Cancer Immunotherapies: An Old Idea Sparks New Studies, Industry Interest

Using the immune system to fight the deadly disease shows promise, executives say, but vaccines may take years to bring to market. Biotech executives and cancer researchers are excited about a resurgence in basic studies and clinical trials involving immunotherapeutic approaches to fighting the disease. They caution, however, that because cancer is so poorly understood, products in the marketplace may still be years away. FIGHTING THE GOOD FIGHT: A technician from Cytel, one of the many immunotherapeutic biotech firms, works on developing a cancer vaccine. Cancer immunotherapy is "very promising, but it needs more research," says T.J. Koerner, scientific program director for the Atlanta-based American Cancer Society. "Because cancer is very diverse in its expression, it's going to take diverse paths to fight it. The important aspect to realize is that there probably isn't going to be a simple panacea for fighting cancer." Dozens of biotech firms are researching and testing various therapeutic agents and a variety of ways of delivering them to patients. Collectively, these therapies are referred to as cancer vaccines. Although vaccines are normally thought of as preventive therapies given to people before a disease is detected cancer immunotherapy is currently targeted at patients who already have cancer. The function of the vaccines is to give the immune system a boost, helping it to better recognize antigens on the surface of different types of cancer cells (see Research), including those from melanoma as well as colorectal and cervical cancer. Although the idea of fortifying or stimulating the immune system to fight cancer has been around for 15 to 20 years, new technologies and a better understanding of immune-system mechanisms have worked together to cause an explosion of research and development in industry, government, and academia, according to observers. "Cancer vaccines are not that new," says Ruth Emyanitoff, director of business development at Therion Biologics Corp., a privately held Cambridge, Mass.-based firm established in 1991. "There have been companies looking into this since the '80s. I think the reason there's a resurgence now is that in the last five or six years we've gained a more detailed understanding of the immune system." Robert Zaugg, vice president of business development of Vical Inc. in San Diego, a publicly traded biotech firm started in 1988, agrees, adding that approaches now target a specific type of tumor with greater precision. Although Food and Drug Administration (FDA) officials say that it is difficult to pin down the total number of cancer vaccines currently in clinical trials, they point out that many trials using gene therapy techniques could fall under the heading of cancer vaccines. For example, out of the 105 gene therapy protocols currently approved by the National Institutes of Health's Recombinant DNA Advisory Committee (RAC), 54 involve cancer. Despite their enthusiasm, biotech representatives cite several difficulties that need to be addressed in the process of developing these therapies: finding the resources to develop an unproven approach in already tough financial times; defining the vaccine's target; testing for possible autoimmune-disease side effects; and gaining approval from such federal agencies as FDA and RAC. The many biotech firms and research labs testing immunotherapeutic vaccines have one goal in mind: to kick- start the immune system. Cancer cell-associated antigens molecules that stimulate an immune response induce a weak reaction, if one at all. To bolster immune response cancer patients are given genetically engineered, synthetic, or natural antigens, which are altered in order to become more visible to the immune system. Sometimes the antigens are administered along with boosters, called adjuvants, that contain substances that stimulate an extraordinary immune response. Emyanitoff says that Therion uses vaccinia, a harmless virus used in smallpox vaccines, to introduce an antigen which is associated with virtually all colorectal cancers, about 70 percent of lung cancers, and half of all breast cancers to a patient's system. "The first vaccine that we have in the clinic is one that expresses carcinoembryonic antigen [CEA]," she relates. "In fact, in Phase I trials, we're beginning to see some good immunogenic results" with late-stage cancer patients. San Diego-based Cytel Corp., a publicly traded biotech company formed in 1988, is currently testing vaccines made from antigen peptides associated with human papilloma virus (HPV)- caused cervical tumors. These HPV antigens are recognized by cytotoxic T cells also known as killer T cells which destroy cells with foreign antigens on their surface by puncturing them. SOME BIOTECH FIRM-SPONSORED CANCER VACCINES IN CLINICAL TRIALS Biotech Firm Vaccine Type Cancer Type Antigenics, New York heat shock protein with Peptides melanoma Appolon, Malvern, Pa. naked DNA lymphoma, cervical, prostate Biomira, Edmonton, synthetic antigens ovarian, breast, melanoma, colorectal Chiron Corp., Emeryville, Calif. gene transfer melanoma Cytel Corp., San Diego peptides melanoma, cervical IDEC Pharmaceuticals, Mountain View, Calif. anti-idiotypic antibodies melanoma ImClone Systems Inc., New York anti-idiotypic antibodies melanoma, colorectal, gastric,ovarian in U.K. Immune Response Corp., San Diego, CA inactivated tumor cells with the cytokine IL-2 colon Jenner Technologies, Tiburon, Calif. recombinant antigens colorectal, lung, prostate MicroGeneSys, Meriden, CN recombinant antigens colorectal Organon-Teknika Corp., Durham, NC gene therapy using patient's own cells colorectal Ribi Immunochem Research Inc, Hamilton, Montana inactivated whole tumor cells melanoma Somatix Therapy Corp. Alameda, CA gene therapy using patient's own cells renal cell, carcinoma, melanoma, prostate Therion Biologics, Cambridge, MA Corporation recombinant poxvirus encoding for MAGE antigen melanoma recombinant vaccinia encoding for CEA colorectal, lung, breast Vical Inc., San Diego, CA naked DNA melanoma, renal, colorectal "By specifically providing these peptides in a highly immunogenic form, we're hoping to jolt the immune system into recognizing the tumor," remarks Robert Chesnut, vice president of research and development for Cytel's immune-stimulation program. Phase I trials for the HPV vaccine have just started on a group of Dutch women. Lynn E. Spitler, president and chief scientific officer of Jenner Technologies in Danville, Calif., a private biotech firm established in 1992, points out that her company's first vaccine also relies on stimulating killer T cells. Jenner's vaccine, however, is based on a prostate-tumor antigen. "We're about to start the Phase I/II clinical trials," notes Spitler. She adds that clinical trials are scheduled for late 1995 for a colorectal and lung cancer vaccine whose "antigen is one that has representation on both tumor types." Other approaches currently being studied involve various ways of inducing antibodies to bind to antigens on cancer cells, thereby arresting their out-of-control multiplication. Still other firms and research facilities are synthesizing antibodies that mimic cancer-associated antigens. One is ImClone Systems Inc., a New York-based, publicly traded company formed in 1986. Samuel D. Waksal, ImClone's CEO and president, says his firm uses many approaches, including the mock antigens, which are called anti-idiotypic antibodies. "The lead product is in Phase II trials in England," he observes. "It's an anti-idiotypic antibody that mimics a molecule on the surface of certain types of cancer cells_colorectal, gastric, and ovarian. In these trials, patients given three doses of the antibody showed a dramatic two- to three-fold increase in life expectancy and survival as compared to patients given chemotherapy." While companies like Therion use an innocuous virus to deliver instructions to cells to produce the necessary antigen, Vical's Zaugg describes his firm's delivery system as more straightforward. "We simply take E. coli plasmid DNA and inject it directly into human tissues. The plasmid will encode what you want it to accomplish, for example, an antigen if you want to induce an immune response." This technique is termed a "naked DNA" vaccine because the genetic instructions to make the appropriate antigen are not elaborately packaged; the DNA is administered in a thin cloak of lipid to facilitate entry into the cancer cells. Another promising use for cancer vaccines, according to researchers, is to destroy cancer cells left behind after removing tumors. Immune Response Corp., a San Diego-based, publicly traded firm started in 1987, is involved in Phase I trials of such an immunotherapy for colon cancer. Steven Basta, executive director for product development, explains that Immune's technique takes fibroblast cells from the cancer patient and transects these with IL-2, a cytokine that stimulates the immune system. The IL-2-producing cells and inactivated tumor cells form the vaccine, which is administered after surgery. "The tumor cells target the cancer cell type and the IL-2 stimulates the immune system," Basta says. Emyanitoff asserts that tough financial times for the biotech industry in general and an as-yet-unclear definition of cancer vaccine products are among the impediments to the vaccines' immediate promise. "We can't define the [vaccine's outcome in all cases]. I can't say to you: 'The cancer vaccine that Therion is going to make for breast cancer will be this and that pox virus expressing this and that antigen plus this and that cytokine.'" Biotech executives also cite other technical details that have to be worked out before the vaccines can move beyond the clinic and into the marketplace. For example, because some of the antigens used as vaccines are "self antigens," ones derived from the patient's own tissue, there is a chance of inadvertently damaging healthy tissue, "thus causing autoimmune disease," notes Chesnut. "These will be safety hurdles [to approval] that the FDA will look at closely." And Zaugg points out that although FDA barriers for drug approval are lower in the area of cancer, regulators are still wary of cancer vaccines that involve depositing genetically engineered DNA into the human genome. "The place where cancer vaccines have their real potential is in patients who have a minimal tumor burden," according to Spitler. "Generally, the approach is not to use vaccines in the same patient population in which you'd use chemotherapy. The upside of that is the patient population who are candidates for cancer vaccines is greater than the number who are candidates for chemotherapy. The downside is that studies to demonstrate the efficacy of a vaccine take longer than studies using chemotherapy." Despite these difficulties, observers agree that cancer vaccine biotechnology is a growing and promising area. "The technology has emerged to the point where we will see an application in the next 10 years," says Cytel's Chesnut. But, he adds, "there's still a lot to be learned." Emyanitoff agrees with Chesnut's time frame, citing the anticipated increase in clinical trials Therion has planned: "If you look at us as an example, we were just this little company that started out in 1991 with some platform [vaccine- delivery] technology, and through our efforts and the National Cancer Institute's cooperative research and development agreements and the explosion of information [about the immune system], we'll hopefully have eight to 10 clinical trials" in the near future. She anticipates that products for the marketplace are years, not decades, away, "certainly within the time frame of other pharmaceuticals [but] with the recognition that you never know from a Phase I trial what's going to work or not work."

Cancer Immunotherapies: An Old Idea Sparks New Studies, Industry Interest

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