Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc 'spacer' domain in the extracellular moiety of chimeric antigen receptors avoids 'off-target' activation and unintended initiation of an innate immune response

作者：Hombach A; Hombach A A; Abken H^*

来源：Gene Therapy, 2010, 17(10): 1206-1213.

DOI：10.1038/gt.2010.91

• immunoreceptor
• chimeric antigen receptor
• redirected T cells
• adoptive immunotherapy

Chimeric antigen receptors (CARs, immunoreceptors) are frequently used to redirect T cells with pre-defined specificity, in particular towards tumour cells for use in adoptive immunotherapy of malignant diseases. Specific targeting is mediated by an extracellularly located antibody-derived binding domain, which is joined to the transmembrane and intracellular CD3 zeta moiety for T-cell activation. Stable CAR expression in T cells, however, requires a spacer domain interposed between the binding and the transmembrane domain and which is commonly the constant IgG1 Fc domain. We here revealed that CARs with Fc spacer domain bind to IgG Fc gamma receptors (Fc gamma Rs), thereby unintentionally activating innate immune cells, including monocytes and natural killer (NK) cells, which consequently secrete high amounts of pro-inflammatory cytokines. Engineered T cells, on the other hand, are likewise activated by Fc gamma R binding resulting in cytokine secretion and lysis of monocytes and NK cells independently of the redirected specificity. To reduce Fc gamma R binding, we modified the spacer domain without affecting CAR expression and antigen binding. Engineered with the modified CAR, T cells are not activated in presence of Fc gamma R(+) cells, thereby minimizing the risk of off-target activation while preserving their redirected targeting specificity. Gene Therapy (2010) 17, 1206-1213; doi:10.1038/gt.2010.91; published online 17 June 2010

• 出版日期2010-10