and Ovarian Cancer at NYU
The challenge of radiation therapy, from either an external beam or an internal emitter, is to target tumor cells while sparing normal tissue. Radioimmunotherapy, a marriage of radiation therapy and immunology, harnesses the ability to tag radiation to antibodies directed against tumor-specific antigens. The selective attachment of this complex to tumor cells focuses the delivery of radiation to a localized tumor, or allows delivery of radiation to widely disseminated tumors, such as in metastatic disease. Thus, radiolabeled immunoproteins have great promise for treating cancers, and hold the potential for further advances yet to be realized. This technique has already reached the clinic for treatment of low-grade lymphomas, but its application in other areas of oncology, especially the treatment of solid tumors, has been more challenging. At NYU we have been actively engaged in developing radioimmunotherapy for breast and ovarian cancer since 1991.
Our initial efforts in radioimmunotherapy at NYU were spurred by collaboration with Roberto Ceriani, M.D., Ph.D., of the Contra Costa Cancer Research Institute. He and his coworkers developed a panel of monoclonal antibodies that recognize antigens or tumor markers associated with breast cancer. One of these, called BrE-3, identifies a tandem repeat of a three-amino acid sequence present in breast epithelial mucin. This antigen, while present in normal breast tissue, normally is not available in amounts sufficient for antibody binding. In breast cancer cells, however, the antigen becomes accessible for binding with an antibody because of the abnormal configuration of sugars in tumor cell surface molecules. Initial investigation began by testing this antibody labeled with a diagnostic radioisotope called Indium-111 (In-111) to determine if the antibody would localize in tumors, and to study if and how much undesired localization of the antibody, or the radioisotope alone, occurred in normal organs like liver, lungs, kidneys, and bone marrow. We further examined whether this distribution of the antibody could be improved upon in patients by giving unlabeled or “cold” antibody first. This was an early, so-called Phase I, trial, where the primary goal was the detection of potential side effects of the treatment. While some antibodies alone have an effect on the tumor cells, through mobilizing cytokines, BrE-3 does not; hence, there was no potential benefit to subjects receiving this antibody without its radiolabel. This antibody was administered to nine generous and very wonderful women with metastatic breast cancer, who understood that they would not benefit individually from participation in this study, but appreciated that the knowledge gained was going to aid in the development of a new treatment for others with metastatic breast cancer. Gamma camera scanning of these patients after they had received the combination of cold and radioactive BrE-3 demonstrated that the antibody localized in 84% of the known metastases. Unexpectedly, a few lesions that were previously unsuspected were revealed. The information from the images, in combination with blood samples, was used to estimate the radiation absorbed dose that could be delivered to tumors if a therapeutic type of radioisotope was linked to the antibody instead of In-111. The same data was used to estimate the absorbed radiation dose to normal organs. Yttrium-90 (Y-90) was ultimately chosen as the therapeutic radioisotope to attach to the BrE-3 antibody; an attractive feature of Y-90 is its short- range emission, which travels only about 5 mm from where the antibody attaches. The estimated radiation dose to the tumors came close to the therapeutic levels of absorbed radiation dose delivered by more conventional external beam radiation treatments. In addition, because the BrE-3 antibody was produced from mouse cells, the antibody caused seven of the nine subjects to produce anti-BrE-3 antibodies. While this did not cause symptoms in these subjects, the production of anti-BrE-3 antibodies would preclude future treatments with BrE-3, or a similar antibody.
Figure 1. The key modes of action of topoisomerase I
(Topo-I) inhibitors. Topoisomerase I changes the degree of
supercoiling of DNA by causing single-strand breaks and religation.
Topoisomerase-1 inhibitors interfere with the cutting and
relaxation steps, resulting in an irreversible arrest of the replication
fork, and consequent formation of a double-stranded break.
The irreversible arrest of the replication fork leads to cell death.
The next phase of the investigation was the development of a treatment regimen using radiolabeled BrE-3. The study was conducted in conjunction with Sally Denardo, M.D., at the University of California Davis (UC Davis). Y-90 BrE-3 in conjunction with In-111 BrE-3 was administered to subjects with metastatic or recurrent breast cancer. In-111 BrE-3 was infused to allow visualization of antibody localization, and to estimate radiation dose delivered to tumors by In-111 and Y-90-labeled antibody. These subjects with advanced cancer had previously undergone a fairly large number of chemotherapy regimens and were considered to have relatively treatment-resistant tumors. In the UC Davis/NYU trial the maximum tolerated dose of the therapeutic antibody (Y-90 BrE-3) was about 20 mCi in this heavily pretreated group of patients. Again, two thirds of the patients developed human anti-mouse antibody or HAMA. Encouragingly, three patients showed minor and transient tumor shrinkage even at these relatively low doses of Y-90-labeled antibody.
Figure 2. Effect of 14-day continuous
administration of topotecan
in combination with Y-90 BrE-3 on
the growth of large, established
MX-1 tumors, as compared to a
nonspecific antibody. Treatments were
administered on day 21 after tumor implantation,
and animals were randomized to
receive the following treatments: untreated
control (green squares); Y-90 BrE-3 alone
(black diamonds), Y-90 BrE-3 plus topotecan
(purple stars); Y-90 MOPC (nonspecific
antibody) (red squares); Y-90 MOPC plus
topotecan (blue diamonds). Only the
combination of topotecan plus Y-90 BrE-3
produced a decline in tumor weight.
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