DURHAM, N.C. -- In initial clinical trials, Duke University Medical Center researchers have significantly extended the survival of patients suffering the most malignant brain cancers by injecting antibodies directly into the cancerous region. The antibodies carry cancer-killing radioactive Iodine-131 to the tumor cells.
Although the treatment is not a cure for the cancer, called glioblastoma multiforme (GBM), the researchers believe it will constitute a powerful new weapon to fight such cancers and could replace external beam radiation therapy for the tumors.
The researchers also have begun initial tests using another radioactive isotope, Astatine-211, that has been a far more efficient cancer-killer in laboratory studies. Also, Astatine's radioactive properties would enable patients to avoid isolation after treatment, enhancing their quality of life and reducing medical costs.
The researchers published their results in the May 28 issue of the Journal of Clinical Oncology. First author of the paper is Darell Bigner, who is the Edwin L. Jones Jr. and Lucille French Jones Cancer Research Professor of Pathology (Neuropathology), and deputy director of the Duke Comprehensive Cancer Center. The research is sponsored by the National Institutes of Health, the American Cancer Society and the U.S. Department of Energy.
"GBM is an extremely lethal cancer, with no significant advances in therapy in the last two decades," Bigner said in an interview. "Almost all patients die within two years, even with the best efforts using surgery, external beam therapy and chemotherapy.
"However, we believe that these initial studies represent a proof of concept of this technique, and offer the potential for significant improvement in survival time for patients with this aggressive cancer."
According to Bigner, the Duke treatment, which was done on 34 patients, began with the careful surgical removal of a patient's main tumor mass by Allan Friedman, professor of surgery and chief of the division of neurosurgery.
While such surgery usually excises the main tumor mass, it cannot remove the cancer cells around the tumor that have infiltrated normal brain tissue. Nor can the surgeon remove tissue too close to sensitive parts of the brain, like motor or speech areas.
To create a way of attacking those cells, after removing the tumor mass Friedman surgically constructed a sealed "resection cavity" at the site and inserted a catheter into the cavity.
In the next phase, a monoclonal antibody called 81C6 prepared in Bigner's lab was chemically linked to Iodine-131 by Professor of Radiology Michael Zalutsky and his colleagues. Professor of Radiology Edward Coleman then injected the preparation into the resection cavities in the patients' brains, where the monoclonal antibody carrying the radioactive Iodine homed in on the tumor cells and killed them.
Other groups have attempted the same direct injection technique with little success, said Bigner, but they used different radioactive isotopes, different antibodies and less effective surgical techniques to seal the cavities from the circulating cerebrospinal fluid.
Antibodies are proteins produced by the immune system that recognize foreign substances called antigens and attach to them to help destroy them. Monoclonal antibodies such as 81C6 are mass-produced in the laboratory from a single clone, enabling researchers to obtain large quantities of pure antibody.
While monoclonal antibodies have been used to carry anti-cancer drugs, toxins and radioactive substances into other cancers, they have not been successfully used in brain tumors. Such efforts have been thwarted by the blood-brain barrier, higher pressure within tumors that excludes the material, a lack of antibody specificity and the breakdown of the radioactive substance before it can reach the tumor.
The 81C6 antibody presents clear advantages, said Bigner, because it targets a tumor antigen called tenascin that is almost uniquely found in cancers of the brain, skin, lung and breast. Tenascin is found around cancer cells and tumor blood vessels, where antibodies can bind firmly to it to deliver their cancer-killing payload.
"We found that the 81C6 treatments delivered a very high radiation dose to the margins of the resection cavity, penetrating about an inch into the area of normal brain that was infiltrated with tumor cells," said Bigner. "But beyond that region, there was a very sharp fall-off in the radiation dose, minimizing the damage to normal brain that is often found with external beam therapy."
Although the newly reported Phase I clinical trial aimed only at establishing the maximum tolerated dosage for the treatment, the researchers found they had achieved a median survival time for the patients of about 56 weeks, twice that of patients who have received other treatments after surgery.
The researchers found they could administer up to 100 millicuries of the radioactive iodine -- sufficient for effective treatment -- before they saw any evidence of neurological toxicity.
The new radioactive antibody therapy will become an important element of a multi-treatment strategy for bringing to bay the aggressive cancer, which strikes some 12,000 adults a year, said Professor of Neuro-oncology Henry Friedman. "GBMs tend to show up as a central mass on MRI scans, but there are also undetected malignant cells disseminated throughout the brain, even in their early stages.
"Our treatment aims at achieving local control of the central mass using surgery and the monoclonal antibodies. Then we use chemotherapy to enhance that local control, and to focus on controlling the disseminated disease.
"With the monoclonal antibodies, it appears that we have been able to control the local disease better than with other methods, although our results will need confirmation in randomized trials," said Henry Friedman.
The current study included only patients with recurrent cancers or those with refractory disease. However, applying the treatment to patients newly diagnosed with GBM will likely significantly improve its effectiveness, said Henry Friedman.
The researchers also plan to broaden the treatment by including patients who have not undergone surgery to remove tumor mass and create a sealed cavity. In such patients, the researchers will infuse the radioactively labeled antibodies directly into the smaller tumors.
Bigner and his colleagues also plan to improve the monoclonal antibody, creating versions that remain stable longer in the body, or are smaller molecules that might penetrate tumors better.
However, the research team has already initiated the most significant advance in the treatment -- using Astatine-211 as the radioisotope carried by the antibody. Astatine-211 has a half-life of only seven hours, versus 193 hours for iodine, meaning that it disappears from the body quicker.
Also, Astatine-211 emits alpha particles that travel through only a few cells, instead of the more penetrating beta particles emitted by Iodine-131. In addition, Astatine-211 produces much lower levels of radioactivity outside the body, eliminating the need for patients to be isolated in a lead-lined room for the week or so required after Iodine treatment.
However, the most important therapeutic advantage of Astatine-211 is its far greater efficiency as a killer of cancer cells, with only one or two radioactive atoms needed to kill a cell. Preliminary results from clinical trials show that only a few millicuries of Astatine-211 on the antibody can deliver a radiation dose to tumors the equivalent of that delivered by 100 millicuries of Iodine-131, said the researchers.
According to Henry Friedman, both Iodine-131 and Astatine-211 will likely find a role in future cancer therapies, with Astatine-211 effectively attacking the thin layer of highly cancerous cells immediately surrounding the resection cavity, and Iodine used to penetrate more broadly. Such treatments could eliminate the need for beam radiation, he said.
Although the potential advantages of Astatine-211 for cancer therapy have been known for some time, the lack of efficient methods for its production and attachment to antibodies have prevented clinical investigations, said the Duke medical center researchers.
However, recent advances by Zalutsky and his colleagues have now made it possible to use Astatine-211 antibodies in patients.
Working with the Napa, California, firm Cyclotron Inc., Zalutsky developed a metal target that could be inserted directly into the Duke medical center cyclotron. When bombarded by the cyclotron beam, the bismuth-coated plate efficiently generated large amounts of the astatine isotope, which could be rapidly isolated.
"We get a yield about 10 times higher than with conventional methods," Zalutsky said. "And now can produce enough Astatine-211 to treat several patients in just a few hours.
"Combined with our methods for attaching Astatine-211 to antibodies that can be quickly and easily carried out by a technician, we can now evaluate the effectiveness of Astatine-211 antibodies for treating cancer patients."
Zalutsky and his colleagues also have developed methods of attaching the Astatine to the antibody that can be quickly and easily carried out by a technician.
However, Bigner and the other Duke scientists emphasized that carrying out the new treatment requires a carefully coordinated multidisciplinary team of researchers and surgeons. Thus, he foresees that the treatment will remain largely a province of major cancer treatment centers.
Other co-authors of the Journal of Clinical Oncology paper, besides Bigner, Zalutsky, Coleman, Allan Friedman and Henry Friedman, are Mark Brown, Gamal Akabani, Wade Thorstad, Roger McLendon, Sandra Bigner, Xiao-Guang Zhao, Charles Pegram, Carol Wikstrand, James Herndon, Nicholas Vick, Nina Paleologos, Ilkan Cokgor and James Provenzale.
Journal
Journal of Clinical Oncology