First RNA Vaccine Approved For Testing By NIH, FDA

June 18, 1997

DURHAM, N.C. -- The Recombinant DNA Advisory Committee of the National Institutes of Health has formally reviewed and voted to continue approval for the first RNA cancer vaccine clinical trial. The trial, involving 18 patients with breast, lung, or colorectal cancers, is under way at Duke University Medical Center.

Duke researchers and NIH officials say this is the first time RNA has beentriedas a therapeutic vaccine to fight both primary cancers as well as protect patients against recurrences. The trial was approved by the federal Food and Drug Administration inFebruary 1997.Approval by the NIH committee is required for such federally funded tests and was informally given in April. Formal approval was granted Thursday, June 12.

Previous tumor vaccines have been laboriously tailored for each patient using his or her own cancer cells, and they haven't worked well. The RNA vaccine is designed to be used broadly to treat a number of cancers in many patients. It uses dendritic immune cells common to all people.

To make the vaccine, the researchers produce mass quantities of dendritic cells and RNA that encodes for a common tumor antigen. RNA, produced by DNA, contains instructions that cells use to produce proteins. In this case, the RNA sequence directs manufacture of a common tumor antigen, CEA (carcinoembryonic antigen). This antigen alerts the immune system that an "invader"-- cancer -- is present.

The dendritic cells and RNA copies are then mixed together. The dendritic cells produce CEA antigens and display them on their surface. This vaccine is injected into patients, and the antigens signal an immune attack on the cancer cells.

"This is the first time we have considered a protocol that uses RNA as a vehicle to transfer genetic information into cells for expression," said Dr. Tom Shih, biotechnology program adviser to the RAC. That strategy plus using "purified, isolated dendritic cells, which is also novel, seems a better, improved way of presenting antigens," he said.

The Duke researchers already have published results of an animal study using the RNA vaccine. The report, in the August 1996 issue of the Journal of Experimental Medicine, showed the vaccine dramatically reduced spread of lung cancer in mice and protected them from developing new cancer. "It produced a remarkable protective immunity, the best we've seen," said Duke's Dr. Eli Gilboa, who led the study.

"This may be the tool we've all been seeking, a `Superman' vaccine that many people can use for the predominant killer cancers," said Dr. H. Kim Lyerly, clinical director of the Gene and Cellular Therapeutics Center at Duke.

The trial represents the newest way to use immunotherapy -- employing the body's own immune system -- to fight cancer. The dendritic cells alert immune system "killer T" cells that foreign tissue has invaded the body. Although scientists have known that these rare cells are crucial to a successful immune system response, technology has only recently developed that can exponentially boost the comparatively few dendritic cells a patient has available to "naturally" fend off a disease. In the face of cancer, that natural response is weak, but employing millions of "pumped up" dendritic cells can elicit a very strong immune response, Lyerly said.

"Traditionally, we have believed that tumor cells stimulated killer T cells directly, but now we understand that the dendritic cell is the vital intermediary player," he said. "Dendritic cells `eat' the antigens, then display them on their surface, which stimulates production of killer immune cells." The Duke vaccine is also novel in the way it genetically modifies these dendritic cells, researchers said. It uses RNA that "codes" for CEA, found in a number of cancers. This RNA is then duplicated millions of times, and mixed with the dendritic cells.

The dendritic cells take up the RNA, which they use to produce and display CEA. Injected into a patient, millions of these dendritic cells should produce an immune system attack on the cancer, Lyerly said.

Using RNA may eliminate the problem of having to tailor a vaccine for each individual patient because of their specific immunity "fingerprint," Lyerly said. Not only is that process laborious, but many patients in remission do not have enough "tumor load" from which to extract enough cancer cells.

"The advantage of RNA is that it can be used for all immunity types and can be taken from a single cancer cell," he said. "It's better than a DNA vaccine because we have eliminated a step. DNA vaccines need to produce RNA which then prompts the manufacture of proteins."To date, researchers said no toxicity has been seen in patients during the ongoing phase 1 stage of the trial, which is designed to test safety. Duke is expected to start phase 2 testing of the vaccine's ability to elicit an immune response later this year.
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Duke University

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