Definition

A preparation of human autologous T lymphocytes gene-edited with the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease complex to disrupt expression of endogenous T-cell receptor (TCR) and modified to express a TCR specific for the tumor-associated antigen (TAA) Wilms tumor 1 (WT1) epitope, WT1 37-45, and human leukocyte antigen (HLA)-A*02:01, with potential immunostimulating and antineoplastic activities. Upon isolation, transduction, expansion ex vivo, and reintroduction into the patient, the autologous WT1-directed CRISPR/Cas9-engineered TCR-T cells NTLA-5001 recognize and bind to WT1-expressing tumor cells. This may result in a specific cytotoxic T-lymphocyte (CTL)-mediated killing of WT1-expressing tumor cells. WT1 protein, a zinc finger DNA-binding transcriptional regulator, is overexpressed in various leukemias and solid tumors, while expression in normal, healthy tissues is very limited; its expression is correlated with aggressiveness and poor prognosis. The removal of endogenous TCR reduces TCR competition for expression, increases the persistence and function of the expressed transgenic TCR, enhances resistance to T-cell exhaustion and increases T-cell activity.