Abstract PR014: A novel immunotherapy for relapsed/refractory pediatric T-cell acute lymphoblastic leukemia

Abstract

Abstract With the recent addition of nelarabine to first-line therapy, the overall 5-year survival for pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients approaches 90%. Patient prognosis for those who relapse is heavily dependent on their specific subtype of ALL: those with B-cell ALL (B-ALL) have several antibody therapies available, including blinatumomab and inotuzumab, which specifically target B-cells for degradation. However, no effective standard therapy is available for patients with relapsed T-cell ALL (T-ALL) and few new therapies are in development; as a result, these patients have a much poorer 5-year survival rate, on the order of 20-30%. Therefore, the development of a targeted immunotherapy for T-cell ALL is critical towards improving patient outcome. The IL-7Ralpha protein is part of the IL-7 receptor complex expressed on the surface of T-cells, and the thymic stromal lymphopoietin (TSLP) receptor complex on the surface of B-cells. The IL-7Ralpha protein is critical for the proliferation and maintenance of T-cells and T-ALL cells, and is overexpressed or constitutively activated in up to 70% of pediatric T-ALL patients. Furthermore, the IL-7Ralpha appears to be overexpressed in chemotherapy-resistant T-ALL cells, highlighting the potential for targeting this protein in relapsed T-ALL patients. Here we describe a novel monoclonal antibody (4A10) raised against the IL-7Ralpha protein which effectively labels T-ALL cells for degradation via antibody-dependent cell-mediated cytotoxicity (ADCC) and independent mechanisms and results in significant control of T-ALL xenografts in animal models, diminished infiltration of T-ALL cells into other organs, and prolonged survival time. The 4A10 antibody is effective against relapsing disease in animal models, and may therefore be effective for relapsed T-ALL patients, or in combination with first-line therapy to further improve initial 5-year survival rates. The 4A10 antibody has undergone extensive optimization and formulation for clinical-grade manufacture and is completing IND-enabling toxicology studies with plans to enter Phase I clinical trials in mid-2021. We are developing a novel clinical trial schema, in collaboration with the Therapeutics Advances in Childhood Leukemia and Lymphoma consortium, to assess tolerability and efficacy via a primarily pediatric Phase I trial, to advance relapsed leukemia patients to curative therapies, including bone marrow transplantation or cell therapies. This abstract is also being presented as PO004. Citation Format: Christopher Foley, Julie Hixon, Wengqing Li, Eric Schafer, Susan Rheingold, Atul Varadhachary, Scott Durum. A novel immunotherapy for relapsed/refractory pediatric T-cell acute lymphoblastic leukemia [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR014.