and Ovarian Cancer at NYU
Figure 5. The degree of huBrE-3 immunohistochemical staining of representative
ovarian tumor tissue. (Above, left to right) None, Low, Medium, and Highly staining ovarian tumor
(100x magnification). Staining shows huBrE-3 uptake in cellular membrane, reflecting the degree of
antibody specificity. Quantitative image analysis of these four groups defines tumor histopathology categories
that can be applied to entry criteria to segregate subjects for a clinical study.
These results prompted us to propose a clinical trial of combined continuous infusion topotecan with a single intravenous administration of Y-90 MXDTPA BrE-3 in patients with breast cancer. There were still challenging problems to solve. First, the toxicity of both radioimmunotherapy and topotecan are primarily hematologic, a combination therefore causing a marked depression in bone marrow activity and blood cell counts. Second, it was becoming clear from the very low response rates in clinical trials of topotecan in metastatic and recurrent breast cancer that topotecan was simply not the drug to use in breast cancer.
To address the issue of hematologic toxicity, two approaches were available: first, one could give much higher doses of the Y-90 huBrE-3 than most patients’ bone marrow could tolerate, and simply give them back blood-forming cells after the treatment, to lessen the toxicity of these high-radiation doses. This was the approach taken at the University of Colorado, where patients were given well over 100 mCi of Y-90 huBrE-3, followed by a transfusion a few weeks later of their own previously harvested stem cells.
At NYU another approach was chosen, that of using a different chemotherapeutic agent which, in combination with the radiotherapy, would not cause severe bone marrow depression. Chemotherapies with known efficacy in breast cancer were initially tested. One new oral chemotherapeutic agent, capecitabine, had recently become available, and by itself caused breast metastases to shrink in up to 40% of patients. When absorbed, capecitabine is converted to 5-FU, a chemotherapeutic drug used to radiosensitize tumors, with established efficacy in the treatment of breast cancer. Even more interesting, the last enzyme in the conversion pathway from capecitabine to 5-FU tends to be present in larger amounts in many tumors compared to normal tissues, making it somewhat tumor specific. Furthermore, radiation was known to cause an increase in that enzyme. These details suggested that the combination of Y-90 huBrE-3-delivered radiation and oral capecitabine could be synergistic. 5-FU was tested in cells with the radiolabeled antibody, resulting in a 38% increase in the number of cells killed by this combination therapy. The next test was a single dose of Y-90 huBrE-3 administered in combination with two weeks of orally administered capecitabine in our mice (FIGURE 3). This combination was found to eradicate the tumor, but only when the capecitabine was started 24 hours before the radioimmunotherapy was given. Based on these findings, supported by a grant from the Chemotherapy Foundation, an early clinical trial in patients with recurrent or metastatic breast cancer has been initiated. Our plan is to start with a therapeutic level of capecitabine, known to be effective in treating breast cancer, and then add increasing amounts of Y-90 huBrE3. We are starting with a small radiation dose (5 mCi) and have treated one patient safely so far (FIGURE 4). The radiation dose will be incrementally increased, to maximize the allowable amount of Y-90 huBrE-3 without causing intolerable depressions in subjects’ blood counts.
In ovarian cancer work which has not yet reached the clinical testing stage, prospects for the treatment of ovarian cancer by adding Y-90 huBrE-3 to the therapy regimen are generating great excitement. Early on we tested huBrE-3 antibody against 50 samples of ovarian cancers obtained at the time of surgery. Herman Yee, M.D., a member of the NYU Department of Pathology, confirmed that 95% of these tumors expressed the substance which causes huBrE-3 antibody binding (FIGURE 5).
Ovarian cancer, a tumor which is difficult to detect in its early stages, presents a particular challenge since most patients have metastatic disease when they are diagnosed. Even though chemotherapy can be effective, many tumors do recur, highlighting the need for more effective treatments. Franco Muggia, M.D., Director of Medical Oncology at New York University, has long been a proponent of intraperitoneal treatment for ovarian cancer. He and his colleagues have demonstrated encouraging responses in the intraperitoneal administration of topotecan and cisplatin in patients with metastatic ovarian cancer. With funding from the Department of Defense, we went back to the laboratory and tested topotecan first in cells and then in growing tumors combined with Y-90 huBrE-3. In both instances the combination therapy was more effective than either topotecan or Y-90 huBrE-3 alone, and the continuous infusion method for topotecan was the most effective approach in combination therapy (FIGURE 6A). We have just begun to explore the mechanisms for this synergy, but have already learned that with topotecan, more Y-90 huBrE-3 enters the tumor, thereby increasing the radiation dose administered for every mCi of Y-90 given. In further investigation, cisplatin, a different chemotherapeutic agent, was then added to the regimen for treating these experimental tumors. With the double combination of chemotherapies, and the Y-90 huBrE-3, enhanced eradication of ovarian tumors in the experimental model was demonstrated (FIGURE 6B). The results of this combined modality approach offer future promise for patients with ovarian cancer who do not respond completely to conventional therapy, or whose tumors recur after initial chemotherapy. With these patients in mind, we are designing a clinical trial to test these prospects.
Figure 6A. Treatment of transplanted SKOV3
ovarian tumors by continuous infusion
topotecan (1 mg/kg/day) over two weeks in
combination with a single intraperitoneal
dose of Y-90 BrE-3. Significant inhibition of tumor
growth was found by topotecan treatment alone
compared to untreated animals, and also by
topotecan + Y-90 BrE-3 compared to either single
agent or untreated controls.
Figure 6B. Treatment of SKOV3 ovarian
tumors by intraperitoneal weekly doses of
topotecan for two weeks in combination with
a single intraperitoneal dose of Y-90 BrE-3.
Each treatment showed reduced average tumor weight
compared to the untreated group. In addition, the
combination of topotecan, cisplatin, and Y-90 huBrE-3
had a greater effect (decreased tumor weight) than either
single-agent treatment alone.
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