Targeted alpha therapy: evidence for potential efficacy of alpha-immunoconjugates in the management of micrometastatic cancer.

There can be little doubt that one of the most important problems in the management of cancer is control of metastatic disease. This objective must be achieved ideally with a systemic therapeutic modality that targets cancer cells and gives minimal collateral damage to critical normal cells. The efficacy of targeted cancer therapy relies on the ability of a toxin to be located in the target cancer cell. The ideal toxin is one that is active only in the cancer cell, and not in critical normal cells. Failing this, the next best approach is a toxin with a short effective lifetime to target early stage micrometastatic disease. This rules out chemical toxins, given that they remain effective until excreted from the body, and localization of dose to the cancer cell rules out beta-emitting radio-isotopes (RI). Alpha-emitting RI, however, are much more appropriate toxins because they are short-lived and because their cytotoxicity is the result of their high rate of energy loss and short range of the alpha particles. These radionuclides have properties that are particularly suited for the elimination of single cells in transit or small nests of cancer cells. In vitro and in vivo experiments with alpha RI show dramatic superiority over beta RI. Only a few nuclear hits are needed to kill cells, and the formation of metastatic lung lesions and subcutaneous lesions in mice can be inhibited by systemic administration of alpha emitters. But alpha RI have not been able to control solid tumours, for which beta RI are better suited. A small number of alpha-emitting radionuclides are currently under investigation. These are terbium (Tb)-149, astatine (At)-211, bismuth (Bi)-212 and Bi-213. Terbium-149 and At-211 both require accelerators in close proximity to the place of application. The Bi isotopes are produced by long-lived parents and, as such, can be obtained from generators. The first phase-1 dose escalation trial with Bi-213 radioimmunoconjugate (RIC) commenced in New York in 1997, and other trials are planned with At-211 RIC and At-211 methylene blue for melanoma. Actinium (Ac)-225 is obtained from the decay of thorium (Th)-229, which is a waste product in the enrichment of fissile Th-233. Alternative accelerator production routes are being investigated, beginning with the European Centre for Nuclear Research (CERN) GeV proton spallation source. The ready and low-cost availability of the Ac:Bi generator is an important element in the implementation of clinical trials for patients with poor prognoses but without evidence of metastatic disease.