Johns Hopkins cancer researchers report the successful use of human gene therapy to activate the human immune system against metastatic prostate cancer. The achievement, believed to be a first, could have implications in the treatment of many kinds of cancer. The study results are published in the October 15, 1999* issue of Cancer Research.
The Hopkins team injected a genetically engineered cancer vaccine in 11 prostate cancer patients whose cancer continued to spread following total surgical removal of their prostate glands. "We were astounded to find that every part of the immune system was alerted and turned on," says Jonathan Simons, M.D., associate professor of oncology and urology and principal investigator of this study, funded by the CaP Cure Foundation, the National Cancer Institute, and the Department of Defense Prostate Cancer Initiative.
"Using gene therapy, we re-educated the immune system to recognize prostate cancer cells as a potential infection and attack," he says. To create the vaccine, the researchers used cancer cells removed from the patient's own prostate tumor during surgery and grew them in the laboratory. GM-CSF, the most potent gene known to activate the immune system to recognize tumor antigens, was inserted into the cancer vaccine cells. The GM-CSF gene transfer into the cells was accomplished via a retrovirus, itself genetically engineered to be safe in humans. The GM-CSF gene-engineered prostate cancer vaccine was then irradiated to prevent the cancer cells from growing and injected into the patient's thigh like a flu shot.
Within four weeks of vaccination, the researchers were able to detect circulation of immune cells throughout the bloodstream. Patients' B-cells produced antibodies against prostate cells, and their T-cells directly attacked the tumor, the researchers report. Once re-educated to see prostate cells as foreign bodies, antigens on the cells' surface serve as red flags to the immune system, causing it to seek out and destroy them.
"The gene we used to turn on the immune system is so good that it activates everything," says William G. Nelson, M.D., Ph.D. "We were not surprised to see T-cell activation, the arm of the immune system triggered by viruses, but this vaccine also stimulated new high-level antibody production. Such a complete and thorough activation of the immune system against prostate cancer has never before been seen," he says.
All prostate cells are targets for this type of gene therapy because any prostate cell that survives surgery has the potential to turn malignant and become lethal to the patient. However, since the prostate is not a vital organ, the researchers say destruction of the prostate cells is safe and should not lead to incontinence or impotency as other therapies sometimes can. In fact, the therapy is so well tolerated by patients that no hospitalization is required. The only side effects associated with this therapy are flulike symptoms and redness and itchiness at the vaccine site for several days.
"The idea of using the immune system against prostate cancer is quite novel, but offers real hope because many of our conventional treatments do not kill metastatic cells efficiently," says Simons. "Genetically engineered vaccines like this could make a real difference when used as adjuvant therapy to 'mop up' microscopic cancer cells left behind following surgery, chemotherapy, and radiation therapy," he continues.
"The ability to activate the immune system to produce antibodies against cancer provides critical new fundamental information that will broaden the potential of these gene therapy trials," Simons notes. Based on the research reported in Cancer Research, Simons, Nelson, and team currently are conducting larger trials using a genetically engineered prostate cancer vaccine that does not require surgery. Advanced prostate cancer patients can obtain information about these trials by calling (410) 614-4234.
Prostate cancer is the most common malignancy, striking more than 330,000 men in the United States each year. New therapies are urgently needed for the approximately 40,000 men who die each year because their cancer has spread beyond the prostate to the bone marrow and other vital tissues and organs.
In addition to Simons and Nelson, other participants in this study included Bahar Mikhak, Ju-Fay Chang, Angelo M. DeMarzo, Michael A. Carducci, Michael Lim, Christine E. Weber, Angelo A. Baccala, Marti A. Goemann, Shirley M. Clift, Dale G. Ando, Hyam J. Levitsky, Lawrence K. Cohen, Martin G. Sanda, Richard C. Mulligan, Alan W. Partin, H. Ballentine Carter, Steven Piantadosi, and Fray F. Marshall.
Related Web Sites:
http://www.med.jhu.edu/cancerctr/
*Editorial Note: The actual publication date of Cancer Research is October 15, 1999. However, distribution was delayed until October 20, 1999, due to printing problems.
Jonathan Simons, M.D., and William Nelson, M.D., are available for interviews Monday, October 18 through Wednesday, October 20, 1999.
[Partial] Funding for the study described in this news release was provided by Cell Genesys Inc. Under a licensing agreement between The Johns Hopkins University and Cell Genesys, Dr. Levitsky is entitled to a share of royalty received by the University from sales of the licensed technology. Dr. Piantadosi is a consultant to Cell Genesys. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.
The Johns Hopkins Oncology Center
The History of Gene Therapy for Cancer
1986: Hopkins researchers Bert Vogelstein, M.D., and Eric Fearon, M.D., and M.D. Anderson researcher Philip Frost, M.D., put foreign genes into cancer cells in an attempt to activate the immune system in colon cancer.
1988: Vogelstein and other Center researchers, including Jonathan Simons, M.D., Drew Pardoll, M.D., and Hyam Levitsky, M.D., identify the immune-stimulating cytokine IL2 as a potential immune system activator against cancer.
1990: In collaboration with Johns Hopkins gene therapy researchers, MIT human gene therapy researcher Richard Mulligan, M.D., and colleague Glenn Drannoff, M.D., identify the GM-CSF gene as the most potent immune system stimulator.
1992: The MIT/Hopkins team develops a vector or retrovirus to enable them to insert the GM-CSF gene into cancer vaccine cells to conduct clinical trials.
Multiple Johns Hopkins investigators simultaneously test genetically engineered cancer vaccines in animal models for a variety of cancers, including lymphoma, melanoma, lung cancer, and kidney cancer. The vaccines are effective in mouse models, and human clinical trials are planned.
Jonathan Simons, M.D., develops a genetically engineered vaccine for prostate cancer using GM-CSF.
1993: Elizabeth Jaffee, M.D., Drew Pardoll, M.D., and Fray Marshall, M.D., demonstrate GM-CSF genetically engineered vaccines can be made from patients' cancer cells following surgery.
1994: Jaffee, Levitsky, Pardoll, Simons, and surgeon Fray Marshall conduct the first human gene therapy trials at Johns Hopkins. Eighteen patients with advanced kidney cancer were treated, and all patients treated with the GM-CSF gene therapy obtained measurable new immune responses against their autologous tumor. One end-stage patient experienced a partial remission for seven months after receiving three vaccinations. Research findings were reported in the April 15, 1996, issue of Cancer Research.
1996: Simons initiates the first human gene therapy clinical trials for prostate cancer. Findings are reported in the October 15, 1999, issue of Cancer Research and in the attached press release.
1997: The entire Hopkins gene therapy team begins development of cancer vaccines and gene therapy approaches for a variety of malignancies, including breast, prostate, pancreatic, and lung cancers, and lymphoma and leukemia.
Current: Simons and William Nelson, M.D., Ph.D., develop "generic" GM-CSF gene-engineered prostate cancer vaccines. Multi-institutional human clinical trials are ongoing.
Using the "Hopkins Approach," Japan has begun its first human trial of gene therapy in kidney cancer using the vector and GM-CSF gene pioneered at Johns Hopkins. The Hopkins therapy was selected because of its safety in outpatients and early evidence of clinical benefit in Phase I studies. In Japan, patients with kidney, prostate, and lung cancers are projected for treatment in clinical trials over the next five years.
Journal
Cancer Research