Targeted killer cells for cancer immunotherapy

Targeted killer cells for cancer immunotherapy

Natural killer (NK) cells are part of the innate immune system and play an important role in the defense against virus-infected and abnormal cells. Their cytotoxic activity can be triggered rapidly, and is regulated by germ line-encoded stimulatory and inhibitory receptors. In addition, NK cells are important mediators of antibody-dependent cellular cytotoxicity (ADCC).

Aim of this project is to develop an approach for adoptive cancer immunotherapy that is based on gene-modified NK cells which express tumor-specific chimeric antigen receptors (CARs). CARs consist of an extracellular single chain Fv antibody fragment (scFv) for target cell recognition that is linked via a flexible hinge region and transmembrane domain to intracellular signal-transducing domains which activate cellular cytotoxicity. CAR-expressing NK cells display efficient ADCC-like activity towards tumor cells independent from the presence of soluble antibodies and largely unaffected by endogenous resistance mechanisms. In previous work, the joint project partners utilized lentiviral transduction to generate a genetically modified variant of the clinically applicable NK cell line NK-92 which stably expresses a CAR with specificity for the tumor-associated surface antigen ErbB2 (HER2).

In this project, the targeted NK cells are being further developed for adoptive immunotherapy of glioblastoma and other ErbB2-expressing malignancies. Glioblastoma is the most common malignant intracranial tumor in adulthood. Despite aggressive multimodal therapy, unselected patients have an average survival time of less than twelve months. Overexpression of receptor tyrosine kinases such as EGFR (ErbB) and ErbB2 is a typical feature that characterizes the neoplastic phenotype of these tumors, and these receptors can be used as targets for directed cancer immunotherapy. Important steps in the project are the molecular and functional characterization of ErbB2-specific NK-92 cells, the optimization of protocols for their continuous expansion, and the determination of their antitumor activity in in vivo models of glioblastoma as a function of the cell dose applied and the form of administration. Based on the data collected in this study, a clinical protocol will be developed for submission to the regulatory authorities.

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