Training the Immune System to Fight Cancer

For more than three decades, scientists have dreamed of unleashing one of nature's most powerful forces, the immune system, on cancer. Now, a wave of immune therapy treatments is beginning to emerge from drug-company laboratories, giving the possibility of longer life to patients with terminal lung cancer, leukemia, brain tumors, and melanoma. The first drug designed to train the body's natural defenses to attack tumors is Dendreon's Provenge, a prostate-cancer vaccine cleared by the U.S. Food & Drug Administration on Apr. 29. Beginning on June 4, at the American Society of Clinical Oncology conference, the world's biggest gathering of cancer doctors and drug and biotech companies will show how medicines now being developed will provoke the immune system to kill cancer cells. Pfizer (PFE) will present data on a brain tumor vaccine. A Bethesda (Md.)-based startup, Micromet, (MITI) will tell doctors about its technology for shrinking tumors. German drugmaker Merck KGaA and Oxford BioMedica of the U.K. will show how their vaccines work against breast and kidney malignancies. What's getting the most buzz is Bristol-Myers Squibb's (BMY) experimental drug for skin cancer. Caught early, the disease is often treatable; late-stage melanoma is usually fatal. Bristol-Myers' drug, which has the generic name ipilimumab, seems to be effective in fighting the disease even in its deadly advanced phases. In three small trials the drug kept more than a third of patients alive for at least 18 months, about a year longer than existing treatments for terminal melanoma. Bristol-Myers' report at the conference will reveal the outcomes of a larger study. If those results are as impressive as the early trials, ipilimumab may get U.S. regulatory approval as early as next year, which would put the drug in doctors' hands in 2012, according to the company. "We have hundreds of patients who are still alive after taking this treatment, and that is something unheard of" in advanced-stage melanoma, said Renzo Canetta, Bristol's vice-president of oncology clinical research. Ipilimumab is derived from mice that were genetically altered to create a human version of an antibody. The antibody speeds up the immune system so that white blood cells attack cancerous tumors, says Steven O'Day, who tested the drug on patients at the Angeles Clinic & Research Institute in California. The drug does this by blocking a protein called CTLA-4, which helps regulate the immune system. Early trials suggested the drug didn't work. Tumors just kept on growing, and some patients were getting even sicker with symptoms such as painful skin lesions, diarrhea, or organ damage. Then the researchers realized that what appeared to be worsening cancer was an inflammatory response from the treatment as the good cells attacked the tumor and other

tissue; those painful symptoms were signs that ipilimumab was doing its job. "Had we been too rash and said this drug is never going to make it, that would have been a tragic mistake," says Bristol's Canetta. The drug may also be effective against tumors of the lung and prostate, says Trevor Polischuk, an analyst with OrbiMed Advisors in New York. "This could be a game changer," he says. Linda Bannister, a health-care analyst at Edward Jones & Co., says the drug could generate $1 billion in annual sales within five years. The concept of immunotherapy has been around a while. In the early 1970s scientists started developing lab-grown proteins called monoclonal antibodies, designed either to block tumor growth or make tumors visible to immune-system cells. They do this by homing in on specific molecules or "targets" on the surface of cancer cells. The first monoclonal drug to be commercially successful was Rituxan, a non-Hodgkin's lymphoma treatment launched in 1997 by Genentech (DNA) and Biogen Idec (BIIB). While these older drugs are a big business for drug companies, most have shortcomings as medicines, says Steven Rosenberg, chief of surgery at the National Cancer Institute in Bethesda, Md. Tumors in many patients grow resistant to the treatments. "We need to do better than prolonging survival by months," Rosenberg says. Next-generation immunotherapies such as ipilimumab may be more effective for longer periods. Instead of focusing on a single target, they train the immune system to destroy cancer cells the way they would a virus. "The hope is there that we aren't just extending [the lives of patients], but that we are really curing people with widespread cancer," O'Day says. "It is a little early to say that, but there is hope." Jedd Wolchok, a skin cancer specialst at Memorial Sloan-Kettering hospital in New York, says he realized ipilimumab was unlike any drug he has seen for melanoma shortly after he started testing it in 2004. One of the first patients Wolchok treated with it was a 24-year-old woman who likely had less than a year to live after other treatments failed. Her tumors eventually disappeared. She has since started a family. "We are resetting the balance between the person and the tumor, and the tumor no longer has the upper hand," Wolchok says. "We have been talking about turning cancer into a chronic disease, and this shows it is possible." The bottom line: A wave of new immunotherapy drugs may help turn some lethal cancers into manageable chronic diseases. Pettypiece is a reporter for Bloomberg News in New York.