Effective Activity of Cytokine-Induced Killer Cells against Autologous Metastatic Melanoma Including Cells with Stemness Features

Gammaitoni, Loretta; Giraudo, Lidia; Leuci, Valeria; Todorovic, Maja; Mesiano, Giulia; Picciotto, Franco; Pisacane, Alberto; Zaccagna, Alessandro; Volpe, Maria Giuseppa; Gallo, Susanna; Caravelli, Daniela; Giacone, Elena; Venesio, Tiziana; Balsamo, Antonella; Pignochino, Ymera; Grignani, Giovanni; Carnevale-Schianca, Fabrizio; Aglietta, Massimo; Sangiolo, Dario

doi:10.1158/1078-0432.ccr-13-0061

Cited by 81 publications

(71 citation statements)

References 55 publications

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“…Meanwhile, immune effector cells not only produce large amounts of inflammatory cytokines to alleviate immune damage caused by anticancer drugs and enhance the immunosurveillance capabilities of patients with cancer, 37 but additionally eliminate potential or residual tumor cells after chemotherapy, including even drug-resistant tumor cells and putative cancer stem cells. [38][39][40] Secondly, alternate application of CIK and NK cells exhibits a synergistic antitumor immunity via different mechanisms compared to the CIT with only CIK cells, which was also found by Maniar et al and Cui et al 34,35 On the other hand, it was reported that the circulating hematopoietic stem and progenitor cells from various patients with solid cancers exhibited a generalized myeloid bias with a skew toward granulocytic differentiation, 41 which increased the neutrophil-to-lymphocyte ratio (NLR), a poor prognostic indicator. 42 Adjuvant CIT could reverse the NLR, resulting in immune equilibrium to reduce tumor recurrence and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Adjuvant cellular immunotherapy in patients with resected primary non-small cell lung cancer

et al. 2015

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Postoperative non-small cell lung cancer (NSCLC) patients require adjuvant therapy to improve their prognosis. In this study, we investigated the efficacy of a sequential combination of autologous cellular immunotherapy (CIT) and chemotherapy for postoperative NSCLC. This retrospective study included 120 postoperative NSCLC patients: 60 cases received only chemotherapy; 33 cases received chemotherapy and sequential CIT with cytokine-induced killer (CIK) cells; and 27 cases received chemotherapy and sequential CIT with alternate CIK and natural killer (NK) cells. Survival analysis showed significantly higher overall survival rates in the CIT group compared with the control group. Overall survival was higher in patients who received CIT with alternate CIK and NK cells than those who received treatment with only CIK cells. Multivariate analysis showed that adjuvant CIT was an independent prognostic factor for overall survival of patients with NSCLC. In subgroup analyses, adjuvant CIT significantly improved the overall survival of patients with less than 60 y old and positive lymph node. In conclusions, these data indicate that adjuvant CIT, especially with alternate application of CIK and NK cells, is an effective therapeutic approach to prolong survival of patients with NSCLC, particularly for patients 60 y old with positive lymph nodes.

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Section: Discussionmentioning

confidence: 99%

Adjuvant cellular immunotherapy in patients with resected primary non-small cell lung cancer

et al. 2015

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“…This was previously described and validated by our group. 30,31,46 We provide a new functional angle of analysis, exploring the sensitivity of putative sCSC to conventional chemotherapy. We acknowledge that the proposed methodology to visualize sCSC has objective limitations and cannot guarantee to capture all the “true” sCSC.…”

Section: Discussionmentioning

confidence: 99%

“…eGFP.Wpre (LV-Oct4.eGFP) was obtained by replacing the expression cassette hPGK.eGFP into LV-PGK.eGFP with the hOct4-eGFP, cleaved from phOct4-eGFP vector, by insertion into SalI and XhoI restriction enzyme sites. 30,31 Physical titers for lentiviral vector stocks were determined on the basis of p24 antigen content (HIV-1 p24 ELISA kit; PerkinElmer).…”

Section: Methodsmentioning

confidence: 99%

“…30 We also provided proof of concept that sCSC could be killed in vitro by a MHC-independent immunotherapy approach based on Cytokine-Induced Killer cells (CIK). 30,31 We now asked whether sCSC were resistant to chemo and targeted therapies currently used in clinical practice, exploring if a sequential immunotherapy with CIK might be effective against chemo- and target- therapy resistant sCSC.…”

Section: Introductionmentioning

confidence: 99%

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Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.

et al. 2018

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Metastatic bone and soft tissue sarcomas often relapse after chemotherapy (CHT) and molecular targeted therapy (mTT), maintaining a severe prognosis. A subset of sarcoma cancer stem cells (sCSC) is hypothesized to resist conventional drugs and sustain disease relapses. We investigated the immunotherapy activity of cytokine induced killer cells (CIK) against autologous sCSC that survived CHT and mTT. The experimental platform included two aggressive bone and soft tissue sarcoma models: osteosarcoma (OS) and undifferentiated-pleomorphic sarcoma (UPS).To visualize putative sCSC we engineered patient-derived sarcoma cultures (2 OS and 3 UPS) with a lentiviral sCSC-detector wherein the promoter of stem-gene Oct4 controls the expression of eGFP.We visualized a fraction of sCSC (mean 24.2 ± 5.2%) and confirmed their tumorigenicity in vivo. sCSC resulted relatively resistant to both CHT and mTT in vitro. Therapeutic doses of doxorubicin significantly enriched viable eGFP+sCSC in both OS (2.6 fold, n = 16) and UPS (2.3 fold, n = 29) compared to untreated controls. Treatment with sorafenib (for OS) and pazopanib (for UPS) also determined enrichment (1.3 fold) of viable eGFP+sCSC, even if less intense than what observed after CHT.Sarcoma cells surviving CHT and mTT were efficiently killed in vitro by autologous CIK even at minimal effector/target ratios (40:1 = 82%, 1:4 = 29%, n = 13). CIK immunotherapy did not spare sCSC that were killed as efficiently as whole sarcoma cell population. The relative chemo-resistance of sCSC and sensitivity to CIK immunotherapy was confirmed in vivo. Our findings support CIK as an innovative, clinically explorable, approach to eradicate chemo-resistant sCSC implicated in tumor relapse.

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“…Adoptive immunotherapy is an effective and safe anticancer therapy (1), and currently used for various tumor treatments, including renal cell carcinoma (2), lung cancer (3), breast cancer (4), melanoma (5), and hepatoma (6).…”

Section: Introductionmentioning

confidence: 99%

Identification of a protein associated with the activity of cytokine‑induced killer cells

et al. 2017

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Abstract. Cytokine-induced killer cells (CIKs) adoptive immunotherapy for efficient antitumor ability is used clinically, but details regarding the proteins associated with CIK activity remain unclear. In the current study, the cytotoxicity of CIKs on hepatoma was identified to be significantly downregulated by 1.61-fold following gentamincin treatment. Further research revealed that a differentially expressed protein (P43) was significantly downregulated by 1.22-fold using one-dimensional gel electrophoresis analysis. Of these, the P43 was identified as human haptoglobin using liquid chromatography-mass spectrometry. Western blotting demonstrated that the haptoglobin specifically reacted with rabbit anti-human-haptoglobin. Furthermore, western blotting results verified that the haptoglobin was significantly downregulated by 1.17-fold compared with the control group. In addition, the expression of haptoglobin mRNA was significantly downregulated by 1.73-fold following gentamincin treatment. Taken together, the results of the present study demonstrated that the expression of haptoglobin protein was associated with the activity of CIKs, and the results will be beneficial to the further investigation of CIK activity-enhancement mechanism.

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Effective Activity of Cytokine-Induced Killer Cells against Autologous Metastatic Melanoma Including Cells with Stemness Features

Abstract: For the first time, the intense killing activity of CIK cells against autologous metastatic melanoma, including mCSCs, has been shown. These findings move clinical investigation of a new immunotherapy for metastatic melanoma, including mCSCs, closer.

Cited by 81 publications

References 55 publications

Adjuvant cellular immunotherapy in patients with resected primary non-small cell lung cancer

Adjuvant cellular immunotherapy in patients with resected primary non-small cell lung cancer

Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.

Identification of a protein associated with the activity of cytokine‑induced killer cells

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