Every year, 50,000 new cases of malignant melanoma – the most serious form of skin cancer – are diagnosed in the United States, and an estimated one in 75 Americans will contract the disease in their lifetime. Detected early, surgery can often destroy it. But when the cancer spreads to lymph nodes and organs, it is often unresponsive to radiation and chemotherapy — and usually deadly.
Physicians at The Ohio State University Comprehensive Cancer Center (OSUCCC) hope to change that with immunological approaches to treating advanced malignant melanoma. Their belief is that immunotherapy, particularly vaccine therapy, may well become a viable fourth option for treating the disease, along with surgery, radiation and chemotherapy.
"Immunotherapy is a blanket term for treatment that uses the body's own immune system to fight disease. Immunotherapies are designed to strengthen the body's defense mechanisms, so that the body can then recognize the cancer as foreign and reject it," says William Carson III, MD, a surgical oncologist at The James Cancer Hospital and Solove Research Institute and a member of the OSUCCC's Immunology Program.
While attempts to control cancer with immunotherapies have been studied for nearly a century, new technologies and important discoveries in the last 10 to 20 years have renewed the interest in immunology — and have paved the way for hundreds of promising new studies.
Carson and Michael Walker, MD, a surgical oncologist specializing in melanoma at The James, are involved in some of these studies. Both physicians are heading up clinical trials based on immunology and the promise of a melanoma "vaccine." But unlike traditional vaccines that keep bacteria and viruses from invading the body, the melanoma vaccines currently being tested do not prevent disease. Instead, they help slow or stop the growth of recurring tumors by helping the body use its own natural killer cells to recognize and destroy cancer cells.
Stunting Hormone Growth
One of Carson's clinical trials, which he directs for the National Cancer Institute (NCI), is a phase II trial that involves anti-angiogenesis, or stopping the growth of new blood vessels. A tumor needs the body to feed it nutrients and oxygen. If tumor cells don't get nutrients and oxygen, they die. But if one cell has mutations that let it produce hormones, the body is essentially tricked into growing new blood vessels to help feed the cancerous cells. But what if those hormones could be "turned off" from sending signals for blood? Could that help slow or stop tumor growth? Carson and his team intend to find out.
Carson's trial involves neutralizing one of the major hormones released by tumors, called vascular endothelial growth factor (VEGF). The theory is that if VEGF can be taken out of circulation, the growth of new cancer cells can be stopped. Carson and his team are testing this theory through the use of an antibody called bevacizumab.
"Bevacizumab has shown promising results in inhibiting VEGF by binding to the hormone and neutralizing it," says Carson. "It has also shown good results in inhibiting VEGF in other cancers, such as breast and prostate. But this is the first time anyone has tested it on patients with advanced metastatic melanoma. We're excited about the possibilities."
Phase I of the trials showed bevacizumab to have fairly low toxicity, giving the trials the green light to proceed. Carson's team at Ohio State and a group of physicians at Christ Hospital in Cincinnati are the only two sites in the U.S. currently administering Phase II of the trials.
Patients in the study will be randomized, and the study will have two arms. Half of the patients will get the bevacizumab antibody alone, every two weeks. The other half will get the antibody and low-dose interferon alpha, another drug proven to be anti-angiogenetic. Carson refers to this as a "double whammy."
"Tumor cells are tricky. Some have multiple mutations and may be producing VEGF while others may be making FGF, or fibroblast growth factor," says Carson. "By giving some patients interferon alpha along with bevacizumab, we're hoping to hit them with multiple anti-angiogenetic drugs to see if the therapy is more effective with both drugs rather than just one."
The OSU Comprehensive Cancer Center received a $500,000 grant from the NCI to conduct the trial and associated research. Carson hopes to get at least 50 stage III or stage IV metastatic melanoma patients for the study, 25 for each arm.
Training T-Cells to Kill
In the mid-1990s, Steven Rosenberg, PhD, MD, and colleagues at the NCI designed a peptide that mimics the antigen that sits on the surface of a patient's tumor cells. This peptide was then used to vaccinate 31 patients whose melanomas had metastasized to other sites in the body.
All of the patients received a vaccine mixture containing the designer peptide (of the antigen gp 100) and an oil-based adjuvant to enhance its uptake by the immune system. In addition, the patients were given interleukin-2 (IL-2), a growth factor isolated from T-lymphocytes (T-cells), white blood cells that orchestrate the immune response. After two to four vaccine injections every three weeks, 13 patients (42 percent) receiving the vaccine and IL-2 combination exhibited a 50 percent or greater tumor shrinkage at all sites. In previous studies, this compared to tumor shrinkage in only 17 percent of patients receiving IL-2 alone.
Rosenberg and his colleagues cautioned that this apparent difference in response rates must be demonstrated in a randomized clinical trial evaluating the peptide vaccine in combination with IL-2, and that's where Carson and OSU’s current phase II trial comes in. "We're trying to train T-cells to recognize the antigen and kill that cell anytime they see it," says Carson.
"Rosenberg found that by giving high-dose IL-2, the peptide seemed to have more of an effect. That kind of muddied the water, because high-dose IL-2 by itself can make tumors shrink. So you're getting A and B: the peptide and IL-2. Which one really does the trick? That's what we're trying to find out."
To do so, Carson and colleagues are running a trial in which stage III and stage IV metastatic malignant melanoma patients will get a low dosage of IL-2 and the gp-100 peptide. He hopes research will show that low-dose IL-2 and the peptide are just as effective in shrinking tumors as higher doses of IL-2, but less toxic to the patient.
"This study is really exciting," said Carson. "It's based on the same idea as immunizing against disease. The thinking is that maybe someday we can give this vaccine to a patient who has just been discovered to have melanoma. In early stages of the disease, we can remove the disease by surgery and get it down to just a few extra cancer cells. Unfortunately, these cells will come back two, three, four years later.
"Intuition and science tell us that those cells were there in the beginning. If we could just get to them when they're in small numbers, we could avoid the problem of having large amounts of disease elsewhere."
Although the vaccine/IL-2 treatments have been tested only on patients with advanced melanoma, Carson hopes to eventually test those in earlier stages of the disease. "Right now we're testing these vaccines on people who have life expectancies of about nine months," says Carson. "They have many tumors, which have worn out their immune systems, making them less likely to respond to a vaccine. Someday we hope to study people who have less disease and stronger immune systems."
Giving the Immune System a Choice
While Carson and researchers study a single-peptide approach to melanoma vaccine therapy, Walker is directing trials regarding the efficacy of a polyvalent, or multiple-protein, vaccine.
The CANVAXIN™ vaccine, manufactured by CancerVax™ Corporation, is the culmination of 35 years of research by Donald Morton, MD, of the Santa Monica, Calif.-based John Wayne Cancer Institute. Morton screened hundreds of tissue samples from which he was able to isolate three cancer cell lines that elicited strong immune system responses. These three cell lines, which contain multiple antigens capable of inducing an immune response in melanoma, form the basis of the CANVAXIN™ vaccine.
Walker says the current trials using the experimental CANVAXIN™ vaccine are interesting because, with a polyvalent vaccine, there is a better chance that treatment will be successful because, patients will be exposed to multiple antigens that they may not have previously encountered.
"Using a vaccine with multiple antigens may give the patient's immune system more to respond to, depending on which antigen is present in their particular melanoma. We hope to see if that is indeed true in a randomized controlled study," says Walker.
Walker's study consists of two trials that provide patients the CANVAXIN™ vaccine plus bacillus Calmette-Guérin, or BCG, a tuberculosis germ known to stimulate the immune system. Some patients get both the CANVAXIN™ vaccine and BCG, while others get BCG and a placebo. Neither medical professionals nor the patient know if they are receiving the placebo plus BCG or the vaccine. Patients with stage III and stage IV metastatic malignant melanoma are being tested at Ohio State and 40 other sites throughout the world. OSU has treated 27 patients since the trial began in 1998.
"This is an important study because I think it will tell us definitively whether the vaccine is worthwhile or not," says Walker. "As much as patients don't like the placebo aspect of the study, it will show us whether the vaccine is any more effective than surgery in treating melanoma, especially in those with stage IV melanoma. I applaud Dr. Morton for organizing these trials."
On the surface, vaccine therapy seems simple enough: The body's immune system already patrols for bacteria and viruses. Why not teach it to hunt for cancer? Traditional vaccines, such as those that immunize against mumps or measles, have easy targets. The germs they are looking for don't look like the body's "good" cells, so they are easy to spot. But cancerous cells look a lot like good cells, making it harder for cancer vaccines to target only the harmful cells without killing innocent bystanders.
Despite inconsistent and sometimes disappointing results in vaccine trials, both Carson and Walker agree that there is merit to studying melanoma vaccines and immunotherapy in general. And both also agree that science and medicine are a long way from being able to offer a vaccine that will prevent melanoma and other types of cancers.
"What we hope is that by learning in the melanoma system, we can apply it to other diseases," says Carson. "Melanoma is a good testing ground for immune therapies. But research needs to be grounded in sound scientific evidence, and there must be good correlative laboratory science associated with the research so that we can look at what really happened with the patient. People tend to forget that a lot can be learned from our failures as well as our successes."
Walker concurs, and says that vaccine therapy should be considered a treatment option to be used in conjunction with other therapies, such as radiation, chemotherapy and surgery. And in the case of melanoma, both doctors say the easiest way to treat it is through behavior therapy — getting people to change the behaviors that can cause melanoma.
"Australia has the highest incidence of melanoma in the world, but it is steadily decreasing," says Walker. "They've shown the world how to decrease melanoma through the consistent use of sun screen, ozone warnings, ultra-violet protections and by encouraging people to see their doctors as soon as an unfamiliar skin lesion appears. "In a perfect world, there shouldn't need to be a melanoma vaccine. It's a highly preventable disease."