History of RIT

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History of Radiommuntherapy

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“We must search for magic bullets. We must strike the parasites and the parasites only, if possible, and to do so, we must learn to aim with chemical substances.” So said German bacteriologist Paul Ehrlich (1854-1915) at a time when scientists had only recently learned that germs caused disease, but they certainly didn’t understand how they spread, much less how to destroy them.

Ehrlich, however, was a visionary. He envisioned chemical compounds that would go straight to disease-causing organisms at which they were aimed and destroy them. At the same time, these compounds would avoid healthy organisms and cause no harmful effect on the body. Magic bullets, he called them.

Searching for a cure for “sleeping sickness,” he instead found that compounds of arsenic were effective against syphilis, a discovery that made the dread disease curable. He called the use of chemical compounds to treat disease “chemotherapy.”

In his quest for the discovery of magic bullets – compounds that would combat specific diseases and leave all else alone – Ehrlich did not fully realize his dream, but he did win a Nobel Prize in 1908 for his studies of the immune system. He theorized that it might be possible to attach substances to antibodies which would kill tumors without harming normal cells.

It was a good theory. The body’s immune system produces antibodies, which are proteins that recognize and seek foreign substances, known as antigens. They then mark the invaders for destruction by calling other components of the immune system into action. But in order for Ehrlich’s theory to work, scientists would have to produce antibodies in the lab, an impossible task until technology caught up.

Even if antibodies could be man-made, scientists would still have to figure out which, if any, substances could be attached to them and which would be therapeutic. In the 1940's, the nuclear age was dawning, and with it, an attempt to use radiation for healing purposes. In 1946, the Atomic Energy Commission offered a short course on radioisotopes - elements that release radiation in small amounts - for medical uses. The chair of the University of Michigan's Department of Internal Medicine, Dr. William H. Beierwaltes, was one of five attendees, and he learned about a radioisotope called radioactive iodine for the study of thyroid metabolism.

Beierwaltes then set up a clinic at Michigan using radioactive iodine to detect abnormal activity in the thyroid gland and to locate tumors. In 1957, with no books available to guide clinicians on the use of radioactive elements, he co-authored and published the first: Clinical Use of Radioisotopes.

Beierwaltes successfully combined radioactive iodine, I-131, with other substances for both imaging and therapeutic effects for thyroid and adrenal disorders. He also proposed attaching radioactive elements to antibodies for the detection of cancer, but man-made antibodies were yet to be made.

That came in 1975. Working at the Medical Research Council (MRC) Laboratory for Molecular Biology in Cambridge, England, an expatriate Argentine immunologist, Cesar Milstein, Ph.D., and Swiss immunologist Georges Kohler, Ph.D., were studying how the body generated antibodies to attack foreign substances. They gathered, from mice, normal B lymphocyte cells, which produce the antibodies that recognize foreign invaders, and fused them with tumor cells, which live indefinitely. The resulting cells, called “hybridomas,” immortalized the normal B cells and produced a steady stream of identical antibodies, known as “monoclonal antibodies” because they come from only one type of cell, the hybridoma. At last, Milstein and Kohler had learned how to mass produce man-made antibodies, for which they would later receive a Nobel Prize in 1984. Their employer, however, saw no commercial potential in monoclonal antibodies and chose not to patent the idea.

Though antibodies could now be produced in great quantities in laboratories, the discovery, at first, generated little interest in the scientific community because the man-made versions lacked one critical feature of natural ones: specificity, meaning the ability to recognize, seek and attach to an antigen. Without this feature, the immune system could not be called into action to destroy the invader.

The specificity problem would be solved, in part, in Boston. In 1979, four years after Milstein and Kohler’s discovery, Lee Nadler, M.D., now senior vice president of Experimental Medicine at the Dana-Farber Cancer Institute, was an oncology fellow at Dana-Farber when he began researching lymphoma. He enlisted the help of a former classmate, Phil Stashenko, D.D.S., who had learned from Milstein and Kohler how to make antibodies because he had hoped to produce a mouthwash which would stop cavities. Nadler convinced Stashenko to show him how to produce antibodies, and together they created four, including one which they named B1, the future foundation of Bexxar.

B1 was significant because it recognized and attached to a specific protein on the surface of B cells, a protein which Nadler identified and named CD20. Scientists now had a “bull’s eye” to target. Nadler and Stashenko tried to interest several biotech companies in their antibody, but were repeatedly told there was no market for monoclonal antibodies against B-cell lymphoma. Eventually, they sold the rights to a small company called Coulter Corporation, but not before Nadler became the first person to successfully administer a monoclonal antibody to lymphoma patients.

Across the country, Ron Levy, M.D., a professor at Stanford University’s School of Medicine, believed that producing antibodies using each patient’s cells would be more effective. In 1981, Levy successfully created a custom-made antibody for a gravely-ill lymphoma patient, Phil Karr, who made a complete recovery and, according to Levy’s office, was alive and well and in his 90’s when they last spoke with him in 2006.

The scientific community noticed Phil Karr’s recovery. Levy had proven that a monoclonal antibody could potentially cure cancer. Companies formed to develop antibody-based therapies and the National Institutes of Health poured money into research. Monoclonal antibodies were suddenly touted as the “magic bullets” that could enlist the body’s own immune system and cure cancer without side effects.

Unfortunately, early monoclonal antibody therapies did not live up to their expectations. There were several problems, but the hardest to overcome was that monoclonal antibodies were made with cells from mice, and mouse-derived antibodies did not mobilize the human immune system very well. Worse, the human immune system often attacked the mouse-based antibodies, and that made people sicker.

That problem was overcome in the mid-1980’s when Dr. Greg Winter, working at the same lab where Milstein and Kohler had first discovered monoclonals, led a team which “humanized” monoclonal antibodies using part-human, part-mouse antibodies. But by that time, most companies had soured on monoclonal antibodies as a way of treating disease, and interest in further research dwindled to a handful of scientists.

Levy and his colleagues persevered, and in 1985 formed a company called Idec to develop patient-specific antibodies, but found that it was too laborious, expensive and time-consuming to make commercial use a viable option. Believing that a “one-size-fits-all” approach would be easier to produce commercially, they turned their attention to making one antibody for everyone rather than a different antibody for each person.

Meanwhile, Coulter requested permission from the FDA to allow the B1 antibody to be tested in humans, but it needed scientists to do so. A handful took up the challenge, but the approach that ultimately succeeded was developed by two University of Michigan scientists: Dr. Mark Kaminski, Director of Michigan’s Leukemia/Lymphoma Program and Dr. Richard Wahl, who had worked under Beierwaltes and who is now Director, Division of Nuclear Medicine/PET at Johns Hopkins University. Kaminski and Wahl decided not to solely rely on the B1 antibody to enlist the aid of the body’s immune system. Instead, they reasoned that the B1 antibody would be more potent against cancer if an additional substance were added to it - namely, the radioisotope iodine 131 (I-131).

Theoretically, this would create the magic bullet about which Ehrlich had dreamed, or to use a more contemporary analogy, a guided missile. The monoclonal antibody would seek the target, CD20, on the surface of the B cells, latch on, and the iodine-131 would plunge through the tumor cells, killing off the cancer only in that vicinity.

In April 1990, the first clinical trial began with 10 patients and the results exceeded anyone’s expectations. Dr. Kaminski recalls standing in the lab with Dr. Wahl looking at a CT scan of Patient #4. “This gentleman had a one-kilogram mass in his abdomen. That’s bigger than a 48-ounce steak, and it had disappeared. We had never seen anything like that. We just sort of looked at each other and nodded. We knew we were on to something very special.” Magic bullet was no longer a theory, but a reality that had the potential to cure cancer.

For the next few years, Kaminski’s team worked on finding the best delivery method and ultimately determined that the safest way was to tailor an individual dose for each patient. Continuing studies showed the treatment superior to standard chemotherapy. In approximately 20% of the patients, their disease completely disappeared for several years. Even better for patients, the duration of treatment was short and because it spared healthy cells, patients experienced none of the debilitating side effects associated with chemotherapy.

In 1995, Coulter Corporation formed Coulter Pharmaceuticals to oversee the development process of Kaminski and Wahl’s drug which by then was known as Bexxar. It was also Coulter’s job to convince the FDA that the drug was better than standard treatments, a process which would take years of regulatory savvy and determination, which was occasionally interrupted by corporate mergers and acquisitions.

In December 1998, Coulter formed a partnership with pharmaceutical company Smith Kline Beecham, a pact that gave Coulter a cash infusion and Smith Kline Beecham the chance to share in the future profits of Bexxar. Coulter subsequently sold out to Seattle-based Corixa Corp. in October 2000. Smith Kline Beecham merged with Glaxo Wellcome in December 2002, instantly creating the world’s second largest pharmaceutical company, Glaxo Smith Kline. Finally, in July 2005, Glaxo acquired Corixa, and with it, the rights to Bexxar.

Idec, meanwhile, had experienced financial problems of its own. In 1993, Idec scientists had begun working with a different monoclonal antibody with the hope that it would attach to the CD20 target on B cells and then, without the addition of a radioactive substance, enlist the body’s own immune system to destroy the cancer cells. By 1995, the company had racked up over $80 million in losses since its inception, leaving it unable to fund Phase III clinical trials of the drug that would become known as Rituxan.

Idec’s only choice was to find a rich partner. Genentech, Inc., one of the world’s largest biotechnology companies, agreed to fund further development of the drug in exchange for the majority of the profit it would generate if it earned FDA approval. In 1997, history was made when the FDA approved the drug, making it the first monoclonal antibody to be approved for use in cancer.

Idec had also begun investigating attaching a radioactive substance to its monoclonal antibody after the results of Kaminski’s work was published in the New England Journal of Medicine in 1993. Like Bexxar, the therapy was given in two doses approximately one week apart, but the therapy consisted of a dose of Rituxan followed by a different radioactive material, Yttrium-90, a combination which would become known as Zevalin. These two drugs, studied independently of each other, showed the same: patients had better results when treated with radioimmunotherapy than they did with chemotherapy.

In 2002, Idec’s merger with Biogen, Inc. created Biogen Idec, Inc., the world’s third largest biotechnology company. That same year, Zevalin became the first radioimmunotherapy treatment to be approved by the FDA for the treatment of cancer. Bexxar’s approval followed in 2003.

At last, after nearly a century of high hopes followed by dashed dreams, magic bullets – compounds that identified, targeted and destroyed diseased cells while leaving healthy ones intact – were finally perfected and approved. No doubt, Paul Ehrlich would be proud.