Pre-clinical studies and phase I clinical trial of the anti-CD22 immunotoxin CAT-3888 (BL22) for pediatric acute lymphoblastic leukemia (ALL)

Abstract

9560 Background: ALL is the most common childhood malignancy. Although highly curable, therapy is associated with multiple toxicities and ALL remains the most frequent cause of pediatric cancer mortality. Most ALL is CD22+ and we evaluated the anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22 or CAT-3888) in the treatment of pediatric ALL. Methods: In vitro cytotoxicity was assessed on blasts from 42 children with CD22+ ALL. In vivo studies were performed using a xenograft model (SCID mouse - EU1 human ALL cell line). A pediatric phase I trial of CAT-3888 was initiated. Results: CAT-3888 induced in vitro cytotoxicity against most ALL samples (median IC50 9.8 ng/ml). A dose response was observed in murine xenografts with significant prolongation of leukemia free survival (p<0.05). 18 subjects (15 ALL, 3 lymphoma; 3 - 22 years of age) were treated on a Phase I trial at doses of 10 - 40 mcg/kg QOD for 3 - 6 doses with cycles repeated every 21 - 28 days. Treatment was well tolerated and no dose limiting toxicity was seen. Pharmacokinetics were influenced by disease burden and T1/2 showed an inverse relationship to marrow blasts (r2=0.5) consistent with rapid drug binding by CD22+ cells. All subjects were heavily pre-treated and had progressive high burden disease at the time of treatment. Transient clinical activity was observed in 16 of 18 subjects as evidenced by decreased peripheral blast count (8), decreased marrow infiltration (3), decreased extramedullary disease (2), increased platelet count (2), increased neutrophil count (1), increased reticulocyte count (1), improved PET scan (1), decreased tumor-associated pain (2), and/or peripheral blast count stabilization (3). A dose response was apparent with 4 of 9 (44%) achieving stable disease at or above doses of 30 mcg/kg. Conclusions: The majority of pediatric ALL blasts are highly sensitive in vitro to CAT-3888 at concentrations far below clinically achievable levels. CAT-3888 is well tolerated in pediatric patients and activity has been seen in most subjects treated on the phase I trial. CD22 represents a relevant target for pediatric ALL. A new higher affinity anti-CD22 immunotoxin (HA22 or CAT-8015) is in development. No significant financial relationships to disclose.