Falsehoods, it's said, come in three degrees of severity - lies, damn lies and statistics.
A specially tooled monoclonal antibody has seemingly made liars of statisticians at the American Cancer Society. They predict that in this year 2002, 17,000 new cases of brain and other nervous system tumors will be diagnosed, with deaths projected at 13,100. These grim forecasts have not changed much during the last 10 years, despite medical advancements. In fact, the death rate has been slowly increasing. But times may be a-changin'.
An article in the December 2002 issue of the American Journal of Clinical Oncology (AJCO) bends these mortality forecasts in a slightly more favorable direction. The paper is titled: "Radioiodinated (I-125) monoclonal antibody 425 in the treatment of high grade glioma patients: Ten-year synopsis of a novel treatment." Its senior author is clinical oncologist Luther Brady, at Drexel University (formerly Hahnemann U.) in Philadelphia.
"The standard surgical treatment and radiation therapy have improved the outlook for the patient," Brady told BioWorld Today. "It's a dismal outlook relative to glioblastoma multiforme, where essentially all of those patients are dead in 12 to 18 months. And we have 50 percent of them alive at 22 to 26 months," he continued, "and we even have three out of that group alive five years or longer. All of these patients have had their tumors reviewed by neuropathologists, so it's not a question of the pathology.
"The less aggressive tumors," Brady went on, "the astrocytomas with anaplastic foci [AAF], essentially all of those patients are dead by two or three years, and we have 50 percent of them alive at almost five years, and eight of them alive five years and longer. Remarkably, 50 percent of them were alive after 56 months, with ages ranging from 11 to 73 years. So the message of this AJCO article, I think" Brady said, "is that we've clearly shifted the potential for long-term survival to a longer expectancy than anything that's been achieved thus far by the one-two-three of surgery, radiation and chemotherapy regimens."
The monoclonal antibody (MAb) in question was designed and developed by the Wistar Institute, designated by the National Institutes of Health's National Cancer Institute as one of only eight Comprehensive Cancer Centers in the U.S.
Recipe For Double-Whammy Antibody
"This antibody was generated at Wistar in the late 1970s," recalled Maryle Melnicoff, the Institute's director of business development - including patent licensing. "My role is seeing that our technology gets commercialized," she observed. "The antibody was produced by immunizing mice with human tumor cells. In that period in the 70s and 80s," Melnicoff told BioWorld Today, "we had the original patent for the use of MAbs to identify and treat cancer." That patent was subsequently licensed to Centocor Inc. "The present MAb 425," she explained, "is a murine Immunoglobulin2a antibody produced by a hybridoma cell line derived from the fusion of spleen cells of Balb/c mice immunized with the A431 human epidermoid carcinoma cell line, and mouse myeloma cell line. It was radiolabeled with iodine isotope 125 coupled to 3.2 milligrams of the antibody," she continued. "This iodination was not as a marker or tracer but a source of therapeutic ionizing radiation targeted right to the tumor. Epidermal growth factor," Melnicoff pointed out, "is a fairly well recognized target, an antigen that is up-regulated in a lot of tumor cells. So the mode of action is that the antibody is going to bind specifically to the up-regulated EGF receptor [EGF-R] on the tumor cells, and presumably the rest of it would be cleared out of the body."
Melnicoff pointed out that "basically, this antibody can have a broad application for any epithelial-cell tumor type. It is also in another clinical trial by our second licensee. This particular AJCO study in collaboration with Drexel," she noted, "was not done for FDA approval. Our current licensee may elect to use some of the Phase II data, but the study was conducted as a research project rather than specifically to seek FDA approval. It doesn't have a control group, so it's not a blinded study in that regard. It looked first for toxicity, then efficacy, then survival."
Brady summed up his results from the first 10 years of the ongoing clinical trial, begun in 1987. It follows up on 180 patients who, after surgery (biopsy and debulking the tumor) plus radiation therapy for their brain tumors received injections of I-125/Mab 425 as outpatients. One hundred eighteen patients with glioblastoma multiforme (GBM) and 55 with astrocytomas comprised the high-grade glioma population analyzed in the trial. "Preliminary data suggest," Brady went on, "that patients who undergo extensive surgery may survive longer. This emphasizes the importance of intensive medical management as a means to increase patient survival when the disease progresses."
"For patients with high-grade gliomas of the brain," he noted, "EGF-R expression can be an order of magnitude or greater than the surrounding normal tissue. The administration of I-125/Mab 425 as adjunctive antitumor therapy, with intensive medical management demonstrates a significant increase in median survival, and should be considered a therapeutic regimen for the management of patients with high-grade gliomas."
Six-Center Phase III Clinical Trial "Imminent"
"Our plan," he went on, "is to translate these data into a randomized controlled Phase III clinical trial. We are now working on a protocol for such a study against surgery, radiation, and chemotherapy versus surgery, radiation and the antibody therapy. We're really pretty close to launching that program. My hope and expectancy is to get all of the accruals within the next couple of months anyway. We have been talking to five other centers that would be involved in the protocol or would be a part of one of the National Cooperative study groups."
Brady added: "This represents one of the growing number of protocol studies looking at the usefulness of antibodies in cancer treatment including other tumor sites such as lymphomas, breast cancer, colon cancer, et cetera. It's just another brick in the wall we're building," he concluded, "the wall against cancer."