Immune Netw.  2015 Apr;15(2):58-65. 10.4110/in.2015.15.2.58.

Adoptive Cell Therapy of Melanoma with Cytokine-induced Killer Cells

• Kim JS
• Kim YG
• Pyo M
• Lee HK
• Hong JT
• Kim Y
• Han SB

• KMID: 2168030
• DOI: http://doi.org/10.4110/in.2015.15.2.58

Abstract

Melanoma is the most aggressive skin cancer and its incidence is gradually increasing worldwide. Patients with metastatic melanoma have a very poor prognosis (estimated 5-year survival rate of <16%). In the last few years, several drugs have been approved for malignant melanoma, such as tyrosine kinase inhibitors and immune checkpoint blockades. Although new therapeutic agents have improved progression-free and overall survival, their use is limited by drug resistance and drug-related toxicity. At the same time, adoptive cell therapy of metastatic melanoma with tumor-infiltrating lymphocytes has shown promising results in preclinical and clinical studies. In this review, we summarize the currently available drugs for treatment of malignant melanoma. In addition, we suggest cytokine-induced killer (CIK) cells as another candidate approach for adoptive cell therapy of melanoma. Our preclinical study and several previous studies have shown that CIK cells have potent anti-tumor activity against melanomas in vitro and in an in vivo human tumor xenograft model without any toxicity.

Keyword

Melanoma; Preclinical study; Cytokine-induced killer cells

MeSH Terms

Cell- and Tissue-Based Therapy*
Cytokine-Induced Killer Cells*
Drug Resistance
Heterografts
Humans
Incidence
Lymphocytes, Tumor-Infiltrating
Melanoma*
Prognosis
Protein-Tyrosine Kinases
Skin Neoplasms
Survival Rate
Protein-Tyrosine Kinases

Figure

• 

  Figure 1 Efficacy of cytokine-induced killer (CIK) cells for melanoma treatment in a mouse model. Generation of CIK cells from human peripheral blood mononuclear cells (PBMCs) was induced by culturing them in the presence of IL-2 and anti-CD3 antibody for 14 days. The resulting CIK cells were stained with human monoclonal antibodies against CD3, CD56, CD4, and CD8 (A). in vitro cytotoxicity of CIK cells was examined by a 51Cr-release assay that used LOX-IMVI and K562 as target cells (B). Effector (E) and target (T) cells (1×104 cells/100µl/well) were mixed at different E:T ratios (1:1 to 100:1). The percentage of cytotoxicity was calculated as following: cytotoxicity=[(sample-spontaneous)/(maximum-spontaneous)] ×100. Spontaneous release was measured upon target cell incubation in medium alone, whereas maximal release was measured after treatment with 2% Nonidet P-40. Nude mice (n=7) were implanted subcutaneously with 1.5×106 LOX-IMVI cells. CIK cells (1 to 10×106 cells/mouse) were injected intravenously once a week. Adriamycin (ADR) was injected intravenously at 2 mg/kg. Tumor size was estimated as length (mm)×width (mm)×height (mm)/2 (C). Body weight was measured to estimate toxicity (D). Mice were sacrificed on day 15 and tumors were weighed (E). Statistical significance was determined by Student's t-test versus the PBS-treated control group (*p<0.01). All experimental procedures were approved by the Animal Experimentation Ethics Committee and by the Institutional Ethics Committee of Chungbuk National University. Informed consents have been obtained from volunteers.

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