Abstract
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.
Highlights
Pediatric patients with very high-risk soft tissue sarcoma (STS) often acquire refractory disease or experience relapse and are simultaneously susceptible to chemotherapy- and radiotherapy-related adverse effects because of cumulative treatment toxicity
The cell expansion rate was significantly higher among WT cytokine-induced killer (CIK) cells than among ErbB2-chimeric antigen receptor (CAR) CIK cells (p < 0.0001)
Our recent clinical trial data showed that non-specific (WT) CIK cell therapy following allogeneic stem cell transplantation did not improve outcome
Summary
Pediatric patients with very high-risk soft tissue sarcoma (STS) often acquire refractory disease or experience relapse and are simultaneously susceptible to chemotherapy- and radiotherapy-related adverse effects because of cumulative treatment toxicity. Easy and manageable ex vivo expansion in accordance with good manufacturing practices (GMP) [1,2,3], wide non-major www.impactjournals.com/oncotarget histocompatibility complex (MHC)-restricted cancer cell recognition and killing as well as low alloreactive activity in preclinical [4, 5] and clinical studies [6, 7], are features of cytokine-induced killer (CIK) cells suggestive of their promise as immune effectors for innovative immune therapeutic interventions in patients transplanted for relapsed or refractory STS. In our previous study, even though disease recurrence was delayed or even prevented after allogeneic stem cell transplantation and allogeneic CIK cell interventions, the outcome in our cohort was dismal due to the occurrence of relapse and treatmentrelated complications (manuscript in preparation). The great promise of any kind of cancer immunotherapy still is to clear the tumor without providing additional toxicity
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