End Of Century Marks Dawn Of Clinical Trial Era For Cancer Vaccines

The ends of centuries are momentous times for immunology. Edward Jenner introduced the first vaccine, against smallpox, in 1798. New York surgeon William Coley originated immunotherapy in 1893, when he infected cancer patients with killed bacteria to stimulate immunity against their tumors. And now, in the 1990s, "cancer vaccines" are finally in widespread clinical trials. Cancer vaccines are making headlines and have been the focus of five international scientific conferences in the past two years. "At least 50 institutions have research groups working on tumor vaccines," says Lynn Spitler, president of Jenner Technologies Inc., a private company based in Danville, Calif. Spitler was chairwoman of the second international conference on Engineered Vaccines for Cancer and AIDS, held in San Francisco March 3 to 5. SHOOTING FOR BEST RESULTS: Lynn Spitler notes that at least 50 institutions are working on cancer vaccines. Among them are her firm, Jenner Technologies Inc. and PerImmune Inc., whose president is Michael Hanna. Cancer vaccines are new in that they shrink tumors, yet follow classical vaccinology against infectious disease because they enhance immune response. One sign of the hybrid nature of the field is that some vaccine pioneers have segued from traditional to contemporary types of vaccines, such as Jonas Salk's AIDS vaccine efforts. Hilary Koprowski, a professor of microbiology and immunology at Jefferson Medical College in Philadelphia, is another example. Working with Albert Sabin, Koprowski administered the first live polio vaccine in 1951, developed a rabies vaccine, and over the past few years has published extensively on T- cell responses to tumor-associated antigens, laying the basic research foundation for cancer vaccines (N. Manabu et al., Hybridoma, 13:241-6, 1994). Cancer vaccines are antigens or cells that trigger an immune response against cancer cells. However, some researchers feel "the terminology is not exactly proper," Spitler notes. "We prefer the term 'cancer immunotherapy,' because 'vaccine' has the connotation of being a preventative rather than an active therapy," explains Dennis Panicali, president and CEO of Therion Biologics Corp., a private company in Cambridge, Mass. Robert Zaugg, vice president of business development at Vical Inc., a public firm in San Diego, is one of many preferring a compromise in nomenclature--"therapeutic vaccine." The principles behind cancer vaccines are straightforward. Cancer cells have distinctive surface antigens or antigen arrangements. The immune system, if properly presented with these differences, can recognize them, and, researchers hope, respond. "Basic to the whole process is stimulating cytotoxic T cells to recognize a tumor, destroy it, and remember [its cell surfaces]," says Panicali. Evidence from experiments with animals for the promise of cancer vaccines is abundant. "If you vaccinate mice with nonliving tumor cells, and then add live tumor cells, the tumor won't grow. Something in the tumor cells is foreign to the immune system," explains Pamrod Srivastava, an associate professor of biology at Fordham University. The first cancer vaccines that were developed target virally induced cancers, because those cancers are most like infectious diseases. These include the feline leukemia vaccine and a vaccine to treat Marek's disease in poultry, a deadly disorder caused by the turkey herpes virus (M.R. Hilleman, Avian Diseases, 16:191-9, 1972). For humans, the hepatitis B vaccine is in a sense a cancer vaccine, because this infection can cause liver cancer. And, in a cancer vaccine trial for advanced melanoma at Thomas Jefferson University, 60 percent of patients receiving the vaccine were tumor-free after three years, compared with 20 percent of patients in a control group. Cancer vaccines are the latest chapter in the continuing tale of immunotherapy, an old idea that has waxed and waned for a century. Many researchers trace its beginning to William Coley (W.B. Coley, Transactions of the American Surgical Association, 12:183, 1894). After he and others had noted that some patients spontaneously recovered from cancer following bacterial infection, in 1893 he intentionally infected patients with killed Streptococcus bacteria. Sometimes, it worked. Unbeknownst to Coley, the active ingredient was tumor necrosis factor, an immune-system biochemical. Although surgery, radiation, and chemotherapy became the primary cancer treatments, immunotherapy efforts continued in the research lab. In the 1950s and 1960s, a flurry of experiments attempted to induce cancer in mice, remove the tumors, then boost the mice's immune systems and implant the tumors back into the mice in an attempt to stimulate immune system to shrink the tumors. Researchers realized, though, that methods used to induce cancer in mice are not the same as the chronic carcinogen exposure that often causes cancer in humans. Similarly, treatments to reduce tumors may not translate from mice to humans. Still, a few long-term animal studies did lead to the clinic. Michael G. Hanna, Jr., president of PerImmune Inc., a private company in Rockville, Md., pioneered a colon cancer vaccine currently in Phase III clinical trials at Georgetown University School of Medicine. "We worked very hard in the guinea pig to develop and optimize the vaccine to get the best clinical response. We translated what we learned to the clinic. That's how science is done," he says (M.G. Hanna, Jr. et al., Cancer Immunology/ Immunotherapy, 7:165-73, 1979). The arrival of biotechnology in the late 1970s enabled targeting of specific cell-surface antigens, a leap forward from the prevailing process of working with crude cell fractions. "First was monoclonal-antibody technology. This allowed us to identify tumor-associated antigens, characterize them, and study their tissue distribution. Then PCR [the polymerase chain reaction] allowed us to clone and express gene products. These technologies combined to allow the development of vaccines in the '90s, with true knowledge of what composes the active ingredients [of vaccines]," Spitler says. Despite the precision that biotech offers in detecting tumor antigens, some researchers, such as Hanna, are still pursuing whole cancer cells as vaccines. The reason is basically timing: The immune response is often launched against tumor antigens that are physically associated with other proteins called major histocompatibility complex (MHC) molecules. MHC proteins "display," or introduce, foreign antigens to the immune system. But in the pre-biotech era, Hanna and others didn't know just what the immune response zeroes in on. "We started before the advent of biotechnology," Hanna recalls. "We didn't think we were smart enough to figure out what parts of cells were functioning as antigens that the patient would respond to, and that would be protective. Rather than guess, we used the whole cell." And, just as traditional vaccines use an attenuated, or disabled, virus and an immunity booster, called an adjuvant, Hanna's cancer vaccines use disabled tumor cells plus an adjuvant. "We looked at what worked for polio and measles," Hanna says. In the ongoing clinical trials at Georgetown, patients have their colon tumors surgically "debulked." Removed tumor cells are irradiated so they cannot restart the cancer, but they retain their surface features. The cells are injected into the patient, along with an adjuvant called BCG, which further stimulates immunity. The vaccine appears to be safe, but efficacy results are not completed for the Phase III trials. A recent turning point in the field was the discovery of a human melanoma-specific antigen by Thierry Boon's group at the Ludwig Institute for Cancer Research in Brussels (P. Van Der Bruggen et al., Science, 254:1643-7, 1991). The gene, called MAGE-1 (for "melanoma antigen"), quickly became a favored study subject among vaccine developers because it was the first tumor-specific antigen identified. Therion Biologics Corp. and Steven Rosenberg, chief of the National Cancer Institute's Surgery Branch, are testing a vaccine called MAGEVAC for melanoma and breast cancer. It is a poxvirus that expresses the MAGE-1 gene. Rosenberg has been a key player in immunotherapy because of his work with lymphokine-activated killer cells to treat various types of cancer (S.A. Rosenberg, Journal of Clinical Oncology, 10:180-9, 1992). He has discovered tumor antigens even more tumor- specific than MAGE-1, called MART-1 and gp100. Therion is working with him to develop them into "generic" melanoma vaccines that patients with certain MHC types can use. Another antigen of interest in cancer vaccinology is mucin, the major glycoprotein in mucus. In normal cells, the carbohydrate portion of mucin masks its peptide portion; in various cancers, the peptide is exposed. Vaccines are being developed to home in on the exposed parts of mucin in cancer cells. Olivera Finn, director of the immunology program at the Pittsburgh Cancer Institute, has spent a decade trying to better reveal mucin peptides on tumor cells to the immune system. "Tumor cells can have good antigens, but they can't start up [an immune response]," she explains. "We present the antigen as a vaccine along with an adjuvant. When the antigen is away from the tumor, we'll see if it can get the immune system to go. If so, the tumor will be a good target because this molecule is on its surface." A Phase I trial showed that the mucin peptide vaccine was not toxic in patients with end-stage breast, colon, or pancreatic cancer. Phase II studies will look for efficacy in patients who are not as ill, Finn adds. Phase I studies of a vaccine based on the carbohydrate portion of mucin, conducted by Biomira Inc., a public biotech company in Edmonton, Alberta, Canada, showed low toxicity and a partial response in some breast cancer patients. And Phase II results on more than 200 patients with colorectal cancer presented at the National Institutes of Health in February show the same median survival period--14.4 months--as with chemotherapy. The vaccine does not produce the unpleasant side effects associated with chemotherapy. Pamrod Srivastava's work on cancer vaccines based on heat shock proteins (hsp) doesn't really fit into a "whole cell" or "tumor antigen" category. Hsps are ubiquitous proteins that have a variety of functions, most notably as "chaperones" that fold proteins as they form. Srivastava was intrigued that hsps on tumor cells elicit an immune response when isolated from animals and injected, unaltered, back into them, while the same proteins from normal cells do not. "We found that it wasn't the heat shock proteins alone that elicited the immune response, but a large spectrum of peptides they are noncovalently associated with," Srivastava says. Tumor cells have the same hsps and certain other peptides as normal cells, but they also have uniquely altered peptides. "When you vaccinate, the immune system ignores the normal [nonaltered] peptides and reacts to the foreign [altered] peptides. The immune system has some special mechanism that can be activated particularly strongly in response to altered peptides if they are associated with heat shock proteins," he explains. Srivastava's vaccine consists of a mixture of hsp-associated proteins from tumor cells. "We've generated a large number of vaccines in mice and rats to a large variety of tumors. It is such a simple procedure," he points out, because he doesn't need to laboriously identify every molecule in the vaccines. Trials of the vaccine for melanoma and kidney and liver cancers are beginning now in Germany and Italy, and may start in the United States later this year, he reports. Srivastava expects few regulatory hurdles because there is no tinkering or foreign material being introduced: "The patient already has the material to cure him or her. We just have to give it back in a way that's more accessible to the immune system." Ricki Lewis is a freelance science writer and biology textbook author based in Scotia, N.Y. She is a cancer survivor. (The Scientist, Vol:9, #7, pg.15, April 3, 1995)

End Of Century Marks Dawn Of Clinical Trial Era For Cancer Vaccines

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SHOOTING FOR BEST RESULTS: Lynn Spitler notes that at least 50 institutions are working on cancer vaccines. Among them are her firm, Jenner Technologies Inc....