Targeted Alpha-Particle Therapy for Hematologic Malignancies

The short range and high linear energy transfer of alpha-particles offer the potential for efficient tumor killing while sparing normal bystander cells. Hematologic malignancies are ideally suited to targeted alpha-particle therapy (TAT) due to easy accessibility of malignant cells in blood, bone marrow, lymph nodes, and spleen as well as their radiosensitivity. Most clinical trials using alpha-particle therapy for hematologic malignancies have focused on acute myeloid leukemia (AML); however, preclinical studies have shown activity against other diseases such as non-Hodgkin's lymphoma and multiple myeloma. To date, the short-lived radionuclide bismuth-213 (Bi-213) and its parent actinium-225 (Ac-225) have been used clinically, but trials with astatinie-211 (At-211) have recently begun, and thorium-227 (Th-227) has shown promising preclinical results. Lintuzumab is a humanized monoclonal antibody that targets the cell surface antigen CD33, which is expressed on the vast majority of AML cells. Initial studies showed that Bi-213-labeled lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine. An initial phase I trial demonstrated that a single infusion of Ac-225-lintuzumab could be given safely at doses upto 111 kBq/kg with antileukemic activity across all dose levels. A second phase I study showed that fractionated-dose Ac-225-lintuzumab could be safely combined with low-dose cytarabine and produced objective responses in 28% of older patients with untreated AML. In a phase II study, treatment with Ac-225-lintuzumab monotherapy for a similar patient population resulted in remission in 69% of patients receiving two fractions of 74 kBq/kg and 22% of patients receiving two 55.5-kBq/kg fractions. Additionally, TAT may be useful in intensifying antileukemic therapy prior to hematopoietic cell transplantation, and pretargeting strategies offer the possibility for improved tumor-to-normal organ dose ratios. (C) 2019 Published by Elsevier Inc.