Abstract 5664: A novel immunotherapy for relapsed/refractory acute lymphoblastic leukemia (ALL)
Authors: Saini Uksha , Hixon Julie , Rodrigues Gisele , Foley Christopher , Chibas Leniher Castan , Hamilton Ross , Li Wenqing , Schafer Eric S. , Rheingold Susan , Heffernan Michael , Breitfeld Philip , Durum Scott , Varadhachary Atul 
Published: April 2023

Abstract
Successful treatment of ALL has been a major feat of modern medicine. Overall, 5-year survival in pediatric ALL patients approaches 90%, but 10-15% of patients will relapse. In relapse, ALL is still challenging to cure with 5-year overall survival rates being at or just below 50% and traditional therapies in this space have been highly toxic. Novel immunotherapies such as blinatumomab, inotuzumab and CAR T-cells have improved outcomes and reduced toxicities but are not curated to some of the most vulnerable patients in relapse including T-cell ALL (for which there are no FDA approved immunotherapies) and Philadelphia-like B-ALL. Thus, unmet needs remain in relapsed/refractory (r/r) ALL. The IL-7 and TSLP axes play an important role in B-ALL and T-ALL including in chemotherapy resistance. CD127 (IL7RA) is an attractive target due to limited expression in normal tissues, as confirmed with a GLP.
We are developing 4A10, a novel monoclonal antibody against CD127 which labels ALL cells for degradation via antibody-dependent cell-mediated cytotoxicity (ADCC) and inhibiting IL-7 signaling in T-ALL. 4A10 has demonstrated robust in-vitro and in-vivo anti-cancer activity in pre-clinical PDX models. The antibody substantially reduces circulating tumor burden and organ infiltration, and prolongs overall survival in both naïve and chemotherapy resistant PDX models. Thus, 4A10 holds promise as a novel agent in patients with r/r ALL.
4A10 manufacturing has been successfully scaled up, with a stable master cell bank and good yields at the 200L scale. Our clinical formulation showed no refrigerated or frozen degradation over 3 months and minimal degradation or aggregation at 25°C. In their pre-IND guidance, FDA confirmed that our approach to physicochemical and biological characterization of 4A10 and our proposed analytical methods and tests appear acceptable for early clinical development.
4A10 was well-tolerated in rodent and non-human primate (NHP) toxicological studies with a No Observable Adverse Event Level (NOAEL) in NHPs well in excess of the expected therapeutic dose. Repeat dose NHP pharmacokinetic and pharmacodynamic studies support weekly dosing and do not indicate dose accumulation. Although pivotal GLP toxicology studies have yet to be completed, initial NHP studies do not provide any indications of concern.
We plan to initiate a Phase I/IIA study in 2023 to assess 4A10 in patients with r/r ALL. The Phase I portion of the study will determine the recommended Phase II dose, and the Phase IIA expansion cohorts have been designed to provide clinical proof of concept. The clinical study will be conducted in partnership with the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium and key adult centers. If our Phase I/IIA is successful, we expect to follow with a single pivotal Phase II trial for marketing approval.
Citation Format: Uksha Saini, Julie Hixon, Gisele Rodrigues, Christopher Foley, Leniher Castan Chibas, Ross Hamilton, Wenqing Li, Eric S. Schafer, Susan Rheingold, Michael Heffernan, Philip Breitfeld, Scott Durum, Atul Varadhachary. A novel immunotherapy for relapsed/refractory acute lymphoblastic leukemia (ALL). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5664.