A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity

作者：Song De Gang; Ye Qunrui; Poussin Mathilde; Liu Lin; Figini Mariangela; Powell Daniel J Jr^*

来源：Oncotarget, 2015, 6(25): 21533-21546.

DOI：10.18632/oncotarget.4071

• folate receptor alpha
• chimeric antigen receptor
• adoptive immunotherapy
• ovarian cancer
• T cells

Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate "on-target" toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (alpha FR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with alpha FR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based alpha FR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for alpha FR protein and exhibited reduced recognition of normal cells expressing low levels of alpha FR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and "on-target off-tumor" toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs.

• 出版日期2015-8-28