Scientists Report First Responses in Cancer Patients to A Recombinant Immunotoxin

National Cancer Institute
Monday, 8 November 1999

Over the last decade, scientists have produced many recombinant immunotoxins – small, bioengineered antibodies linked to a toxin – as part of an experimental strategy to directly target and deliver deadly poisons to tumor cells. However, despite the great promise of this approach, there have been no published reports of cancer patients responding to a recombinant immunotoxin.

That is, until now. In the Nov. 15 issue of the journal Blood*, a team of scientists from the National Cancer Institute (NCI) reports that four out of four patients with hairy cell leukemia, an uncommon cancer of immune B cells, had "major responses" to a recombinant immunotoxin called LMB-2. All of the patients previously had not responded to standard treatments for the cancer, including chemotherapy and removal of the spleen.

Robert Kreitman, M.D., lead author on the study, said one patient in this early stage clinical trial had a complete remission after treatment with the immunotoxin and has not relapsed 16 months later. For the three other patients, Kreitman and colleagues observed partial responses, detecting a 98 percent to 99.8 percent reduction in malignant circulating cells. All of the side effects were reversible and usually lasted less than a week. These included fever, nausea, vomiting, and rash. "This offers a proof of principle that recombinant immunotoxins will one day have an important role in treating cancer," said Ira Pastan, M.D., senior author on the paper. "But there is still much work to be done to maximize their potential for cancer patients."

For the last 20 years, immunotoxins have been one of the great new ideas on the horizon in cancer research. However, scientists say generating viable immunotoxins has proved over the years to be a technically tall task.

They note that in early human studies, many of the first immunotoxins were too large to effectively penetrate into tumors and were expensive to produce. As a result, researchers frequently had to go back to the drawing board and design new techniques to produce smaller, more compact antibodies and toxins that would be better suited to infiltrate tumors.

There also have been the more standard clinical obstacles in developing a new treatment. Some patients mounted immune responses against the immunotoxin, neutralizing the treatment before it ever reached the tumor cells. Another problem was chronic side effects, such as vascular leak syndrome, that prohibited patients from receiving continued treatment. But in the current study, Kreitman et al. take an important step forward in showing that these problems can be overcome. The NCI scientists say they evaluated a second-generation recombinant immunotoxin, known as LMB-2. Whereas antibodies naturally have four large chains, a source of their bulkiness, LMB-2 consists of only the most essential, functional parts from two of the chains. The regions of the antibody gene encoding these essential parts are spliced together and expressed in a bacterial vector as a smaller, but stable, single-chain antibody. Fused to the chain is a potent, genetically trimmed down exotoxin from the bacterium Pseudomonas aeruginosa.

Pastan said LMB-2 is programmed to seek out tumor cells that display a protein called CD25 on their surface. "The immunotoxin binds to CD25, then it is internalized into the tumor cell," said Pastan. "The exotoxin enters into the cell, where it is activated and eventually stops protein synthesis in the cell. This causes the tumor cell to commit suicide."

To further evaluate the immunotoxin, the NCI scientists began treating people with various hematologic cancers, including four adult patients with refractory hairy cell leukemia that tested positive for the CD25 antigen. Because this was a Phase I study, which is designed primarily to evaluate the safety of a new therapy, all four patients received slightly different doses of LMB-2. The immunotoxin was administered every other day for three doses by intravenous injection.

After just one cycle of treatment, all patients had major reductions in circulating malignant cells, either within days or shortly thereafter. For three patients, the scientists characterized the response as "partial," defined, in part, as at least a 50 percent reduction in tumor cell count for at least four weeks. For the fourth patient, although very minimal residual tumor cells are present, the researchers said they are satisfied that the response was complete.

"What is especially exciting about these findings is that our group already has new-and-improved, third and fourth generation immunotoxins in the pipeline for further development," said Kreitman.

Hairy cell leukemia makes up 2 percent of all leukemias. Though most patients can control the disease with chemotherapy, up to 25 percent of patients with hairy cell leukemia become resistant to treatment, indicating the need for alternative treatments for the cancer.

For more information, or to contact National Cancer Institute, see their website at: www.cancer.gov