Researchers at the Johns Hopkins Oncology Center and the Department of Urology have confirmed successful activation of patients' immune systems in one of the first human trials of a genetically engineered cancer vaccine. Their findings, reported in the April 15, 1997, issue of Cancer Research, are the result of more than eight years of laboratory, animal and preclinical human studies.
In the study, the researchers gave the vaccine to eighteen patients with metastatic or widespread kidney cancer to test safety and effectiveness in humans. One patient, whose tumor continued to grow and spread to his lungs after surgery, obtained a substantial remission for seven months after receiving the vaccine. The rest all had measurable immune responses, but not remissions. Many patients died from their disease within the first year of the trial.
"The purpose of this study was to determine whether the vaccine could cause an immune response in patients and be administered safely, and we proved that it could," says Fray Marshall, M.D., professor of urology and oncology and senior author of the study. "The patients we treated had extremely advanced disease so we did not expect to cure anybody." He cautions patients and their families that there is much more research to do before the treatment is widely available.
"There have been too many promises made in the study of gene therapy, without much delivery. We proceeded slowly and cautiously, verifying and re-verifying the findings over this eight-year period. We believe these results demonstrate that the vaccine has clinical potential." The next step, he adds, is to test the vaccine in high risk patients with less widespread disease, following them over a longer period of time. Those studies will begin this year in Japan, he says.
In the randomized, double-blinded study, one group of patients received a tumor vaccine with a potent immune system activating gene (GM-CSF) inserted into the cells. The other group received a tumor vaccine without the inserted gene. The vaccine therapy began with surgical removal of the kidney tumor. The researchers collected a small sample of cancer cells from the tumor and radiated them to stop growth. In the gene vaccine group, the researchers used an inactive virus, called a retrovirus, to carry the GM-CSF gene into the cancer cells. These genetically engineered cells were then injected under the skin of the patient. Once inside the body, the GM-CSF gene supercharges the immune system, causing it to seek and destroy cancer cells throughout the body. Although patients receiving both types of tumor vaccines showed immune responses, patients with the gene vaccine also showed activation of immune cells called eosinophils, believed to be important in antitumor immunity.
Unlike chemotherapy, the vaccine therapy caused few side effects. Some patients experienced inflammation and skin rashes at the injection site, which is actually an indication of immune response, the researchers say.
Though the Hopkins team is optimistic about these preliminary results, they believe it will take several years to fully test the vaccine. "This is one more piece of the puzzle, but it is not a magic bullet," says Jonathan Simons, M.D., assistant professor of oncology and urology and principal investigator. "We are like the Wright brothers at Kitty Hawk. We've proven that we can fly, but it will take more research before we cross the Atlantic," he says.
The Hopkins researchers believe the vaccine could be useful in the treatment of a variety of solid tumors, in combination with surgery, chemotherapy and radiation therapy. They are currently testing it in small clinical trials in prostate and pancreatic cancers.
The genetic vaccine was first developed and tested in animal models in 1989 by Drew Pardoll, M.D., Ph.D., Elizabeth Jaffee, M.D., and Hyam Levitsky, M.D. at Hopkins. Glenn Dranoff, M.D., of Dana Farber Cancer Institute, and Richard Mulligan, M.D., of Harvard University, identified the immune system activating GM-CSF gene and developed the gene transfer system. Methods for the production of vaccines from human tumors were developed by Jaffee and Somatix Therapy Corporation. The human trials--the first gene therapy trials at Hopkins--were approved by the National Institutes of Health in 1993 and were sponsored and developed by Somatix and the entire research team.
Kidney cancer strikes more than 30,000 people in the U.S. each year, killing more than 10,000. Once disease spreads, it frequently becomes unresponsive to treatment.
In addition to Marshall, Simons, Pardoll, Jaffee, Levitsky, Dranoff, and Mulligan, other participants in this research include Christine Weber, R.N., William G. Nelson, M.D., Ph.D., Michael A. Carducci, M.D., Christy C. Finn, Karen M. Hauda, Lisa A. Beck, M.D., Albert H. Owens, Jr., M.D., and Steven Piantadosi, M.D., Ph.D. of Johns Hopkins; Audrey J. Lazenby, M.D. of the University of Alabama at Birmingham; Kristen M. Leiferman, M.D. of the Mayo Clinic, Rochester, Minn.; and Lawrence Cohen, M.D. and Shirley M. Clift, Ph.D. of Somatix Therapy Corporation, Alameda, CA.
Partial funding for this study was provided by Somatix Therapy Corporation. Under an agreement between Somatix and the Johns Hopkins University, Drew Pardoll, M.D., Ph.D. is entitled to a share of sales royalty received by the University from Somatix. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.