Hitting a Genetic Jackpot<\/strong>
\nTo 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\u2019 ability to fight tumors has generally been temporary.
\nThe 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 \u201cmemory\u201d cells that can quickly proliferate again if needed.<\/p>\nThe researchers said they were not sure which parts of their strategy made it work \u2014 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.
\nThe 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 \u2014 protein complexes that transform the cells into, in Dr. June\u2019s words, \u201cserial killers.\u201d<\/p>\n
Mr. Ludwig\u2019s disease, chronic lymphocytic leukemia is a cancer of B-cells, the part of the immune system that normally produces antibodies to fight infection. All B-cells, whether healthy or leukemic, have on their surfaces a protein called CD19. To treat patients with the disease, the researchers hoped to reprogram their T-cells to find CD19 and attack B-cells carrying it.\u00a0But which gene sequences should be used to reprogram the T-cells, from which sources? And how do you insert them?
\nVarious research groups have used different methods. Viruses are often used as carriers (or vectors) to insert DNA into other cells because that kind of genetic sabotage is exactly what viruses normally specialize in doing. To modify their patients\u2019 T-cells, Dr. June and his colleagues tried a daring approach: they used a disabled form of H.I.V.-1. They are the first ever to use H.I.V.-1 as the vector in gene therapy for cancer patients (the virus has been used in other diseases).<\/p>\n
The AIDS virus is a natural for this kind of treatment, Dr. June said, because it evolved to invade T-cells. The idea of putting any form of the AIDS virus into people sounds a bit frightening, he acknowledged, but the virus used by his team was \u201cgutted\u201d and was no longer harmful. Other researchers had altered and disabled the virus by adding DNA from humans, mice and cows, and from a virus that infects woodchucks and another that infects cows. Each bit was chosen for a particular trait, all pieced together into a vector that Dr. June called a \u201cRube Goldberg-like solution\u201d and \u201ctruly a zoo.\u201d\u00a0\u201cIt incorporates the ability of H.I.V. to infect cells but not to reproduce itself,\u201d he said.<\/p>\n
To administer the treatment, the researchers collected as many of the patients\u2019 T-cells as they could by passing their blood through a machine that removed the cells and returned the other blood components back into the patients\u2019 veins. The T-cells were exposed to the vector, which transformed them genetically, and then were frozen. Meanwhile, the patients were given chemotherapy to deplete any remaining T-cells, because the native T-cells might impede the growth of the altered ones. Finally, the T-cells were infused back into the patients.\u00a0Then, Dr. June said, \u201cThe patient becomes a bioreactor\u201d as the T-cells proliferate, pouring out chemicals called cytokines that cause fever, chills, fatigue and other flulike symptoms.<\/p>\n
The treatment wiped out all of the patients\u2019 B-cells, both healthy ones and leukemic ones, and will continue to do for as long as the new T-cells persist in the body, which could be forever (and ideally should be, to keep the leukemia at bay). The lack of B-cells means that the patients may be left vulnerable to infection, and they will need periodic infusions of a substance called intravenous immune globulin to protect them.
\nSo far, the lack of B-cells has not caused problems for Mr. Ludwig. He receives the infusions every few months. He had been receiving them even before the experimental treatment because the leukemia had already knocked out his healthy B-cells.<\/p>\n
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\u2019 activity. But they cannot be sure. It may also be that his disease was too severe.<\/p>\n
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 \u2014 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.\u00a0What the journal article did not mention was that Patient 3 was almost not treated.<\/p>\n
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 \u2014 only 14 million (\u201ca mouse dose,\u201d Dr. Porter said), versus 1 billion for Mr. Ludwig and 580 million for Patient 2. After debate, they decided to treat him anyway.
\nPatient 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, \u201cI was sure the war was on \u2014 I was sure C.L.L. cells were dying.\u201d
\nHe 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, \u201cI never imagined I would be part of the experiment.\u201d
\nWhen he told Patient 3 that he was remission, Dr. Porter said, they both had tears in their eyes.<\/p>\n
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.\u00a0She developed severe breathing trouble 15 minutes after receiving the T-cells, had to be put on a ventilator and died a few days later. Apparently, a protein target on the cancer cells was also present in her lungs, and the T-cells homed in on it.<\/p>\n
Researchers at Memorial Sloan Kettering Cancer in New York also reported a death last year in a T-cell trial for leukemia (also published in Molecular Therapy). An autopsy found that the patient had apparently died from sepsis, not from the T-cells, but because he died just four days after the infusion, the researchers said they considered the treatment a possible factor.<\/p>\n
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.
\nEven if the T-cells do not hit innocent targets, there are still risks. Proteins they release could cause a \u201ccytokine storm\u201d\u2014 high fevers, swelling, inflammation and dangerously low blood pressure \u2014 which can be fatal. Or, if the treatment rapidly kills billions of cancer cells, the debris can damage the kidney and cause other problems.<\/p>\n
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.
\n\u201cThen I think they\u2019ll jump into it,\u201d he said. \u201cMy challenge now is to do this in a larger set of patients with randomization, and to show that we have the same effects.\u201d
\nMr. Ludwig said that when entered the trial, he had no options left. Indeed, Dr. June said that Mr. Ludwig was \u201calmost dead\u201d from the leukemia, and the effort to treat him was a \u201cHail Mary.\u201d<\/p>\n
Mr. Ludwig said: \u201cI don\u2019t recall anybody saying there was going to be a remission. I don\u2019t think they were dreaming to that extent.\u201d\u00a0The trial was a Phase 1 study, meaning that its main goal was to find out whether the treatment was safe, and at what dose. Of course, doctors and patients always hope that there will be some benefit, but that was not an official endpoint.
\nMr. Ludwig thought that if the trial could buy him six months or a year, it would be worth the gamble. But even if the study did not help him, he felt it would still be worthwhile if he could help the study.
\nWhen the fevers hit, he had no idea that might be a good sign. Instead, he assumed the treatment was not working. But a few weeks later, he said that his oncologist, Dr. Alison Loren, told him, \u201cWe can\u2019t find any cancer in your bone marrow.\u201d
\nRemembering the moment, Mr. Ludwig paused and said, \u201cI got goose bumps just telling you those words.\u201d
\n\u201cI feel wonderful,\u201d Mr. Ludwig said during a recent interview. \u201cI walked 18 holes on the golf course this morning.\u201d
\nBefore the study, he was weak, suffered repeated bouts of pneumonia and was wasting away. Now, he is full of energy. He has gained 40 pounds. He and his wife bought an R.V., in which they travel with their grandson and nephew. \u201cI feel normal, like I did 10 years before I was diagnosed,\u201d Mr. Ludwig said. \u201cThis clinical trial saved my life.\u201d
\nDr. Loren said in an interview, \u201cI hate to say it in that dramatic way, but I do think it saved his life.\u201d
\nMr. Ludwig said that Dr. Loren told him and his wife something he considered profound. \u201cShe said, \u2018We don\u2019t know how long it\u2019s going to last. Enjoy every day,\u2019 \u201d Mr. Ludwig recalled.
\n\u201cThat\u2019s what we\u2019ve done ever since.\u201d
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