Cell-based immunotherapy with cytokine-induced killer (CIK) cells: From preparation and testing to clinical application

Meng, Yiming; Zhong, Yu; Wu, Yefeng; Du, Tao; Shi, Chunlei; Fanjuan, Meng; Su, Nan; Ma, Yangyang; Li, Xiaoxi; Sun, Song; Zhang, Guirong

doi:10.1080/21645515.2017.1285987

Cited by 40 publications

(31 citation statements)

References 90 publications

(21 reference statements)

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“…Early evidence from clinical trials support the feasibility and safety profile of CIK immunotherapy, with initial signs of activity and positive impact on survival outcomes in multiple solid tumors, including ovarian cancer either in advanced 31,34,38,42,[59][60][61] or even adjuvant or post-chemotherapy maintenance settings 62 .…”

Section: Discussionmentioning

confidence: 99%

“…from peripheral blood mononuclear cells (PBMC), cord blood 37,38 , bone marrow 39 or other sources 40 , in presence of INF-ϒ, Ab-anti-CD3 and interleukin 2 (IL2) 41 . The cytotoxic activity is mostly mediated by the interaction of their NKG2D membrane receptor with several members of stress-inducible molecules expressed on tumors, such as UL-16-binding proteins (ULBPs) and MHC class I-related chain A and B (MIC A/B) 42,43 .…”

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confidence: 99%

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Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer

Capellero

Erriquez

Melano

et al. 2020

Sci Rep

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Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients. Their antitumor activity was tested in vitro and in vivo against platinum-resistant patient-derived ovarian cancer cells (pdOVCs) and a Patient Derived Xenograft (PDX), respectively. CIK were efficiently generated (48 fold median ex vivo expansion) from EOC patients; pdOVCs lines (n = 9) were successfully generated from metastatic ascites; the expression of CIK target molecules by pdOVC confirmed pre and post treatment in vitro with carboplatin. the results indicate that patient-derived CIK effectively killed autologous pdOVCs in vitro. Such intense activity was maintained against a subset of pdOVC that survived in vitro treatment with carboplatin. Moreover, CIK antitumor activity and tumor homing was confirmed in vivo within an EOC PDX model. our preliminary data suggest that ciK are active in platinum resistant ovarian cancer models and should be therefore further investigated as a new therapeutic option in this extremely challenging setting.Standard therapy of epithelial ovarian cancer (EOC) includes cytoreductive surgery to no residual disease associated with platinum-based chemotherapy 1-3 . Unfortunately recurrence rate of remains high and at the day EOC represent the main cause of death among gynecological neoplasm for women in developed countries 4,5 . It's reported that platinum-based re-challenging brings benefit in platinum-sensitive patients, while platinum-resistant patients are treated with single-agent chemotherapy (e.g., pegylated liposomal doxorubicin 6,7 paclitaxel 8 gemcitabine 9 , topotecan 10,11 , or docetaxel 11,12 ). Several new drugs have been recently approved, such as bevacizumab [13][14][15][16] and PARP inhibitors 17-23 , for BRCA-mutated EOCs, but nevertheless the prognosis remains severe and it is necessary discovered new strategies to prevent tumor spreading, progression and overcome drug resistance.In the last few years strong evidence showed that immunotherapy is effective both in solid and hematological malignancies. Currently, most of the efforts are directed towards immune checkpoint inhibitors (anti PD-1, PD-L1, CTLA4) which are able to induce long lasting remissions in specific settings of metastatic solid tumors (e.g. melanoma, Non small cell lung cancer), although if still in limited numbers of patients [24][25][26][27] . Recently, immune checkpoint inhibitors have shown activity but only in small subsets of EOC patients with BRCA mutations or microsatellite instability (MSI) 28 . Defects in tumor antigen presentation and antigen-presenting machinery are emerging among the possible causes of resistance to immunotherapy with checkpoint inhi...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer

Capellero

Erriquez

Melano

et al. 2020

Sci Rep

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“…The hypothesis of the protein serum effect on cultured CIK cells was followed by Guo et al [30], Meng et al [21], and Li et al [37]. On the contrary, Niam et al [31] used a complete nutrient medium of RPMI-1640 and 10% fetal calf serum, claiming that this was the optimal medium for CIK cell expansion, better than other serum-free MNCs culture media, despite that, the CD3 + CD56 + effective subset reported comprised a median of 26.6%.…”

Section: Discussionmentioning

confidence: 99%

“…The functional assays for CIK cells include the production of cytokines and the CIK cells' cytotoxic effect on HepG2 cell line in vitro. TNFα is one of the main cytokines produced by CIK cells and should be fit as a test for cytokines secreted by CIK cells [21]. TNFα can transmit apoptotic signals inside cells that can be killed by ligand binding.…”

Section: Discussionmentioning

confidence: 99%

“…CIK cells have advantages of a higher proliferation rate, MHC-unrestricted activity, a strong activity against tumors with minimal toxicity and graft versus host disease [19], and exceptionally important, they are not hindered by immune-suppressive drugs [20]. Interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) are the principle cytokines produced by CIKs [21].…”

Section: Introductionmentioning

confidence: 99%

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Cytokine-Induced Killer Cells as an Adoptive Cellular Immunotherapy Strategy for Hepatocellular Carcinoma

El-Ashmawy¹

2019

BMB

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Background: Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer. HCC is the second highest mortality rate out of all major malignant carcinomas worldwide. Objectives: The aims of this study were to establish a rapid and easily handled culture method for sufficient expansion of viable and cytotoxic cytokine-induced killer (CIK) cells against HCC. Also, this study aimed to examine the morphologic, phenotypic, and functional characteristics of CIK cells. Method: Peripheral blood mononuclear cells (PBMCs) were cultured in a preliminary static culture to remove adherent cells. The suspended cells were cultured for 14 days with interferon-γ, human monoclonal anti-CD3 antibody and interleukin-2. Aliquots of induced PBMCs were harvested weekly to assess informative morphologic and phenotypic features of CIK cells. Mature CIK cells were subjected to functional assays that included the production of TNFα and the cytotoxic effect on HCC cell line, HepG2. Findings: CIK cells could be successfully expanded from all samples with a significant increase in T cells, natural killer cells, and natural killer T cells. TNFα concentration in the culture supernatant was significantly increased. The cytotoxic effect of CIK cells on HepG2 cells was nearly 60% at 40:1, effector: target ratio. Regression analysis was used to predict the CIK: HepG2 ratio required to achieve complete cytotoxicity. Conclusion: This study provides a detailed and simple strategy for culturing effective CIK cells. Mature CIK cells showed a high functional capacity against HCC; which will support the further ongoing practice of immunotherapy integration into different current cancer treatment protocols.

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Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen

Nie

Liu

et al. 2018

Intl Journal of Cancer

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The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty‐five patients received either the 5‐day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine‐primed chemotherapy, D‐C cohort) or the aforementioned regimen followed by cytokine‐induced killer cells therapy (D‐C and cytokine‐induced killer [CIK] cell treatment, D‐C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment‐related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment‐free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D‐C + CIK cohort. Consistently, the progression‐free survival (PFS) of the D‐C + CIK cohort compared favorably to the best PFS of the pre‐resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non‐significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large‐scale evaluation of drug‐resistant R/R AT cancer patients with advanced stage disease.

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Cell-based immunotherapy with cytokine-induced killer (CIK) cells: From preparation and testing to clinical application

Cited by 40 publications

References 90 publications

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer

Preclinical immunotherapy with Cytokine-Induced Killer lymphocytes against epithelial ovarian cancer

Cytokine-Induced Killer Cells as an Adoptive Cellular Immunotherapy Strategy for Hepatocellular Carcinoma

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

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