Targeted Alpha-Particle Immunotherapy for Acute Myeloid Leukemia

Abstract

Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ( 213 Bi)-labeled lintuzumab. In a subsequent study, 213 Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of 213 Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ( 225 Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that 225 Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose 225 Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using 213 Bi- and astatine-211 ( 211 At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios. KEY POINTSThe use of targeted alpha-particle immunotherapy could potentially result in more efficient tumor cell killing with decreased toxicity to surrounding normal tissue compared with radioimmunotherapy with beta-emitting radionuclides.Treatment with lintuzumab, a humanized anti-CD33 monoclonal antibody, labeled with the alpha-emitter bismuth-213 demonstrated antileukemic activity as a single agent, and produced remissions in patients with acute myeloid leukemia when combined with cytarabine.Actinium-225–labeled lintuzumab overcomes the logistical challenges posed by the short half-life of bismuth-213, demonstrated safety and antitumor effects in a phase I trial, and is now under study in combination with low-dose cytarabine for older patients with untreated AML.Preclinical studies show that targeted alpha-particle immunotherapy can provide selective antileukemic effects and immunosuppression as part of conditioning before hematopoietic cell transplantation.Novel pretargeted radioimmunotherapy strategies to further improve tumor-to-normal organ dose ratios should lead to additional clinical trials using alpha-emitting constructs.