Chimeric antigen receptors (CARs) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3-ζ and costimulatory receptors have provided a potent method for engineering T cell cytotoxicity towards B-cell leukemia and lymphoma; however, resistance to immunotherapy due to loss of T cell effector function remains a significant barrier, especially in solid maligancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an ITAM-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior anti-tumor activity compared to standard first and second generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced anti-tumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes (TILs). These results support the exploration of KIR-CARs for adoptive T cell immunotherapy, particular in immunotherapy-resistant solid tumors.
- Received February 25, 2015.
- Revision received April 10, 2015.
- Accepted April 14, 2015.
- Copyright © 2015, American Association for Cancer Research.