WASHINGTONMonoclonal antibodies are the basis of many diagnostic tests, but now are catching on as therapy as well, said Neil Bander, MD, surgical director, Urologic Oncology Program, Cornell University and New York Presbyterian Hospital, New York. This particular type of approach has now been validated clinically and is being used to treat patients with various types of cancer, Dr. Bander said at the Kidney Cancer Association Annual Convention.
Monoclonal antibodies (MoAbs) already approved include treatments for breast cancer and non-Hodgkins lymphoma [rituximab (Rituxan)]. Another is in the pipeline: Bexxar is under FDA review on fast-track status, he said. It is expected to become the first approved radiolabeled MoAb therapeutic.
The MoAb edrecolomab (Panorex, Centocor), approved for adjuvant colon cancer treatment in Germany, is in phase III testing in the United States. About one quarter of all of the drugs in late-stage clinical trials in the area of cancer are monoclonal antibodies, he said.
Dr. Bander and his colleagues are developing MoAb treatments for kidney cancer. One uses the G250 antibody to target carbonic anhydrase 9, which is not present in normal kidneys but is expressed in clear cell renal carcinomas. The clear cell variation represents 85% to 90% of all kidney cancers, he said.
In clinical trials several years ago, Dr. Banders team showed that G250 was excellent at being able to target kidney tumor sites, while avoiding normal tissues. Some 150 patients have received the antibody, he said, and wherever the tumor site iskidney, bone, liver, lung, etcwe can get antibody to the site.
However, in early trials, the researchers were limited to giving the antibody in a single dose because it was mouse-derived and patients immune systems mounted a quick reaction. Using genetic engineering, researchers were able to convert the mouse version of G250 to a version that is at least partially human. So far, none of the patients to whom it was given have developed an adverse immune reaction, he said, and the antibody targets just as well as the original antibody. We are now in a mode where we are giving multiple doses of the antibody.
Two ongoing phase I trials, one in Holland and one in New York, are using the G250 antibody carrying 131-iodine in kidney cancer patients. In the Dutch trial, patients receive a high dose of the radioactive agent; in New York, patients are given up to 27 lower doses.
The New York trial, a collaboration between Cornell-New York Presbyterian and Memorial Sloan-Kettering Cancer Center (with C. Divgi, MD, as principal investigator), will last until the end of the year, at which time a phase II trial will begin, and all of the patients will receive the maximum tolerated dose. So far, patients have experienced no significant toxicity, Dr. Bander said.
A second approach targets prostate-specific membrane antigen (PSMA). We and others fortuitously found that in addition to being present in prostate cancers, PSMA is expressed in the blood supply to other tumor types, Dr. Bander said. In a recent paper (S. Chang et al), Dr. Banders team reported that in 65 tissue specimens from 17 kinds of cancer (including renal cancer), the blood supply was positive for PSMA in 96% of the samples. Normal vessels were negative.
The antibody may be an important approach because kidney cancers are among the most vascular cancers known, he said. The size of the tumor would present no hindrance because, regardless of size, it would have a blood supply.
The antibody could be used with a thrombogenic agent to induce clots in the tumors blood vessels, he said, or a cytotoxic drug or isotope could be attached to the antibody to kill blood vessel tissue. A third approach would be to induce a blood vessel leak so that conventional cytotoxic drugs would leak into the tumor more readily than they would into normal tissues. The mouse version of the PSMA antibody is in phase I clinical trials for prostate cancer, while phase I trials of the new human version are slated to begin by early October.
We need to build on our ability to target the tumor by adding other mechanisms that would lead to the destruction of cancer cells, Dr. Bander said. If the success that we are seeing in other cancers is any indication, I feel very optimistic about being able to translate this approach to success in patients with kidney cancer over the next few years.