I recently attended the 8th International Symposium for Targeted Alpha Therapy (TATS 2013) at Oak Ridge National Laboratory (ORNL). The conference presenters confirmed that alpha-emitting radioisotopes derived from the thorium fuel cycle are very promising agents in the fight against cancer, HIV, and other diseases.

Scores of researchers from around the world assembled to present the results of their clinical studies and various related drug developments, all based on miniscule amounts of available alpha-emitter source material. Dr. Thom Mason, ORNL’s director, started off the conference by explaining how the lab’s very small inventory of TAT source material, nearly the total world supply, was obtained from resources originally devoted to the Thorium Utilization Program. This program was intended to support the thorium-fuel-cycle reactors that were once to follow from the successful Molten Salt Reactor Experiment (MSRE).

Modern liquid fluoride thorium reactors (LFTR) could make this critical TAT source material more readily available for drug development, clinical trials, and eventually for treating many thousands of cancer patients. In fact, each utility-scale LFTR power plant will produce enough long-lived source material annually to treat thousands of new patients a year for thousands of years.

Following is a summary of the key points from the Conference:

International interest in targeted alpha-therapy (TAT) is evidenced by the range and number of clinical trials and animal studies underway in at least the United States, Sweden, Norway, Germany, France, Russia, Japan, Brazil, and Poland.
Targeted alpha-therapy is highly effective because it only kills the cells close to where it is targeted.
Clinical trial results ranged from prolonged survival to nearly curative effects for a range of micro-tumor, solid tumor and metastatic bone, brain, lung, ovarian, prostrate, pancreatic and blood-borne cancers.
Targeted alpha-therapy presents opportunities for development of a wide-range of co-products, including, antibodies, chelators, delivery mechanisms, co-dose imaging agents, pretreatments, daughter product recoil capture mechanisms, nano-particle encapsulators, uptake inhibitors and enhancers, etc.
A common conference theme was that alpha-emitters were in great demand but short supply and the industry sentiment seemed to be that if they demonstrated TAT efficacy, private industry would step forward to supply TAT source materials.
Three of four natural decay chains (thorium, actinium, and neptunium) include candidate alpha-emitters, but the two preferred candidates actinium-225 and bismuth-213 (Ac-225 and Bi-213) are available only on the neptunium decay chain and are vastly preferred for a number important reasons.
No longer occurring in nature, the neptunium chain is now reconstituted by the formation of U-233 from neutron capture on Th-232 as part of the thorium fuel cycle.
Several current studies employ man-made astatine-211 (At-211) created using cyclotrons. However, At-211 (a halogen) does not readily chelate to delivery mechanisms and does not allow sufficient chemical stability of compounded drugs for many applications.
Radium-223 (Ra-223), which occurs naturally as part of the actinium chain, is absorbed by bones similar to calcium and so is useful for bone cancers, however, radium has little application to other types of cancers. A radium chloride TAT agent was recently approved by the FDA for certain bone cancer treatments.
Lead-212 and bismuth-212 of the thorium chain are theoretically useful, however, high-energy gamma emissions from daughter products such as thallium-208 make production and administration difficult.
The uranium decay chain offers no TAT candidates, largely because of the lifetime and toxicity of polonium-210.
Ac-225 and Bi-213 of the neptunium decay chain are unique and superior to the other candidates in that:
Ac-225 and Bi-213 exhibit ideal half-lives (10 days and 45 minutes respectively) and greater range of chemical stability and compatibility with delivery mechanisms and cotreatments.
Ac-225 will produce four alpha emissions, creating manifold efficacy at lower doses relative to other candidates, when internalized to the target cancer cell.
Bi-213 is preferred to Ac-225 for those instances in which the TAT agent is not to be internalized to the cancer cell, e.g., for targeting of external cell wall binding sites.
Bi-213 has been shown effective in crossing the blood-brain barrier without barrier disruption and is highly effective in targeting HIV-infected cells.
the Th-229 precursor obtained from U-233 has a 7800 year half-life and so will continue to produce Ac-225 (10 day half-life) and Bi-213 (45 minute half-life) for tens-of-thousands of years.
unlike the other decay chains, the neptunium decay chain does not produce gaseous radon during its decay, greatly simplifying production and processing.
the daughter products of Ac-225 and Bi-213 present reduced toxicity relative to daughter products of other candidate alpha-emitters.
Internalization of TAT agents with multiple alpha-emissions into the target cell is important as the daughter products can otherwise break free of the delivery mechanism in the first alpha-emission and then roam free, leading to unintended alpha-emission cell damage.
Thus, Bi-213, with a single alpha-emission, should be used when cellular internalization is not possible.
Researchers are exploring direct production of Ac-225 via linear accelerators, however, Ac-225 has a half-life of only 10-days and thus cannot be stockpiled. In contrast, production from U-233 of the parent material Th-229, with a 7800 year half-life, offers thousands of years of “stockpiled” Ac-225 and Bi-213.
Implementation of the thorium fuel cycle within LFTRs will produce U-233 and Th-229 from decay of U-233. This Th-229 will produce daughter product Ac-225 and Bi-213 for many thousands of years. Wide-scale implementation of LFTR power generation will lead to widespread of use of Ac-225 and Bi-213 to treat virtually any kind of cell for which a targeted delivery mechanism can be developed.