Mar. 27, 1998 DURHAM, N.C. -- Researchers at Duke University Medical Center reported Tuesday that they have taken a significant step forward in the laboratory in demonstrating that a person's own immune system may be the best weapon they have to fight cancer.
The concoction they are testing is an unusual form of gene therapy. Its ultimate goal is to wipe out cancer cells and then keep the body protected from new cancer growth but much work remains to be completed before such an agent could be available.
The potential therapy, which already is being tested in cancer patients, just requires a sample of blood to extract white immune cells and a few cancer cells from which to distill the genetic material RNA. Mixed together, the tumor RNA produces everything the immune system needs to launch an attack on the cancer.
Laboratory proof of the cancer vaccine concept is published in the April issue of Nature Biotechnology. The research, supported by the National Institutes of Health and the CapCure Foundation, found that the vaccine stimulated an immediate and sustained assault on human cells targeted for destruction in 15 out of 18 test tube experiments.
"This is a very powerful response compared to what has been seen in other cancer vaccines," said the scientist who led the study, Eli Gilboa, research director of the Center for Genetic and Cellular Therapies at Duke. "It's a pre-clinical study that shows the vaccine can work very effectively in human cells although it has yet to be proved effective in humans," added the study's senior investigator, Smita Nair. "The vaccine is expected to be in tests for the next several years."
Usually, cancer vaccines require large loads of tumor from individual patients from which researchers extract protein antigens, which they then use to prime that patient's immune system. Not all cancers express the same antigens, so this method requires analysis of the proteins each patient's tumor expresses. The Duke cancer vaccine skips that step because, by inserting tumor RNA directly into immune cells, the RNA can produce the proteins specific to each patient's cancer. Furthermore, unlike proteins, tumor RNA can be amplified many times over, so only a small amount of tumor is needed from a patient.
Such a vaccine can be produced in an assembly line fashion, and in fact, a new cell processing laboratory at Duke is now gearing up to produce mass quantities of this vaccine. "While we need the RNA from a patient, we do not need to determine the antigen it expresses, or a patient's immune fingerprint, and we don't need a lot of tumor material," Nair said.
The center, under the leadership of surgeon Dr. H. Kim Lyerly, will be making vaccines for about 100 patients to be enrolled in the second phase of a clinical trial, testing the vaccine for breast, lung and colorectal cancers. The first phase of the trial has shown that the vaccine is not only safe but can produce immune responses in cancer patients.
Additionally, Lyerly has received federal Food and Drug Administration approval to start another phase 1 trial, using RNA extracted from colon cancer cells.
The Duke cancer vaccine harnesses two biological powerhouses: the potency of rare immune cells, called dendritic cells, whose job it is seek out foreign tissue and alert the immune system, and RNA, the agent that transfers information from a cell's genome to the protein synthesis machinery of the cell.
Dendritic cells circulate throughout the body, looking for "foreign" protein, such as that produced by invading bacteria. The dendritic cells then "eat" the antigens, to display them on their own cell surface. This show of a foreign antigen signals a strong response from immune system fighters known as "killer T" cells which move out from the spleen and lymph nodes to attack the invader.
Cancer cells also produce a variety of atypical proteins, Gilboa said, but tumor cells have evolved ways of effectively hiding these proteins from surveying dendritic cells. In this way, cancer is virtually invisible to the immune system, which can only mount a very weak response at best.
The Duke researchers have devised a way to engineer dendritic cells to display tumor antigens. Now they are testing whether these cells will signal an effective immune response. They reasoned that the best way to get cancer antigens into dendritic cells is to have those proteins produced within the dendritic cell itself. To do this they isolate and remove RNA from tumor cells and infuse it into dendritic cells. RNA thus "transfected" into a host cell uses that cell's machinery to make tumor proteins, which are then chopped up and displayed on the cell surface.
Mass quantities of the vaccine can be produced for each patient using a special cell processing laboratory. The vaccine is then injected into the patient to elicit an immune system against cancer in their body.
Using a patient's own RNA to produce red-flag antigens leaps a major hurdle that has halted other attempts at devising an effective and widely applicable cancer vaccine, Gilboa said. It produces antigens that are specific to that individual's cancer. Many cancer immunotherapies may fail because they rely upon a single specific protein antigen that may or may not be found in that patient's tumor cells, Gilboa said. "It's difficult to find a protein fragment that works well for all patients, so the idea is to have a patient's own RNA make its cancer antigens."
In some vaccine trials, researchers have had to isolate antigens directly from tumors of cancer patients ? which is expensive and problematic, Gilboa said. This new strategy allows large quantities of vaccine to be produced from a small amount of tumor taken from a patient. Duke researchers have the technology to isolate dendritic cells from blood and then grow mass quantities of them.
The RNA from cancer cells also can be reproduced millions of times using current technology. The batch of RNA is then transfused into the mass of dendritic cells and injected into patients. "The problem has been that most cancer patients don't have enough tumor tissue in which to isolate enough antigen for vaccination," Gilboa said. "With this method, we just need a small quantity of cells."
To prove that the concept worked, the researchers refined the vaccine several times, as outlined in the study report. They tested the vaccine using RNA that coded for a specific antigen known as CEA (carcinoembryonic antigen). CEA is often expressed in breast, lung and colorectal cancer. They mixed this RNA sequence with dendritic cells and the CEA was produced and displayed on the dendritic cell. A strong immune response was seen when this concoction was exposed to the patient's cancer cells in a test tube. This type of vaccine is what is currently being tested in 18 patients, all of whom expressed CEA antigens.
The final test will be to see if "transfecting" the entire RNA from tumor cells into dendritic cells will produce a response, whether or not the patient's cancer expressed the CEA antigen. Their assumption is that the RNA will produce many antigens specific to that patient, and will induce potent immune responses that will eradicate the cancer. This vaccine, when tested in animals and in laboratory studies in a test tube was effective, said center researcher David Boczkowski, a contributing author. This is the type of vaccine that will be tested in the new clinical trial of colorectal cancer patients
Other researchers contributing to the clinical study included Dr. Michael Morse and Dr. Yuping Deng.
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