ID: 64: Targeting the IL-7R pathway in leukemia

Abstract

Acute lymphoblastic leukemia, derived from immature T or B cells, is the most common cancer in children. Current chemotherapeutic regimen are effective in over 80% of T-ALL, but the failure rate and the harshness of current treatments makes new approaches desirable. We and others have recently identified gain-of-function mutations in IL-7R alpha in T cell acute lymphoblastic leukemia (T-ALL) which serve as driver oncogenes. Most of these mutations consist of insertions containing cysteine into the juxtamembrane region, creating homodimers. These signal independently of IL-7 or the gamma-c chain of the IL-7 receptor, and constitutively activate Jak1. Two approaches have been undertaken to target the IL-7R pathway in T-ALL: inhibition of Jak1, and development of monoclonal antibodies (MAbs) against IL-7R alpha. Ruxolitinib is a recently FDA approved inhibitor of Jak1, and we show it is an effective inhibitor of cells driven by mutant IL-7R alpha in vitro and in immunodeficient mice. Tofacitinib, which is more selective for Jak3, was effective in vitro but there was no therapeutic window in vivo in immunodeficient mice. Two novel mouse MABs were developed that are directed against two different epitopes on human IL-7R alpha, and they recognize both mutant and WT proteins. MAbs were chimerized with human IgG1 to optimize antibody-dependent cell mediated cytotoxicity (ADCC). These MAbs were highly effective in ADCC assays, mediating NK cell killing of T-ALL cells harboring mutant IL-7R alpha, and they also target normal T cells which express IL-7R alpha. These approaches are being developed as new therapeutics for acute lymphoblastic leukemia.