Genetically Engineered Cells Can Transform Immune Cells Into Tumor Fighters In Humans

A team of researchers has genetically engineered normal immune cells to become specialized tumor fighters, demonstrating for the first time that these engineered cells can persist in the body and shrink large tumors in humans.

Two of the 17 people with advanced melanoma who received the experimental treatment saw their tumors shrink and were declared clinically free of disease more than a year and half after the therapy began, Steven A. Rosenberg of the National Cancer Institute and his colleagues report in a study published online by the journal Science at the Science Express website on 31 August. Science and Science Express are published by AAAS, the nonprofit science society.

So far, the therapy has only been used in this small group of melanoma patients, but Rosenberg says his team has demonstrated ways to engineer similar immune cells in the laboratory that would attack more common tumors such as breast, lung and liver cancers.

The technique developed by the Science researchers “represents the first time that gene manipulations have been shown to cause tumor regression in humans,” Rosenberg says.

“This work marks an important next step in harnessing the power of our immune systems to fight cancer. The publication of this paper should help highlight the significant work to a broad spectrum of people, including patients, clinicians and those involved in basic research,” said Stephen Simpson, Science’s senior editor, immunology.

Rosenberg and colleagues have a long history of looking for ways to boost the body’s natural immune defenses against cancer, focusing specifically on T cells, a special type of immune cell that can recognize and attack “foreign” cells such as those found in tumors. In their earlier experiments, the researchers removed tumor-fighting T cells from melanoma patients and multiplied these cells in the laboratory. After using chemotherapy to clear out a patient’s old T cells, the researchers repopulated the patients’ immune systems with these new fighters.

But some people with melanoma don’t have these tumor-fighting T cells, and in other types of cancer it’s difficult to identify T cells that attack tumors, Rosenberg says, so the researchers had to come up with a way to create these types of T cells from scratch.

T cells carry a receptor protein on their surface that recognizes specific molecules called antigens on tumor cells. The receptor’s genetic makeup determines the antigen types that the T cell can recognize, so that some cells contain genes that make a T cell receptor that homes in on melanoma cells, while other cells contain genes that make a T cell receptor that recognizes breast or lung cancer cells.

With this in mind, Rosenberg and colleagues created tumor fighters by removing normal T cells from people with advanced metastatic melanoma, genetically engineering these normal cells to carry the receptor that recognizes melanoma cells and returning these “re-armed” cells to rebuild the patients’ immune systems.

“We can take normal lymphocytes from patients and convert them to tumor-reactive cells,” Rosenberg says, adding that the engineered cells could be tailored to fight tumors other than melanoma. “We’ve identified T cell receptors that will now recognize common cancers,” he notes.

The newly engineered T cells showed signs of persistence in 15 of the patients in the study, making up at least 10 percent of their circulating T cells for at least two months after treatment. New T cell levels were higher in the two people whose tumors shrunk noticeably with the treatment.

Rosenberg and colleagues are now searching for ways to fine-tune the treatment so that greater numbers of the engineered T cells will survive and continue expressing their new receptor genes, since their expression does seem to wane over time, the Science researchers found.

Devising new ways to insert the receptor genes in the T cells, usually encoded in a retrovirus, has been one of the most challenging aspects of the treatment, Rosenberg says. “It’s a lot of sophisticated molecular biology and most of our work is going into designing retroviruses, putting genes into cells efficiently and getting them expressed.”

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“Cancer Regression In Patients Mediated by Transfer of Genetically Engineered Lymphocytes” by R.A. Morgan et al.

Rosenberg’s co-authors are Richard A. Morgan, Mark E. Dudley, John R. Wunderlich, Marybeth S. Hughes, James C. Yang, Richard M. Sherry, Richard E. Royal, Suzanne L. Topalian, Udai S. Kammula, Nicholas P. Restifo, Zhili Zheng, Azam Nahvi, Christiaan R. de Vries, Linda J. Rogers-Freezer and Sharon A. Mavroukakis of the National Cancer Institute.

The study was supported by the National Cancer Institute.

The American Association for the Advancement of Science (AAAS) is the world’s largest general scientific society, and publisher of the journal, Science (www.sciencemag.org). AAAS was founded in 1848, and serves some 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of one million. The non-profit AAAS (www.aaas.org) is open to all and fulfills its mission to “advance science and serve society” through initiatives in science policy; international programs; science education; and more. For the latest research news, log onto EurekAlert!, www.eurekalert.org, the premier science-news Web site, a service of AAAS.

Erbitux approved in countries all over the world, thanks to a British-led study, is able to arrest growth and spread of aggressive tumours and causes cancer cell death. Oncologists say it has produced some of the longest survival rates ever seen in mCRC. But a draft appraisal issued June 2006 by NICE, the UK’s National Institute For Clinical Excellence, indicated Erbitux and another targeted drug Avastin (bevacuzimab) will be turned down for use in Britain on cost-effectiveness grounds. A final decision will be made in November.

Dr Oliver Kisker, Medical Director of Merck KGaA which makes Erbitux said this week: “The UK is the only country in Europe where the drug has been approved but is not available. In all other European countries, specialists can use the drug and get the cost reimbursed.”

Speaking in Barcelona during the 8th World Congress in Gastrointestinal Cancer, Professor Heinz-Josef Lenz said the trial that led to Erbitux being approved all over the world was led by Professor David Cunningham in Britain. “Originally the trial had the number 007 but to the British that means James Bond so the trial in known as BOND.” The trial showed Erbitux could overturn a cancer’s power to resist chemotherapy and increase survival. “No other drugs have shown that,” he commented. Since BOND, Erbitux has gone on to produce astounding results in other trials and is now being tested in much larger numbers of patients, he said.

Shrinking liver tumours become respectable

A major benefit to emerge is the ability of the drug to shrink liver metastases in around a quarter of patients with advanced disease to the point where they can be resected, ie, surgically removed. Resecting liver secondaries gives patients the best chance of survival, he added. “New combinations of Erbitux and the chemotherapy regimen FOLFOX 4 are expected to translate to a cure for an increasing number of patients. Studies are now examining the role of Erbitux as a first and second-line treatment. But in the US, the drug is already used as second-line therapy in specialised centres.”

Also speaking in Barcelona, Tim Maughan, Professor of Cancer Studies at Cardiff University said: “Where tumours in the liver are resectable, long term follow up shows that half are still alive after five years and almost a third are still alive a decade later.” If tumours in the liver become resectable after Erbitux and chemotherapy, more patients will become survivors, he explained. Three studies show that about 23 or 24 per cent of previously inoperable patients become candidates for surgery. “This is recent data and it opens up the hope of a radically different long-term outcome than we have come to expect. The ball park in mCRC treatment is shifting raipidly. We can get long-term survival benefits without compromising quality of life.”

Professor Maughan is one of few cancer specialists likely to see any benefits of Erbitux in Britain because he practices in Wales. Until the NICE decision is finalised, Wales is permitting its gastro-intestinal cancer specialists to prescribe the drug strictly within its licensed indication for patients who have failed chemotherapy with irinotecan.

Professor Maughan happens also to be leading from Wales, the UK Medical Research Council’s independently-financed massive study of Erbitux and chemotherapy. The COIN study is comparing continuous and intermittent chemotherapy with and without Erbitux in over 2000 patients.

Any discoveries made by the COIN study are unlikely to be enjoyed by the UK, the country that paid for the study via its sponsorship of the MRC, however.

As Neil Brookes, CEO of the UK colon cancer charity “Bowel Cancer UK” commented: “It is ironic that while the UK has been in the forefront of developing both Erbitux and Avastin, including in clinical trials, it looks as if we will, once again, be at the very back of the queue when it comes to being able to make them available to patients. It is also very hard not to be angry and cynical when NICE appears to be making its decisions on the basis of financial expediency rather than clinical efficacy.”

By Olwen Glynn Owen

ERBITUX (cetuximab)