NEWS

Scientists Recall Progress and Promise of Translational Research

Charles Marwick

In the past 50 years, there has been major growth in biomedical knowledge. But there has been a gap between the findings from the laboratory bench and their application to the patient.

One of the pioneers in bridging this gap is Thomas A. Waldmann, M.D., chief of the Metabolism Branch at the National Cancer Institute. Noting what he describes as the "bewilderingly rapid progress in biomedical research," Waldmann recalls that when he was in medical school in the 1950s, the immune system was largely a closed book. The function of the lymphocyte was unknown as was the difference between T and B cells, retroviruses had not been discovered, receptors for cells had not been discovered. But today "questions that could not even be asked 4 decades ago when I joined the [National Institutes of Health] in 1956 have been definitively answered. Yet without translational research, all this information doesn’t do the patient much good."



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Dr. Thomas A. Waldmann

 
There is a need to translate these fundamental insights into new approaches for prevention, diagnosis, and treatment of human disease for the benefit of patients, and this can only be addressed by patient-oriented clinical research, he said in an interview. "One needs to exploit, to convert, to translate basic insights from the laboratory first into a new understanding of human disease; secondly, to new approaches to prevent human disease; thirdly, to new ways of diagnosing disease; and, fourthly, to therapy that is effective."

In fact, it takes much more, as Waldmann makes clear. Certainly it starts with the patient, testing hypotheses concerning the pathogenesis of disease, defining the functional defects on tissues from the patient, and developing and evaluating novel therapeutic agents in small-scale but carefully conceived clinical trials. But translating the results of these studies into an agent that can be widely used means seeing that these findings are taken to large-scale clinical studies that, because of logistics and cost, can only be undertaken by large pharmaceutical concerns or the government.

As an example, Waldmann related the story of how an immunosuppressive agent to prevent organ graft rejection was developed in the clinic, seen through extensive trials and ultimately, in 1997, approved by the U.S. Food and Drug Administration.

It started in 1980 with the preparation of a mouse monoclonal antibody to one of the three chains of the interleukin 2 (IL-2) receptor, an anti T-cell activator popularly known as anti-tac. It was the first antibody to be made to a cytokine receptor. Initially this isn’t translational, Waldmann pointed out. "It’s about the structure of a growth factor receptor, how it signals."

Then came the recognition that, while the resting cells of normal individuals don’t express this receptor, it is expressed by activated cells such as leukemic T cells, T cells involved in autoimmune disease, or T cells involved in graft rejection. Studies with anti-tac showed that not only did it block the IL-2 receptor, but it prevented the division of these activated T cells. "So here was a difference between the cells of patients with disease, with leukemia, and the cells in normal individuals. It helped in diagnosing leukemias," Waldmann said. The research was beginning to be translated to patients.

Then preclinical animal studies with this mouse antibody were started. One example was the control of graft rejection in monkeys. "We showed that without any toxicity we could prolong the survival of the graft."

It was then applied clinically to a form of leukemia, adult T-cell leukemia, which is caused by a retrovirus known as a human T-cell lymphotropic virus (HTLV-1). The virus makes cells divide by forcing them to make IL-2 and the IL-2 receptor. The virus was isolated at the NIH, and it was the first retrovirus known to cause a human disease. The cells of a patient with adult T-cell leukemia were used to make anti-tac.

"So we began to treat patients with anti-tac. In the first group of 19 patients with this adult T-cell leukemia, for which there is no chemotherapy that benefits their survival, six of 19 went into remission, two completely and two more are still living 10 years later," Waldmann said.

But because this anti-tac was a mouse antibody, it had a short half-life that limited its efficacy. There was a need to humanize it. To achieve this Waldmann and his colleagues joined forces with a biotechnology company, Protein Design Labs in Palo Alto, Calif., a company started by Cary Queen, Ph.D., himself a former NCI researcher. The group retained the essential function of the antibody but armed it with human immunoglobulin. The result, Waldmann noted, was much longer survival of the molecule in humans: It has a 20-day half-life instead of 2 days, it is active against human cells, and it is virtually nonimmunogenic, it does not raise antibodies to itself that might eliminate it.

However, Protein Design does not have the facilities or the resources to do the necessary large clinical studies to show efficacy, so the next step was to interest industry, "Big Pharm," as Waldmann puts it. They approached Hoffmann-La Roche, in Nutley, N.J. The company mounted a 36-center study involving 535 patients and, in 1997 the agent, which Roche called called Zenapax, was approved by the FDA for preventing human kidney transplant rejection.

This, said Waldmann, is one example of translational research. "To have a nice paper in a good journal is wonderful, but what you want is something that people can actually use. We started with a basic observation, then, after animal studies, it moved to the clinic, then to patients in small phase I trials and then to phase II trials, and then to phase III trials done by a large company which can provide the data needed for FDA approval."

This work has now been extended to T-cell–mediated uveitis, an autoimmune blinding disease. "We have shown with Robert Nussenblatt of the National Eye Institute that one can eliminate the use of such agents as steroids and cyclosporin A and do at least as well if not better just by using anti-tac every 3 weeks," Waldmann said.

In short a whole panoply of autoimmune diseases such as multiple sclerosis, sarcoid, and systemic lupus erythematosus are potential candidates for humanized anti-tac therapy.

This concept of translational research and the results of the work at the Metabolism Branch has not gone unnoticed. In 1992 the NCI introduced a new program called Specialized Programs of Research Excellence (SPORE) specifically to encourage scientific approaches focused on translational research but using the extramural funding mechanisms, which are flexible enough to allow the development of pilot projects and to test new technologies. Initial results of this program, which now include studies into breast, prostate, gastrointestinal and ovarian cancers, have been promising, said Alan Rabson, M.D., NCI’s deputy director.

Waldmann noted that the Technology Transfer Act of 1986 encouraged NIH to have its findings go ultimately to industry and so benefit the public. "I think it’s important for academia and the NIH to be a part of this endeavor," he said. "At NIH there is a richness and an ability to do this type of translational research. We have highly skilled basic scientists, we have the resources to make agents, and to test them clinically. You need to be able to do the basic science, gain insight about the disease, develop the drugs, and apply them to one’s own patients. The goal is translating the things that help in the therapy of human disease."


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