Seek and destroy: radioisotope cancer treatment finds and irradiates tumors.
March 1, 2016
Exposure to nuclear radiation causes cancer—and sometimes cures it. But radiation, like chemotherapy, can be an indiscriminate killer, attacking cancerous and healthy cells alike. The damage to healthy cells can be quite widespread, which is why the prospect of cancer treatment often generates apprehension nearly on par with the cancer itself.
However, a treatment called radioimmunotherapy (RIT) delivers specialized, radioactive isotopes, or radioisotopes, directly to cancerous tumors within a patient’s body. There, cell-killing radiation from the radioisotope bombards cancer cells while minimizing damage to the surrounding healthy tissue. The key to success is multi-pronged, requiring the ideal radioisotope to obliterate the tumor, a biological delivery system to get it there, and a specialized molecule that holds the radioisotope tightly within the delivery system.
RIT targets cancer cells that express a distinctive antigen on their outer surfaces. An antibody specific to that antigen is attached to the radioisotope, and when the antibody encounters its antigen, that means the medicine has reached the tumor, even if tumors are scattered all over the body. Not all cancers produce a distinctive antigen for targeting, and therefore not all cancers can be treated with RIT, but those that do include heavy hitters such as prostate cancer, colorectal cancer, melanoma (skin), leukemia (bone marrow), and non-Hodgkins lymphoma (blood). Finding suitable antibodies to deliver the radioisotopes is a major challenge, and it is likely that better antigens to target have yet to be discovered, but several successful antibodies have already been demonstrated.
Eva Birnbaum runs the Los Alamos program for isotope production and applications, and Kevin John leads the national tri-lab isotope effort, which engages the Los Alamos, Oak Ridge, and Brookhaven national laboratories to produce RIT isotopes. While other researchers work to refine the antibodies, Birnbaum and John focus on finding and demonstrating the most effective radioisotope for treatment—and then making a lot of it.
“The optimal radioisotope needs to do two almost contradictory things,” John explains. “It has to deliver a powerful dose of radiation to kill the tumor completely—without damaging healthy tissue in the immediate vicinity of the tumor and without lingering too long in the patient’s system. It has to show up, do its job, and then go away.”
Birnbaum and John believe the tri-lab team has found its winner with the isotope actinium-225, which undergoes radioactive decay by emitting an alpha particle. Being far more massive than the particles produced by any other form of radioactivity, alpha particles are released with high energy and relatively slow speed. As a result, they deliver a powerful punch in a short distance—typically only a few cell diameters—thereby affecting the tumor cells but not many of the surrounding healthy cells.
Actinium-225 also has the benefit that, after its nucleus decays by expelling an alpha particle, what’s left behind is no longer actinium-225 but francium-221, which is also an alpha emitter. So, too, are the next two decay products—four alpha particles for every atom of actinium-225. So a little goes a long way. “The four alphas are especially important,” Birnbaum says. “It’s like repeated hammer blows in the same spot. After the initial hit, each successive impact multiplies the damage.”
Additionally, actinium-225 has a half-life of just ten days—long enough that most of the administered dose has time to reach the tumor before decaying but short enough that very little of it lingers in a patient’s body in the months following treatment. (Francium and its decay products have a half-life of only minutes or seconds.) The short timescale in which the isotope’s powerful four-alpha radiation dose is concentrated and its subsequent radiological inertness are what make actinium-225 such an ideal nuclear weapon against cancer.
Because of its brief half-life, actinium-225 cannot be found in nature and must be made in a laboratory. Los Alamos and Brookhaven are doing so with their powerful proton-accelerator beams trained on a thorium target, resulting in a variety of radioisotopes, including actinium-225. Scientists then apply a series of chemistry-based purification methods to isolate the actinium from the other elements produced. It might sound straightforward, but the details matter. The targets have to be designed to withstand irradiation conditions that could otherwise melt them, and the chemistry process has to isolate highly pure actinium-225 from approximately 400 other isotopes.
RIT with actinium-225 can only become a reliable cancer-treatment option if the isotope’s production can be scaled up to meet the increasing medical demand. Indeed, actinium-225 was originally developed for clinical research at Oak Ridge around 15 years ago, but practical applications remained limited by an insufficient supply. Fortunately, tri-lab scientists have successfully demonstrated the first major steps toward a large-scale, economically viable supply of the needed isotope. They estimate that once the full production pipeline is established—an investment of 5–10 years—it will take only a few days of beam time to match the present global annual production of actinium-225. Thereafter, accelerators at Los Alamos and Brookhaven, and chemical-processing capabilities at Oak Ridge, are planning to keep pace with the growing medical need.
So will it cure, or at least treat, different cancers? To find out, the tri-lab team has been collaborating with international clinical research leaders, building on years of research using the original Oak Ridge supply of actinium-225 on cancer-cell cultures and cancer-afflicted mice. In addition, human clinical trials performed to date show great effectiveness with a variety of actinium-225-based drugs. One such drug under development to treat acute myeloid leukemia (AML), for example, has been tested on 18 patients at varying dosages and every time showed significant anti-leukemic activity with no toxicity to the patient. An expanded clinical trial is currently seeking additional AML patients to further assess the drug’s effectiveness, and several others drugs based on actinium-225 are in the development pipeline as well.
“It looks really promising right now,” Birnbaum says. “If FDA-approved clinical trials continue to pan out, then doctors can establish guidelines for actinium-225 treatments, what dosages to use, and so on. It’s a real opportunity to deliver life-saving medicine in quantities that can have a tremendous impact.”
“Through nuclear physics and chemistry,” adds John.