti-apoptotic molecules by RT-PCR, Western blot analysis, IHC, and cytotoxicity assays using siRNA or transfection-modified RMS cell lines, together with engineered RMS-directed cytotoxic T cells specific for the fetal acetylcholine receptor. We found that costimulatory CD80 and CD86 were consistently absent from all RMSs tested, whereas inducible T-cell co-stimulator ligand (ICOS-L; alias B7H2) was expressed by a subset of RMSs and was inducible by tumor necrosis factor a in two of five RMS cell lines. Anti-apoptotic survivin, along with other inhibitor of apoptosis (IAP) family members (cIAP1, cIAP2, and X-linked inhibitor of apoptosis protein), was overexpressed by RMS cell lines and biopsy specimens. Down-regulation of survivin by siRNA or pharmacologically in RMS cells increased their susceptibility toward a T-cell attack, whereas induction of ICOS-L did not. Treatment of RMS-bearing Rag À/À mice with fetal acetylcholine receptorespecific chimeric T cells delayed xenograft growth; however, this happened without definitive tumor eradication. Combined blockade of survivin and application of chimeric T cells in vivo suppressed tumor proliferation during survivin inhibition. In conclusion, survivin blockade provides a strategy to sensitize RMS cells for T-celle based therapy. (Am J Pathol 2013, 182: 2121e2131; http://dx

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Cytotoxicity of Activated Natural Killer Cells against Pediatric Solid Tumors

Cited by 202 publications

References 45 publications

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

Survivin Blockade Sensitizes Rhabdomyosarcoma Cells for Lysis by Fetal Acetylcholine Receptor–Redirected T Cells

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