Vaccine that targets nicotine rather than the brain's reaction to it

Nov 3 2005

Since smoking became popular in America in the 1930s, lung cancer rates have continued to climb. Today, it is still the leading cause of cancer-related deaths, with totals more than the other five leading cancers combined.

Armed with these sobering statistics, scientists have launched several innovative projects to find therapies that will effectively treat, and hopefully reduce the overall incidence of lung cancer. Several are being presented today during the American Association for Cancer Research's 4th annual Frontiers in Cancer Prevention Research meeting in Baltimore.

"We have begun to develop innovative strategies to target lung cancer with targeted medicines and new vaccines, but we have a long way to go," said William G. Nelson, V, M.D., Ph.D., of Johns Hopkins University and Program Chair of the meeting. "We hope that increased attention to research and treatment options will improve the outlook for the increasingly large patient population."

To combat cigarette smoking, researchers are seeking ways to combat the habit which affects more than 45 million Americans. One new option is a vaccine that targets the nicotine rather than the brain's reaction to it. Researchers from the University of Minnesota, supported by the National Institute of Drug Abuse and Nabi Biopharmaceuticals, have tested this new vaccine in humans with positive tolerability and efficacy.

"We are encouraged by the results of this study, which suggest that a nicotine vaccine may be a safe and potentially effective way to reduce tobacco dependence or as a relapse prevention aid," said Dorothy Hatsukami, of the University of Minnesota and lead author of the study.

The nicotine vaccine in question stimulates the immune system to develop antibodies that specifically attach to the nicotine molecules. The resulting antibody-nicotine combination is too large to pass through the blood to the brain, resulting in less nicotine in the brain.

Animal studies have confirmed that the vaccine works by reducing and also slowing the amount of nicotine that enters the brain, reducing nicotine's addictive effect.

Preliminary human studies have been conducted to determine the safety of the nicotine vaccine, as well as the best dosage and optimal dosing schedules. A multi-site clinical trial randomly assigned 68 smokers to receive different doses of vaccine, or placebo, and followed them over 38 weeks. The vaccine was well tolerated among the subjects. Aches and tenderness at injection sites were reported; systemic reactions included headaches, malaise or myalgia or muscle pain, although these latter reactions were similar between the vaccine and placebo. Most symptoms were mild and self-limited, resolving within a few days, and none required medical intervention.

There was no evidence of withdrawal after vaccine injection or evidence that smokers increased smoking intensity to compensate for the reduced nicotine in the brain. Preliminary analysis shows that the highest dose of vaccine in participant smokers, who had not necessarily been interested in quitting, showed significantly higher rates of 30-day abstinence than placebo.

"Two additional human clinical trials with other nicotine vaccines have been conducted which showed similar safety profiles and higher abstinence rates in the highest nicotine vaccine dose or antibody level groups, and we hope to conduct further trials to confirm these results," said Hatsukami.

Doctors are working diligently to make progress in preventing lung cancer, the deadliest cancer in America today. To do so, researchers are trying to better understand the biology of lung tumor development and design tactics using effective clinical models to interrupt the process without undue side effects. Efficacy and minimal toxicity are critical features of a successful treatment strategy. Doctors are working to identify populations who are at high-risk for the disease outside of tobacco exposure so that prevention strategies can focus on those who are most likely to benefit from them.

Using the documented role of inflammation in cancer development, doctors have identified key enzymes involved in the metabolism of arachidonic acid (AA) as potential targets for the prevention of a variety of epithelial cancers (in cells that line organs). AA, which is involved in inflammatory and other processes that regulate organ function, is generated from lipids and is metabolized by cyclooxygenases (COX-1 and COX-2 enzymes that control the production of prostaglandins and are blocked by aspirin) and lipoxygenases (LOX enzymes involved in diseases like cancer, inflammation, and asthma).

Animal tumor studies have suggested that inhibiting AA interrupts the growth of lung tumors, and have found that glucocorticoids (steroid hormones produced by the adrenal gland) are particularly effective in inhibiting cancer formation in mice. A recent phase IIb study of inhaled budesonide, a corticosteroid, did not show any efficacy in regressing or preventing precursor lesions for squamous cell cancer, but the treatment did reduce peripheral lung nodules, which may be precursors to lung adenocarcinomas. With regard to testing and review mechanisms, the recent availability of improved spiral CT images may now allow for clinical trials that specifically address cancer prevention in the peripheral lung compartment.

Agents that are currently being studied include inhibitors of AA metabolism such as non-steroidal anti-inflammatory agents and the leukotriene inhibitor and anti-asthma drug zileuton. With the promise of COX and LOX inhibitors, researchers are developing dual function COX-LOX inhibitor products to offer an alternative to combination therapies. In addition, PPARg ligands (peroxisome proliferator-activated receptor gamma), which include anti-diabetic drugs, have shown tumor inhibition in a variety of lung cells. Newer molecularly targeted drugs, which are potent anti-cancer drugs in mice, are struggling in lung cancer prevention trials due to concerns with drug-associated side effects.

However, as targeted agents with fewer side effects and preventive efficacy enter clinical trials, researchers will soon be able to evaluate "prevention-relevant" variables during early drug development to evaluate effects on precancerous lesions, providing valuable information for subsequent prevention trials. Such data may help to determine if promising agents that may have some side effects should be investigated further for cancer prevention in people at particularly high risk for lung cancer development.

"A better understanding of the mechanisms leading to the development of lung cancer is crucial to developing targeted therapies for prevention of the disease," said Eva Szabo, of the National Cancer Institute. "The combination of new clinical trial formats and new chemopreventive treatment options will help provide the answers necessary to reduce the incidence of this devastating disease."