The Potential Complementary Role of Targeted Alpha Therapy in the Management of Metastatic Melanoma

Abstract

Standard treatments for metastatic melanoma have recently extended survival although many patients still succumb. Targeted alpha therapy (TAT) is a new therapeutic approach in which a cancer-targeting vector is labeled with an alpha-emitting radioisotope. Alpha-particles have the shortest range and highest energy transfer, and produce localized, high-density and lethal ionization damage to DNA. Thus, the targeted radiation can kill isolated cancer cells circulating in blood and lymphatic vessels, regress metastatic cancer cell clusters, and disrupt the vasculature of solid tumors. Preclinical and clinical studies of TAT for metastatic melanoma demonstrate its safety and anti-tumor activity. We recommend ways in which TAT can be used to treat small-volume disease sometimes in conjunction with cytoreductive anti-melanoma therapies.

Review of current status of targeted alpha therapy in cancer treatment

“…Ipilimumab (Yervoy®), pembrolizumab (Keytruda®) and nivolumab (Opdivo®) are worldwide-approved immune therapies for unresectable or metastatic melanoma [60]. Radiation therapies include Plaque brachytherapy, Stereotactic radiosurgery (SRS) with gamma knife and proton beam radiotherapy (PBT) [61]. For tumors where surgery is not a treatment of choice, intralesional TAT will be the best substitute and results in an increased survival rate.…”

“…TAT therapy has been proven useful by disrupting tumor-feeding vasculature. Additionally, TAT with longer-lived radioisotopes (for example 225 Ac and 227 Th) will result in larger and homogenous radiation doses to tumors as compared to radioisotopes having short half-lives (for example 213 Bi with a half-life of 46 minutes) [61].…”

Synthesis and Stability of Actinium-225 Endohedral Fullerenes, 225Ac@C60

“…Endohedral metallofullerenes have been prepared for all of the lanthanides (except Pm) and a few of the actinides. , Further, fullerenes exhibit physical and chemical properties that make them well suited as nanocarriers of α-emitting actinides such as 225 Ac, a medically useful radionuclide. Extensive preclinical and clinical studies have shown the potential applications of α-particle-emitting radionuclides in a variety of cancer systems and targeted radiotherapy. − In particular, the clinical trials for the treatment of acute myeloid leukemia, − a therapy for recurrent glioblastoma, , and treatment of metastatic melanoma have all demonstrated the effectiveness of the α-emitter 225 Ac ( t 1/2 = 10 days) and its decay daughter, 213 Bi ( t 1/2 = 46 min), in killing cancer cells. The significant radiotoxicity associated with the actinides, particularly 225 Ac, emphasizes the need for special facilities for the safe handling of actinides.…”