LRRC15-CAR T Cells for the Treatment of Osteosarcoma.

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy offers a promising approach to improve outcomes for patients with relapsed, refractory, or metastatic osteosarcoma. However, novel target antigens are needed to overcome obstacles limiting CAR T-cell efficacy against osteosarcoma and other solid tumors. Leucine-rich repeat-containing 15 (LRRC15) has been identified as a promising target in patients with osteosarcoma. Given these findings, we aimed to develop LRRC15-CAR T cells and evaluate their antitumor activity and safety in preclinical models. EXPERIMENTAL DESIGN: We evaluated LRRC15 expression in normal tissues and pediatric solid tumors using gene expression and immunohistochemical (IHC) approaches. We generated LRRC15-CAR T cells using a binding domain that recognizes human and murine LRRC15 and evaluated their specificity, antitumor activity, and safety in preclinical studies. RESULTS: Gene expression analysis demonstrated limited Lrrc15 expression in normal tissues and high expression in osteosarcoma, which was confirmed at the protein level by IHC staining of primary pediatric osteosarcoma tumors. In vitro, LRRC15-CAR T cells demonstrated specificity and cytotoxicity against LRRC15-positive targets. In vivo, LRRC15-CAR T cells exhibited antitumor activity in both human xenograft and immunocompetent murine osteosarcoma models, leading to significantly increased survival compared with controls. Finally, comprehensive toxicity analysis demonstrated a positive safety profile of intravenously administered LRRC15-CAR T cells. CONCLUSIONS: LRRC15-CAR T cells exert anti-osteosarcoma activity while maintaining a positive safety profile. These promising findings support the clinical translation of LRRC15-CAR T cells for patients with osteosarcoma and potentially other LRRC15-positive solid tumors.