A Novel Immunotherapy for Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)
Introduction
Successful treatment of ALL has been a major feat of modern medicine. Although 5-year survival in pediatric ALL patients is approaching 90%, 10-15% of patients will relapse. In relapse, the 5-year overall survival rates are only at or just below 50%, indicating that ALL is still challenging to cure, 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. However, these 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, significant 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 (IL-7R subunit alpha) is an attractive target due to limited expression in normal tissues. Allterum Therapeutics, Inc. is developing 4A10, an anti-CD127 antibody licensed from NCI.
Methods
Functional in vitro and in vivo assays
4A10 efficacy was examined in-vitro for functional activity via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and direct inhibition of IL-7 signaling. The in-vivo anti-cancer activity was confirmed in multiple pre-clinical PDX mouse models of T-ALL and B-ALL.
Manufacturing process
Development of the 4A10 manufacturing process has included generating a stable master cell bank and conducting a 10L proving run, which was successfully scaled up to a 200L demonstration run. A drug formulation was developed, and preliminary stability tests have been performed.
Toxicology, pharmacokinetics and pharmacodynamics
Preliminary toxicology studies in rodents and non-human primates (NHPs) were conducted. Repeat dose NHP pharmacokinetic and pharmacodynamic studies to monitor dose accumulation are also underway.
Results
Functional in vitro and in vivo assays
Functional in vitro assays with ALL cells have confirmed that 4A10 activity is mediated by ADCC, ADCP, and direct inhibition of IL-7 signaling (measured via p-STAT5). 4A10 has demonstrated robust in-vivo anti-cancer activity in pre-clinical PDX models of T-ALL and B-ALL. The antibody not only reduces circulating tumor burden and organ infiltration substantially, but also prolongs overall survival in both naïve and chemotherapy-resistant PDX models.
Scale up and manufacturing
Efforts for successful scale up and manufacturing of 4A10 are already in place, with a master cell bank that is stable out to 60 generations. The 200L scaled-up batch had good yields and high purity (>95%). Our clinical formulation showed no refrigerated degradation over 3 months and no frozen (-65°C) degradation over 2 years. In their pre-IND guidance, FDA confirmed that our approach to physicochemical and biological characterization of 4A10 and our proposed analytical methods/tests appear acceptable for early clinical development.
Toxicology, pharmacokinetics and pharmacodynamics
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.
Conclusion
4A10 holds promise as a novel agent in patients with r/r ALL. We will initiate a Phase I/IIA study in 2024 to assess safety and efficacy of 4A10 in patients with r/r ALL. 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 trial is successful, we expect to follow with a single pivotal Phase II trial for marketing approval.