Abstract
Interleukin-3 receptor (IL-3R) proteins are over-expressed on blasts and cancer stem cells of multiple hematologic malignancies. The recombinant diphtheria toxin fusion protein, DT388IL3, specifically targets IL-3R and is composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3). DT388IL3 demonstrated selective toxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo, and was prepared for a Phase I clinical study in AML and myelodysplasia (MDS) patients. FDA approval (BB IND#11314) and IRB approvals were obtained. 80 AML and MDS patients were screened and 38 AML and 3 MDS patients were treated. The median age of treated patients was 62 years (range, 25–81 years). There were 22 males and 19 females. AML disease was de novo in 5, 1st relapse in 12, 2nd relapse in 8, and refractory in 12. MDS disease was high-grade in one and intermediate-grade in 2. Five AML patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. AML cytogenetics was unfavorable in 15, intermediate in 21, and not done in 2. Seven patients were treated with 4 ug/kg, eight patients with 5.3 ug/kg, thirteen patients with 7.1 ug/kg, seven with 9.4 ug/kg, and six with 12.5 ug/kg DT388IL3 for up to six treatments (one cycle). Of note, patients have not yet received a second cycle. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, transaminasemia, hypoxemia, and hypoalbuminemia. Pretreatment anti-DT antibody levels ranged from 0 – 9.6ug/mL (mean = 2.3ug/mL); day 15 post-treatment antibody levels were 0 – 600ug/mL (mean = 92ug/mL); day 30 antibody levels were 1.1 – 306ug/mL (mean = 82ug/mL). Day 1 Cmax ranged from 0 – 350 ng/mL and correlated with dose; Day 12 Cmax ranged from 0 – 179 ng/mL and correlated with Day 12 anti-DT antibody levels. Development of anti-DT antibody levels at Day 15 and 30 did not interfere with response. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among 38 evaluable AML patients, we have observed one CR of 8 months duration, 2 partial remissions (PRs) lasting one and three months, and 3 minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90%, and 90% lasting one to two months. In one evaluable MDS patient, we achieved a PR lasting four months with improvement in hematologic parameters and conversion to transfusion independence. Patient accrual is proceeding with correlative IL3R content of blasts and cancer stem cells. These results of activity and tolerability are encouraging and suggest that DT388IL3 may achieve a role in the management of patients with myeloid malignancies.
Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency
