National Cancer Institute researcher Steven A. Rosenberg became a media sensation in 1985 when he achieved surprising success with cancer patients--including one complete cure--using an experimental technique called immunotherapy. His method made perfect sense: Since cancers can evade the immune system, why not flood the body with killer immune cells, along with special chemical messengers called cytokines that give the body's weapons an extra kick. Dr. Rosenberg and others used one of the most promising of these compounds, interleukin-2. Sadly, the results, even 10 years later, haven't lived up to the initial hype.
Undeterred, scientists are still struggling to harness the human body's exquisitely complex immune system to fight cancer. They're priming patients' white blood cells to help them withstand chemotherapy. And they're tackling so-called "therapeutic vaccines," which could shrink existing tumors and reduce the odds of recurrence. Full-blown preventative inoculations probably are still decades away. But the past 10 years of intense research have produced a leap in molecular understanding.
MARROW HELPER. The first triumph of this deeper knowledge of immunology--long before any miracle drugs arrive--will be making life more comfortable for cancer patients. Doctors at Memorial Sloan-Kettering Cancer Center in New York can now increase and harvest "stem cells" from chemotherapy patients' blood using genetically engineered growth factors such as G-CSF. When they are reinjected into the patient's bloodstream, these rare cells multiply and mature into key immune cells. That helps the patients withstand high doses of chemotherapy and radiotherapy. The technique is more effective than standard bone-marrow transplants. It also costs far less and can be performed on an outpatient basis.
Within a few months, Sloan-Kettering's Malcolm A.S. Moore, who discovered G-CSF in 1984, hopes to start clinical trials on a more advanced technique: growing precursors of immune and mature blood cells by culturing them in a cocktail of growth factors. Long-term, says Moore, "I see no rationale for using bone marrow" to help chemotherapy patients.
All this is good news for Amgen Inc., Immunex Corp., and other biotechnology companies that produce colony-stimulating factors (CSF). According to analyst Steven C. Tighe at J.P. Morgan Securities Inc., CSF sales in the U.S. were roughly $1.5 billion in 1994 and are growing by 12% to 15% a year. These drugs are a far cry from cancer cures. But they could increasingly provide "a major advance in patient comfort and cost reduction," Tighe says.
Therapeutic vaccines are a tougher challenge for researchers. Tumors growing in the body produce antigens--molecules on the tumor cell surface that identify them as cancer. For reasons that scientists are still struggling to understand, the antigens often fail to goad the immune system into action (box).
Such limited-use vaccines are under development at several biotech companies, including Montana's Ribi Immunochem. Some of them are trying to make existing tumor cells more visible to the body's killer T-cells, either by enhancing the chemical communication lines in blood and tissue, or by forcing tumor cells to display their antigens more clearly.
Early attempts at therapeutic vaccines failed, most researchers agree, because they simply weren't specific enough. Doctors would inject patients with a "chicken soup" of molecules, including mashed bits of the excised tumor and chemicals such as interleukin-2, gamma interferon, and generic boosters called "adjuvants." These provoked clear, often violent immune responses. But the fury was rarely unleashed directly on the tumors.
"BETTER AND SMARTER." Now, armed with better molecular maps, scientists say they can precisely target their assault. In 1992, Thierry Boon of the Ludwig Institute for Cancer Research in Brussels identified the first known tumor antigen from melanoma tumor cells. Since then, many scientists have identified these key molecules and even smaller protein fragments from them. In human clinical trials, some show promise of triggering T-cell reactions. Compared with the early therapeutic vaccines, says Immunex Senior Vice-President Douglas E. Williams, "the next generation will be better and smarter."
Researchers are racing to employ well-known cytokines--the chemical threads that immune cells use to communicate--in gene therapies and to identify new ones. Of the 61 gene-therapy protocols that were approved by the National Institutes of Health in the past two years, "the largest single category is for cytokines as cancer vaccines," says Nelson A. Wievel, director of the Office of Recombinant DNA Activities at the NIH.
Problems that confounded early vaccine efforts, however, still remain to be solved. Because immunotherapy is experimental, says Alain B. Schreiber, chief executive of San Diego-based Vical Inc., doctors and pharmaceutical manufacturers have tested their ideas only on patients for whom conventional therapies failed. They often have large, solid tumors, to which the body, over time, has become "tolerized." Says Schreiber: "It's unlikely immunotherapy will be spectacular when the tumor burden is very high."
The encouraging corollary: Any response in patients with advanced cancer offers hope that immunotherapy can be effective--especially for mopping up after surgery. When Dr. Gary J. Nabel at the University of Michigan reported that a melanoma patient showed tumor regression following a preliminary gene-therapy treatment, Vical was sufficiently impressed to initiate larger trials.
The most provocative data come from recent animal experiments. Although mouse tests have only limited relevance to human biology, the findings suggest new ways to attack wandering tumor cells that cause "metastatic" cancer. Johns Hopkins School of Medicine oncologist and geneticist Drew Pardoll says he has successfully vaccinated mice using mouse tumor cells that are genetically engineered to release the growth-factor GM-CSF. The cells, when irradiated, emit cytokines for at least one week, says Pardoll, helping the mouse produce killer T-cells that seek out and destroy metastatic tumors. Human trials should show if the technique is viable within two years.
The Holy Grail--still many years away--is a long-term, preventative cancer vaccine offering permanent protection against particular kinds of cancer. To create that, doctors must identify specific cancer antigens present on tumor cells of all the victims of that disease. Many researchers are focusing on cervical cancer, which has long been linked with human papillomavirus. Scientists at Johns Hopkins, Bristol-Myers Squibb Co., and elsewhere have immunized mice against papillomavirus antigens, then introduced tumor cells that express the antigen, and demonstrated protection.
WILD SWINGS. Even short of a universal vaccine, however, scientists may someday be able to help individuals whose genes place them at a high risk. Michael T. Lotze, professor of surgery and molecular genetics at Pittsburgh Cancer Institute, says it should be possible to sensitize the immune systems of such people by periodically administering "a wake-up call"--possibly, low doses of interleukin-12. It's not "a preposterous notion," he says. Animal tests are under way at Pittsburgh, using a "gene gun" that shoots DNA-clad gold particles into the skin to activate the dendritic cells.
Many scientists worry that too much attention to experimental results could once again trigger wild swings of public expectations and disappointment. George P. Canellos, chief of medical oncology at the Dana-Farber Cancer Institute in Boston, points out that only 50% of all cancers are curable today, and a decade of immunotherapies has done little to improve that ratio. Trumpeting early lab results raises false expectations among cancer patients, Canellos says, "followed by devastating disappointment."
The last thing any scientist wants is to repeat these wrenching cycles of hope and despair. But as the molecular understanding of the immune system races forward, therapeutic improvements seem certain to follow.
Helping The Body Fight Cancer
One-shot inoculations against cancer may still be decades away. But scientists are slowly unlocking secrets of the immune system. A better molecular understanding should yield improved immunotherapies. Here are some early advances:
ADVANCE Chemotherapy patients often need marrow transplants, but doctors can achieve the same result with transfusions thanks to improved "colony stimulating factors" for blood.
PLAYERS Amgen, Immunex
ADVANCE Doctors use everything from "gene guns" to retroviruses to insert specialized genes in cancer cells, thus boosting the immune system's ability to fight tumors.
PLAYERS Somatix, Vical, Pittsburgh Cancer Institute
ADVANCE Scientists are enhancing tumor-infiltrating lymphocytes, or TILs, which the body sends to tumor sites.
PLAYERS Applied Immune Sciences
ADVANCE Whole-body hyperthermia (WBH) raises patients' bodies to 107 degrees to help ward off the side effects of chemotherapy.
PLAYERS The Cancer Research Institute, University of Wisconsin