Pre-TCR-Targeted Immunotherapy for T-cell Acute Lymphoblastic Leukemia

Targeted immunotherapy for T-cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T-cell progenitors, is an urgent unmet need, especially for relapsed/refractory (r/r) disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-TCR, a surface receptor essential for T-cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL. Loss-of-function genetic approaches demonstrate that pre-TCR signaling is necessary for LIC activity and tumor progression in pre-TCR+ T-ALL patients xenografts. Furthermore, we demonstrate the specific therapeutic targeting of pre-TCR with a monoclonal antibody against the invariant pT subunit of the human pre-TCR, and validate an anti-pT antibody-drug conjugate treatment as a potent immunotherapy for inhibiting LIC activity and tumor progression of T-ALL in vivo. These findings reveal the suitability of pre-TCR targeting as a promising therapy for the treatment of (r/r) patients with T-ALL expressing the pre-TCR.