Pioneers of Promise
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On the Path to a
By Melissa Hendricks
In its earliest incarnation, gene therapy involved administering normal copies of a gene to compensate for one a patient lacked. But a decade ago, Hopkins molecular biologist Drew Pardoll envisioned a variation on this theme, which he now calls immunotherapy. He and his colleagues proposed introducing genes into cancer patients to induce the immune system to seek out and destroy tumor cells. The treatment would be a vaccine against cancer, and could be used to prevent regrowth in recovering cancer patients--or possibly even to prevent cancer in people who have never had the disease.
Today, their vision has reached the stage of clinical trials as Hopkins scientists test various versions of immunotherapy to prevent postsurgical relapses in patients who have had prostate or pancreatic cancer.
While the Hopkins team was not the only group to begin thinking about the use of gene therapy for cancer, Pardoll, along with oncologists Jonathan Simons and Hyam Levitsky, and other colleagues were the first to publish a paper (in the February 9, 1990, Cell) demonstrating the feasibility of the approach in laboratory animals. Since then, the researchers have conducted intensive studies at the bench and in the clinic.
The outline of their technique is relatively simple. Start with cells from a patient's tumor removed during surgery. Grow the cells in the laboratory. Insert into those cells a gene for a natural immune-stimulating molecule called a cytokine. Irradiate the cells to prevent them from growing. Inject them back into the patient. In theory, the cells then produce the cytokine, which alerts the immune system to recognize tumor antigens as a potential infection and to attack cells bearing those antigens.
Of course, reality is rarely as simple as an outline, and seeing their plan to fruition involved intensive studies. For example, the researchers investigated which of the 30 or so cytokines and related molecules elicited the most powerful immune response. Their first experiments involved interleukin-2, a cytokine that had shown promise when injected intravenously into cancer patients. But the scientists eventually rejected interleukin-2, in part because it was proving toxic. Finally, Pardoll, Levitsky, and Hopkins oncologist Elizabeth Jaffee, and their colleagues, determined that a cytokine called GM-CSF was the powerful immune trigger they had been searching for.
"What's made the program here what it is has been a balance of
basic science with a commitment to translating that knowledge to
the clinic," says Pardoll. The basic scientists have sought to
understand how the immune system functions and interacts with
tumor cells and the clinicians have applied those findings.|
More than a dozen research groups around the country are now running clinical studies of GM-CSF–based cancer vaccines.
Currently, Simons is leading a team that is testing a version of the GM-CSF–containing vaccine that targets prostate cancer, which claims the lives of 40,000 men in the United States each year. In an initial study, they injected the vaccine into 11 patients whose blood PSA levels had begun to rise after surgery to remove the prostate, an indication that their cancer had recurred. After giving the vaccine, researchers detected a huge surge of antibodies and immune cells targeted against the tumor cells. Simons, who is moving to Emory University, and Hopkins oncologist William Nelson are now expanding the study.
Hopkins oncologist Elizabeth Jaffee is testing a vaccine containing GM-CSF for pancreatic cancer, the deadliest form of cancer. Eighty percent of pancreatic cancer patients who have their pancreas removed have a recurrence of cancer within one year. With Jaffee's project, patients receive varying dosages of the vaccine alongside radiation therapy, following removal of the pancreas. So far, three of eight patients who received the highest dose of the vaccine have remained disease-free for more than two years. Jaffee and Pardoll believe that more widespread use of immunotherapy will involve such combination therapies: surgery plus radiation plus immunotherapy, for example.
Finally, in the next-generation of immunotherapy, molecular microbiologist Tzyy-Choou Wu is creating a series of vaccines for cervical cancer. Instead of GM-CSF, these vaccines incorporate genes of the human papilloma virus (HPV), which is the initiating factor of all cervical cancers (see p. 70). He and head and neck surgeon David Sidransky are also building a similar vaccine for a category of head and neck cancers, which also stems from HPV. Wu expects the vaccines to go into clinical trials within one or two years.
New therapies are not without risks, as has been made baldly clear by the recent headline-grabbing death of a patient enrolled in a gene therapy experiment at the University of Pennsylvania. The public must understand that "gene therapy" is not one but actually 1,000 different therapies, Pardoll points out. Furthermore, immunotherapies are generally being tested in patients who have exhausted their clinical options. "We've basically been focusing on patients who have a death sentence," says Pardoll.
Immunotherapy may be their last--and only--ray of hope.
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