Science

At first, nothing happened. But after 10 days, hell broke loose in his hospital room. He began shaking with chills. His temperature shot up. His blood pressure shot down. He became so ill that doctors moved him into intensive care and warned that he might die. His family gathered at the hospital, fearing the worst.  A few weeks later, the fevers were gone. And so was the leukemia.  There was no trace of it anywhere — no leukemic cells in his blood or bone marrow, no more bulging lymph nodes on his CT scan. His doctors calculated that the treatment had killed off two pounds of cancer cells. 

A year later, Mr. Ludwig is still in complete remission. Before, there were days when he could barely get out of bed; now, he plays golf and does yard work. "I have my life back," he said. Mr. Ludwig's doctors have not claimed that he is cured — it is too soon to tell — nor have they declared victory over leukemia on the basis of this experiment, which involved only three patients. The research, they say, has far to go; the treatment is still experimental, not available outside of studies.  But scientists say the treatment that helped Mr. Ludwig, described recently in The New England Journal of Medicine and Science Translational Medicine, may signify a turning point in the long struggle to develop effective gene therapies against cancer. And not just for leukemia patients: other cancers may also be vulnerable to this novel approach — which employs a disabled form of H.I.V.-1, the virus that causes AIDS, to carry cancer-fighting genes into the patients' T-cells. In essence, the team is using gene therapy to accomplish something that researchers have hoped to do for decades: train a person's own immune system to kill cancer cells. Two other patients have undergone the experimental treatment. One had a partial remission: his disease lessened but did not go away completely. Another had a complete remission. All three had had advanced chronic lymphocytic leukemia and had run out of chemotherapy options. Usually, the only hope for a remission in such cases is a bone-marrow transplant, but these patients were not candidates for it.

Dr. Carl June, who led the research and directs translational medicine in the Abramson Cancer Center at the University of Pennsylvania, said that the results stunned even him and his colleagues, Dr. David L. Porter, Bruce Levine and Michael Kalos. They had hoped to see some benefit but had not dared dream of complete, prolonged remissions. Indeed, when Mr. Ludwig began running fevers, the doctors did not realize at first that it was a sign that his T-cells were engaged in a furious battle with his cancer. Other experts in the field said the results were a major advance. "It's great work," said Dr. Walter J. Urba of the Providence Cancer Center and Earle A. Chiles Research Institute in Portland, Ore. He called the patients' recoveries remarkable, exciting and significant. "I feel very positive about this new technology. Conceptually, it's very, very big." Dr. Urba said he thought the approach would ultimately be used against other types of cancer as well as leukemia and lymphoma. But he cautioned, "For patients today, we're not there yet." And he added the usual scientific caveat: To be considered valid, the results must be repeated in more patients, and by other research teams. Dr. June called the techniques "a harvest of the information from the molecular biology revolution over the past two decades."

Hitting a Genetic Jackpot

To make T-cells search out and destroy cancer, researchers must equip them to do several tasks: recognize the cancer, attack it, multiply, and live on inside the patient. A number of research groups have been trying to do this, but the T-cells they engineered could not accomplish all the tasks. As a result, the cells' ability to fight tumors has generally been temporary. The University of Pennsylvania team seems to have hit all the targets at once. Inside the patients, the T-cells modified by the researchers multiplied to 1,000 to 10,000 times the number infused, wiped out the cancer and then gradually diminished, leaving a population of "memory" cells that can quickly proliferate again if needed. The researchers said they were not sure which parts of their strategy made it work — special cell-culturing techniques, the use of H.I.V.-1 to carry new genes into the T-cells, or the particular pieces of DNA that they selected to reprogram the T-cells. The concept of doctoring T-cells genetically was first developed in the 1980s by Dr. Zelig Eshhar at the Weizmann Institute of Science in Rehovot, Israel. It involves adding gene sequences from different sources to enable the T-cells to produce what researchers call chimeric antigen receptors, or CARs — protein complexes that transform the cells into, in Dr. June's words, "serial killers."

One thing that is not clear is why Patient 1 and Patient 3 had complete remissions, and Patient 2 did not. The researchers said that when Patient 2 developed chills and fever, he was treated with steroids at another hospital, and the drugs may have halted the T-cells' activity. But they cannot be sure. It may also be that his disease was too severe. The researchers wrote an entire scientific article about Patient 3, which was published in The New England Journal of Medicine. Like the other patients, he also ran fevers and felt ill, but the reaction took longer to set in, and he also developed kidney and liver trouble — a sign of tumor lysis syndrome, a condition that occurs when large numbers of cancer cells die off and dump their contents, which can clog the kidneys. He was given drugs to prevent kidney damage. He had a complete remission.

What the journal article did not mention was that Patient 3 was almost not treated. Because of his illness and some production problems, the researchers said, they could not produce anywhere near as many altered T-cells for him as they had for the other two patients — only 14 million ("a mouse dose," Dr. Porter said), versus 1 billion for Mr. Ludwig and 580 million for Patient 2. After debate, they decided to treat him anyway.

Patient 3 declined to be interviewed, but he wrote anonymously about his experience for the University of Pennsylvania Web site. When he developed chills and a fever, he said, "I was sure the war was on — I was sure C.L.L. cells were dying." He wrote that he was a scientist, and that when he was young had dreamed of someday making a discovery that would benefit mankind. But, he concluded, "I never imagined I would be part of the experiment." When he told Patient 3 that he was remission, Dr. Porter said, they both had tears in their eyes.

Not Without Danger to Patients

While promising, the new techniques developed by the University of Pennsylvania researchers are not without danger to patients. Engineered T-cells have attacked healthy tissue in patients at other centers. Such a reaction killed a 39-year-old woman with advanced colon cancer in a study at the National Cancer Institute, researchers there reported last year in the journal Molecular Therapy.  Dr. June said his team hopes to use T-cells against solid tumors, including some that are very hard to treat, like mesothelioma and ovarian and pancreatic cancer. But possible adverse reactions are a real concern, he said, noting that one of the protein targets on the tumor cells is also found on membranes that line the chest and abdomen. T-cell attacks could cause serious inflammation in those membranes and mimic lupus, a serious autoimmune disease. Even if the T-cells do not hit innocent targets, there are still risks. Proteins they release could cause a "cytokine storm"— high fevers, swelling, inflammation and dangerously low blood pressure — which can be fatal. Or, if the treatment rapidly kills billions of cancer cells, the debris can damage the kidney and cause other problems. Even if the new T-cell treatment proves to work, the drug industry will be needed to mass produce it. But Dr. June said the research is being done only at universities, not at drug companies. For the drug industry to take interest, he said, there will have to be overwhelming proof that the treatment is far better than existing ones. "Then I think they'll jump into it," he said. "My challenge now is to do this in a larger set of patients with randomization, and to show that we have the same effects."

At Penn, our Comprehensive Cancer Programs provide the full spectrum of treatment and follow-up care. The goal of any cancer treatment is to eliminate the cancer and prevent or reduce the chance of recurrence in the future. The various types of cancer therapy may be used alone or in combinations, depending on the type of cancer as well as other factors, such as stage of tumor, and your medical condition. Your physicians will recommend the best combination of treatments for your individual condition and assist in making the choice that's right for you.

Visit the University of Pennsylvania's Abramson Cancer Center Web Site for more information on their innovative research for attacking cancer tumors.