The latest and most promising treatment for end-stage melanoma begins by emptying the patient's immune system of nearly all its pathogen-slaying T lymphocytes.
This seemingly contrarian therapeutic strategy aims at giving the space normally occupied by those all-purpose T cells elbow room to accommodate highly specialized, high-potency anti-melanoma T cells.
Sciencexpress released online Sept. 19, 2002, calls the shots in its article titled "Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes." The paper's senior author is immunologist/oncologist Steven Rosenberg, chief of surgery at the National Cancer Institute in Bethesda, Md.
"We've been able to accomplish something we've been trying to do for 20 years," Rosenberg told BioWorld Today. "That is, we raised very high levels of antitumor lymphocytes in 13 melanoma patients. This experimental adoptive transfer approach," he continued, "has shown promising results in patients with metastatic melanoma who have not responded to standard treatment. Our treatment resulted in at least 50 percent tumor shrinkage in six of the 13. In four additional patients, some cancer growths disappeared.
"This therapy takes advantage of the immune system's ability to deliver a specially targeted assault on an unwanted invader, and helps boost that assault by multiplying the number of immune cells involved inside the patient's body. Unlike many other cancer experiments that are done on mice, this study was done on human patients. We removed parts of their tumors, which contained relatively small amounts of antitumor T cells, and grew those cells in culture until they had multiplied approximately 1,000 times. To be able to do something as complex as this in humans, where every person is different and every tumor varies, has been quite difficult," Rosenberg commented.
"With this approach, we've been able to get 90 percent - in one patient, 97 percent - of all the killer lymphocytes," he recounted." Most of the CD8 T cells in their blood reacted against their melanoma, and the cancer went away. These T cells activated against melanoma became the major component in patients' immune systems. They persisted for several months, destroying metastases throughout the body. The ability to do this in a human, to convert almost a whole immune system to fight a specific cancer antigen is, I think, unique.
"We used two differences - innovations - compared to what we'd done before," Rosenberg explained. "First, we eliminated the patient's own immune system, and second, replaced it with a highly selected immune system, using techniques for growing antitumor cells.
"All 13 of the patients had metastatic melanoma, for which they received surgical resections, aggressive chemotherapy and high-dose interleukin-2, which stimulates the growth of T cells in the body. IL-2 is the only known anticancer curative treatment. With interleukin-2 if you have a complete response, 80 percent of those are durable out to 15 years. But with this treatment, we've only followed them for two years."
Two-Year Box Score: Six Cures, Four Mixed
"Having failed all these treatments," Rosenberg pointed out, "these were patients in the end stages of their disease. We treated them with our new adoptive therapy, and when we could achieve these persistent effects, we saw good objective cancer regressions. That was true in six of the 13 patients, and another four had mixed responses. Certain tumors shrank, while others did not.
"Of the 13," Rosenberg went on, "the first patient we treated, in September of 2000, was a boy 19 years old, who had a kilogram of tumors. He was bed-ridden on around-the-clock narcotics. We treated him two years ago, and today this young man is completely normal and disease-free. So our experimental adoptive transfer approach worked.
"Patients nine and 10 had almost 100 percent disappearance of their tumors," he said. "Just a few residual nodules that we took out for study. Those two men, in their mid-50s, experienced complex, positive reactions to the NCI adoptive therapy regimen. Patient nine showed a 95 percent regression of his melanoma, results that were still ongoing eight months later. And 99 percent of patient 10's tumors had disappeared seven months after the treatment. We are currently working to improve the therapy," Rosenberg observed, "so that a greater proportion of patients respond the way patients nine and 10 did.
"Most of these 13 patients reacted against two unique melanoma antigens that we discovered. One is MART [short for Melanoma Antigen Recognized by T Cells], the other GP100. Patients nine and 10 incurred side effects in reaction to the MART antigen. It's involved in producing pigmentation to the body's normal melanin protein, which colors hair, skin and the eye's iris. They developed a form of autoimmunity in which their T cells reacted to MART antigens in healthy tissue. Thus, patient nine developed vitiligo - white patches on his arms and swatches of hair."
Small Price For Transient Eye Irritation
"Patient 10 came up with uveitis, inflammation in the iris. Steroid drops cleared up this condition successfully. We didn't observe any autoimmune disorders more serious than vitiligo and uveitis," Rosenberg said, adding, "If the therapy works, it's a small price for getting rid of your cancer."
He foresees extension of adoptive transfer to other therapies. "The next antigen we're probably going to attack," he suggested, "is ESO, an antigen expressed on a quarter of breast cancers and variant prostate cancers, as well as three-quarters of small-cell lung cancers. But that won't be for another few months."
"We haven't done anything with viral diseases," Rosenberg said, "but, of course, T cells are the main defense against viral infection, and you can easily raise T cells against HIV antigens. We'll be presenting our adoptive transfer to the NCI's AIDS group here next week."
"We're working around the clock," Rosenberg observed, "to try to make our approach better. We're treating additional melanoma patients - four more since the initial 13. We have ideas how to improve it, and intend moving on to other diseases. We've already instituted some improvements and are actively studying the cells that we gave, to figure out what their important characteristics are.
"To the best of my knowledge, the NIH is applying for a patent on this adoptive transfer approach. A challenge to the biotech industry," he concluded, "will be finding ways to make cell therapy practical."