BioWorld International Correspondent
LONDON - A vaccine made of DNA that can produce a 50 percent cure rate in a mouse model of leukemia is expected to enter clinical trials soon as a treatment for the equivalent human disease. If successful, the discovery could bring hopes of new, more effective treatments for a range of cancers.
The approach could be applied to any type of cancer caused by reshuffled genes, otherwise known as translocations. Scientists already know the translocations responsible for about half of the myeloid and lymphoid leukemias. Some also have been found in tumors of the breast, ovary and pancreas, and in sarcomas. Some researchers predict that a proportion of other common cancers also will be found to be due to translocations.
The study in mice, carried out by researchers at King's College London with collaborators in France, Wales, England and the U.S., is groundbreaking because it is the first DNA vaccine to be directed against a cancer gene itself that has shown a therapeutic effect against active disease - unlike similar vaccines that aim to prevent recurrence.
Rose Ann Padua, principal clinical scientist at King's College London, who led the research, told BioWorld International: "This is an extremely important result. We are writing the protocol for a clinical trial at the moment and hope to have an industrial partner in place by early next year. The human clinical trials will be led by Christine Chomienne at the H pital Saint-Louis in Paris, but we intend to open the trial up across Europe as quickly as possible."
An account of the study appears in Nature Medicine, published online Oct. 19, 2003, and titled "PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia."
The type of leukemia that Padua and her collaborators have been working on is a rare disease called acute promyelocytic leukemia (APL). They chose that particular leukemia because their collaborators in Paris had already isolated the gene at the point of the translocation. In addition, a mouse model of APL was readily available from Padua's collaborator, the Nobel Laureate Michael Bishop at the University of California at San Francisco. Inducing the disease in those mice involves giving them a transplant of leukemic cells. Death normally follows after three to four weeks.
The cause of APL is a translocation that results in the fusion of two genes called PML and RARA. Other genes also play a role. People with APL are treated with all-trans retinoic acid (ATRA), a metabolite of vitamin A, which helps to induce maturation of the leukemic cells, but cannot cure the disease on its own.
Padua and her colleagues set out to investigate whether a DNA vaccine might be able to induce an immune response that could eliminate the leukemic cells. The aim is to allow cells to take up DNA, so that they will make the protein or peptide it encodes, which will then be taken up by antigen-presenting cells to trigger an immune response.
Following that principle, the group cloned a sequence of DNA spanning the fusion between the PML and RARA genes and coupled that to a fragment of tetanus toxin, which is highly immunogenic. They then injected that into the muscles of APL mice in which leukemia was well established. A control group of mice received placebo injections.
The team found that the survival of the treated group was significantly longer than the placebo group. When they added ATRA to DNA, survival was even longer.
Padua said: "If you give ATRA as monotherapy, they live to a maximum of 100 days, while with the combination of DNA vaccine and ATRA, 50 percent of them live to 300 days and probably for a lifetime as, at this point, they are fine and healthy."
Tests showed that the animals that responded well to the treatment made antibodies to the fusion protein. Padua said although the group had not been able to demonstrate the presence of cytotoxic T lymphocytes as a mechanism for killing leukemia cells, she was sure that that type of response had occurred because it was essential if a cure was to be effected.
APL is a rare leukemia, she added, but if that approach works for APL, it might be possible to apply it to all the leukemias for which the gene fusions are known. "So this study is really a proof of principle. We can make all of the fusion genes if we want," Padua said.
She predicted that it might be possible to improve the 50 percent cure rate by improving the delivery of the DNA into the muscle. One strategy, she said, might be to use electroporation or to isolate dendritic cells and introduce the DNA vaccine in culture, before reinfusing the cells.