细胞毒性T细胞
卵巢癌
抗原
癌症研究
表位
嵌合抗原受体
抗体
T细胞
肿瘤抗原
癌细胞
癌症
生物
化学
免疫学
医学
体外
免疫系统
内科学
生物化学
作者
Sung Soo Mun,Leila Peraro,Jeremy Meyerberg,Tatyana Korontsvit,Manish Malviya,Thomas J. Gardner,Chrisann Kyi,Roisin E. O’Cearbhaill,Cheng Liu,Tao Dao,David A. Scheinberg
出处
期刊:Research Square - Research Square
日期:2023-05-08
标识
DOI:10.21203/rs.3.rs-2887299/v1
摘要
Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR-T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR-T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR-T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR-T cell therapy in epithelial ovarian cancer and other cancers.
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