Cytokine-Induced Killer Cells as Immunotherapy for Solid Tumors: Current Evidence and Perspectives

Giraudo, Lidia; Gammaitoni, Loretta; Cangemi, Michela; Rotolo, Ramona; Aglietta, Massimo; Sangiolo, Dario

doi:10.2217/imt.15.61

Cited by 24 publications

(24 citation statements)

References 97 publications

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“…Clinical studies with CAR T cell strategies, showed that T cells exhibit the capability to home to tumor sites, as well as to proliferate, persist, and release cytokines upon encountering tumors. In comparison, these capabilities were minimal among WT CIK cells showing limited anti-tumor activity in preclinical analysis [ 50 - 53 ]. However, CAR engineering may comprise synergism or even additive effects of CAR- and NKG2D-mediated killing provided by CIK cells.…”

Section: Discussionmentioning

confidence: 99%

Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children

et al. 2017

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Pediatric patients with recurrent, refractory or advanced soft tissue sarcoma (STS) who are simultaneously showing signs of cumulative treatment toxicity are in need of novel therapies. In this preclinical analysis, we identified ErbB2 as a targetable antigen on STS cells and used cytokine-induced killer (CIK) cells transduced with the lentiviral 2nd-generation chimeric antigen receptor (CAR) vector pS-5.28.z-IEW to target ErbB2-positive tumors. Solely CIK cell subsets with the CD3+ T cell phenotype showed up to 85% cell surface expression of the respective CAR. A comparison of wildtype (WT), mock-vector and ErbB2-CAR-CIK cells showed, that engineered cells exhibited diminished in vitro expansion, retained WT CIK cell phenotype with higher percentages of differentiated effector memory/effector cells. Activating natural killer (NK) cell receptor NKG2D-restricted target cell recognition and killing of WT and ErbB2-CAR-CIK cells was maintained against ErbB2-negative tumors, while ErbB2-CAR-CIK cells demonstrated significantly increased cytotoxicity against ErbB2-positive targets, including primary tumors. ErbB2-CAR- but not WT CIK cells proliferated, infiltrated and efficiently lysed tumor cell monolayers as well as 3D tumor spheroids.Here, we demonstrate a potential cell therapeutic approach using ErbB2-CAR-CIK cells for the recognition and elimination of tumor cells expressing ErbB2, which we identified as a targetable antigen on high-risk STS cells.

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Section: Discussionmentioning

confidence: 99%

Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children

et al. 2017

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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%

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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“…In addition to differentiation therapeutic strategy, HLA-I-independent tumor cell killing by cytokine-induced killer cell may be another promising method to target these HLA-I(−) cells (Giraudo et al , 2015). Our future efforts are focused on the characterization of the similarities and differences of the HLA-I enriched population in other sarcomas, given the breadth of biologies they represent, as well as the mechanisms at hand in the parallel differentiation and loss of neoplastic potential of HLA-I(−) cells in different cancer subtypes.…”

Section: Discussionmentioning

confidence: 99%

Targeting sarcoma tumor-initiating cells through differentiation therapy

et al. 2017

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Human leukocyte antigen class I (HLA-I) down-regulation has been reported in many human cancers to be associated with poor clinical outcome. However, its connection to tumor-initiating cells (TICs) remains unknown. In this study, we report that HLA-I is down-regulated in a subpopulation of cells that have high tumor initiating capacity in different types of human sarcomas. Detailed characterization revealed their distinct molecular profiles regarding proliferation, apoptosis and stemness programs. Notably, these TICs can be induced to differentiate along distinct mesenchymal lineages, including the osteogenic pathway. The retinoic acid receptor signaling pathway is overexpressed in HLA-1 negative TICs. All-trans retinoic acid treatment successfully induced osteogenic differentiation of this subpopulation, in vitro and in vivo, resulting in significantly decreased tumor formation. Thus, our findings indicate down-regulated HLA-I is a shared feature of TICs in a variety of human sarcomas, and differentiation therapy strategies may specifically target undifferentiated TICs and inhibit tumor formation.

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Cytokine-Induced Killer Cells as Immunotherapy for Solid Tumors: Current Evidence and Perspectives

Cited by 24 publications

References 97 publications

Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children

Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children

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

Targeting sarcoma tumor-initiating cells through differentiation therapy

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