An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities

The Ral (Ras-like) GTP-binding proteins (RalA and RalB), as effectors of the proto-oncogene Natural killer (NK) cells are an important component of the antitumor response. Tumor recognition by NK cells was found to be partly triggered by molecules termed natural cytotoxic receptors (NCRs). Adoptive transfer of geneticallyengineered tumor-reactive T-lymphocytes can mediate remarkable tumor regressions mostly in melanoma and leukemia patients. Yet, the application of such treatments to other cancers is needed and dependent on the isolation of receptors that could facilitate efficient recognition of these malignancies. Herein, we aimed at combining NK tumor recognition capability with the genetic modification of T-cells to provide the latter with a means to recognize several tumors in a non-MHC restricted way. Consequently, we generated and evaluated several chimeric receptors based on the extracellular domain of NCR1 (NKp46) fused to multiple signaling moieties and assess their antitumor activity when retrovirally expressed in T-cells. Following coculture with different tumors, primary human T-lymphocytes expressing a chimeric NCR1 molecule recognized target cells derived from lung, cervical carcinoma, leukemia and pancreatic cancer. In addition, this receptor mediated an upregulation of surface activation markers and significant antitumor cytotoxicity both in vitro and in vivo. These results have meaningful implications for the immunotherapeutic treatment of cancer using gene-modified T-cells.