Radiata | Radioimmunotherapy for Breast and Ovarian Cancer at NYU (page 2)

By Elissa Kramer and Leonard Liebes

Figure 3. Effects of combination treatment of capecitabine (Xeloda) with Y-90 BrE-3. The combination of Xeloda and BrE-3 was more effective than each agent given singly. Starting the combination treatment with a Xeloda treatment alone for 24 hours was more effective than starting with Y-90 BrE-3. XEL-BrE-3 capecitabine was started 24 hours prior to radioimmunotherapy. BrE-3-XEL animals received radioimmunotherapy 24 hours prior to institution of capecitabine treatment. For Combo animals received simultaneous radioimmunotherapy and capecitabine.

Results of these initial studies revealed two perplexing issues, which became the basis of a two-pronged approach for further investigations. First, the development of anti-BrE-3 antibody in our patients potentially would prevent repeat treatment by radioimmunoconjugates. Addressing this problem, Dr. Ceriani went back to his laboratory group and successfully engineered a humanized form of BrE-3 with more than 90% similarity to human IgG, retaining only the part of the mouse-derived antibody that attached to the tumor-specific sequence of the amino acids, thereby diminishing the formation of anti-BrE-3 antibodies. An unusual feature of this humanized antibody was that the affinity of huBrE-3 for the antigen increased by three times over the murine (mouse) antibody’s affinity for the tumor antigen.

Based on promising results from other clinical trials ongoing at NYU under the guidance of Howard Hochster, M.D., of the NYU Division of Oncology, the utility of adding a topoisomerase I inhibitor, topotecan, to radioimmunotherapy was examined. The topoisomerase I enzyme works in the repair of single-stranded DNA breaks, is often more abundant in tumor cells than in normal organs, and sensitizes tissue, especially tumor tissue, to radiation (FIGURE 1). Dr. Hochster had shown an improved therapeutic index for low-dose continuous infusion of topotecan compared to other schedules; that is, when topotecan was given with this low-dose schedule, patients experienced fewer nonhematologic side effects. Furthermore, in order to take advantage of the radiosensitization by topotecan, a trial combining external beam radiation and topotecan was being tested in lung cancer at NYU. We thought the prolonged infusion of topotecan combined with the prolonged, low-dose radiation of radioimmunotherapy might provide matching of antitumor effects and improved radiosensitization. Also, exposure to radiation is known to cause synchronization of cells in S-phase, the portion of the cell cycle where they are most sensitive to topoisomerase I inhibitors like topotecan. We thus theorized that the combination might be synergistic on many levels.

Returning to the laboratory at NYU, working with Philip Furmanski, Ph.D., then Chair of the Department of Biology, testing began on in vitro and in vivo combination therapeutic approaches that might improve the delivery of radioimmunoconjugate to the tumor, or might increase the efficacy of the radiation at the tumor site. Initially, based on Dr. Furmanski’s observation that Interleukin-1 (IL-1) increased tumor vessel permeability, this cytokine was administered with Y-90-labeled BrE-3 to nude mice bearing MX-1 human breast cancer xenografts on their flank, testing the theory that IL-1 enhanced vessel permeability might increase access of radioimmunoconjugate to the tumor. Tumor growth in animals receiving the combination treatment was compared to untreated animals, and to animals treated with either of the single agents. Disappointingly, the combination offered no advantage over the Y-90 BrE-3 alone.

Figure 4. In-111 huBrE-3 distribution in a patient with a history of a right breast tumor. Whole-body scan shows increased uptake of the In-111 huBrE-3 at the site of the tumor. A radioactive standard is observed at the bottom of the image.

Initial in vitro studies using MCF7 human breast cancer cells confirmed the markedly increased cytotoxicity of the combination of topotecan and Y-90 BrE-3 antibody. When the radiolabeled antibody/topotecan regimen was tested against cells that did not have the antigen on their surface, the additive effect of the radiation was lost without the specific binding of the Y-90 BrE-3. The same treatment combination was then tested in another model, MX-1 human mammary tumorbearing nude mice. Y-90 huBrE-3 (200 uCi) was administered as a single intraperitoneal injection, and topotecan was administered at its maximally tolerated dose by implanting small diffusion pumps to simulate a prolonged intravenous infusion. In addition, the question of whether the specificity of the antibody mattered was examined by substituting a nonspecific antibody, MOPC, for the BrE-3 in the treatment of some of the mice. As a solitary treatment both the topotecan and the radiolabeled antibody slowed tumor growth; however, with the combination treatment the tumors were eradicated for the entire 12-week observation period. The specificity of BrE-3 was clearly necessary for the treatment effect since the Y-90 MOPC-treated tumors showed almost no response (FIGURE 2).

Simultaneously, In-111 humanized BrE-3 was being studied in patients with metastatic or recurrent breast cancer at NYU. Again addressed was whether the antibody localized in tumors, whether subjects made an anti-BrE-3 antibody, and the potential for delivering radiation to tumors was estimated. This time only 76% of the known tumors were visualized, a decline likely attributable to the prolonged retention of the humanized antibody in the blood and normal organs, which obscured the tumor activity. More importantly, patients did not make antibody to the humanized BrE-3 and the potential for delivering radiation to tumors was not less than with the mouse form.

<< Previous Page
>> Next Page
Page: 1 2 3