Genetically Modified T cells Targeting Interleukin-11 Receptor a-Chain Kill Human Osteosarcoma Cells and Induce the Regression of Established Osteosarcoma Lung Metastases

The treatment of osteosarcoma pulmonary metastases remains a challenge. T cells genetically modified to express a chimeric antigen receptor (CAR), which recognizes a tumor-associated antigen, have shown activity against hematopoietic malignancies in clinical trials, but this requires the identification of a specific receptor on the tumor cell. In the current study, we found that interleukin (IL)-11Ra was selectively expressed on 14 of 16 osteosarcoma patients' lung metastases and four different human osteosarcoma cell lines, indicating that IL11Ramay be a novel target for CAR-specific T-cell therapy. IL-11Ra expressionwas absent or low in normal organ tissues, with the exception of the gastrointestinal tract. IL-11Ra-CAR–specific T cells were obtained by non-viral gene transfer of Sleeping Beauty DNA plasmids and selectively expanded ex vivo using artificial antigenpresenting cells derived from IL-11Ra þ K562 cells genetically modified to coexpress T-cell costimulatory molecules. IL-11Ra-CARþ T cells killed all four osteosarcoma cell lines in vitro; cytotoxicity correlated with the level of IL-11Ra expression on the tumor cells. Intravenous injection of IL-11Ra-CARþT cells intomice resulted in the regression of osteosarcoma pulmonary metastases with no organ toxicity. Together, the data suggest that IL-11Ra-CAR T cells may represent a new therapy for patients with osteosarcoma pulmonary metastases. Cancer Res; 72(1); 271–81. 2011 AACR.