Can lung cancer be stopped before it starts?

Lung cancer is by far the leading cause of cancer death. Each year, more people die of lung cancer than of colorectal, breast and prostate cancers combined. Because lung cancer may not produce noticeable symptoms in its early stages, more than 60% of people are diagnosed after the cancer has spread beyond the lungs and is more difficult to treat.

But now, a first-of-its-kind clinical trial at MD Anderson is training the immune system to prevent lung cancer from developing. This new approach that’s studying how to stop lung cancer before it starts is called immunoprevention.

We talked with the clinical trial’s leader, lung cancer specialist Jay Zhang, M.D., Ph.D., to learn more.

How do you explain cancer immunoprevention to your patients?

We all have cancer cells in our bodies. But many of us never develop cancer because our immune systems recognize and kill cancer cells early, before they have time to grow and form tumors.

People with small nodules of tissue in the lungs that may be precancerous may benefit from immunoprevention – a new field in the world of cancer. Immunoprevention uses a drug or vaccine that rallies the immune system to identify and kill cancer cells.

Why do people get cancer? Did their immune systems fail?

This is controversial, but, to a certain degree, it may come down to bad luck. Our bodies contain 70 trillion cells that form our organs, such as our lungs, heart, brain, skin and so forth. These cells are constantly replacing each other to keep our organs healthy and functioning normally. Old cells die and give way to new ones. Ordinarily, this cell regeneration is exquisitely controlled.

But with so many cells in our bodies, there’s great potential for error, particularly in the gatekeeping processes that control how quickly and efficiently the cells regenerate. These mistakes allow cells to grow out of control. That’s what cancer is – uncontrolled cell growth.

Maintaining a healthy lifestyle can lower the chance of mistakes, but that’s not a guarantee. One wayward cell could still cause cancer, no matter how healthy you are. A lot of people think lung cancer is always caused by smoking, but almost two-thirds of all new diagnoses are in people who are not current smokers or have never smoked. In fact, up to 30,000 Americans who have never smoked get lung cancer every year. This group of never-smokers account for about 15% of lung cancer cases in the U.S.

Tell us how your immunoprevention trial seeks to prevent lung cancer from developing

The name of the trial is the IMPRINT-Lung trial, which stands for “Immunotherapy with Pembrolizumab for the Prevention of Lung Cancer.” It’s the first trial in the world that uses an immunotherapy drug – in this case, pembrolizumab (brand name Keytruda) – to attempt to prevent lung cancer in patients who have lung nodules.

Normally, immunotherapy drugs stimulate the immune system to attack tumors. But in our study, there are no tumors to attack because our patients don’t have lung cancer. Instead, they have lung nodules that have begun to change and may be precancerous – but they’re not yet cancer. Our goal is to use immunotherapy to prevent these pre-cancers from becoming invasive cancers in the future. We’re giving cancer treatment drugs to patients who don’t have cancer – and hopefully never will.

What’s the advantage of intervening at the pre-cancer stage?

Cancer cells are very sneaky. They develop ways of hiding from the immune cells that are out to kill them. As cancer advances, its cells get even more sneaky. Stage IV cancer cells are likely to develop more ways of escaping an immune system attack than stage I cancer cells. Also, more advanced cancer stages produce more cells. By stage IV, cancer cells have had more time to multiply than stage I.

Immune cells take a beating when fighting advanced cancer. When we look at stage IV cancer tissue under a microscope, we see fewer immune cells remaining – the cancer cells kicked them out. Many of these remaining immune cells may be corrupted – they may have transformed into different types of cells that support cancer growth. But in earlier-stage cancers, the immune cells are in better shape – they’ve been fighting hard, but they’re holding their own.

In the pre-cancer stage, the cells have only just begun to undergo some changes that signal they might become cancerous. It’s still early in the game, and immunotherapy may work much better at this point. The pre-cancer cells haven’t yet become sneaky and sophisticated, and there aren’t many of them. Our army of immune cells likely will have a much better chance to win this battle – we’ve seen in laboratory experiments that pre-cancer cells are eliminated much more efficiently than cancer cells. This is the main idea behind immunoprevention.

Can you tell us more about the IMPRINT-Lung trial?

It’s a small study. We’re enrolling 81 patients with “high-risk” nodules, many which may be pre-cancerous.

Most lung nodules grow slowly. You’re more likely to die with them than from them. But there are some high-risk individuals whose nodules are more likely to transform into invasive lung cancer within the next two to four years. We use an algorithm, or formula, to identify these people. The algorithm considers age, gender, smoking history, family history of lung cancer, and the location and number of nodules. It adds all these things together and produces a cancer risk score. The patients whose nodules have a 15% or higher chance of becoming cancer within the next two to four years are eligible for our study.

Participants are randomly assigned by a computer to one of two groups. The first group is monitored every three months with a CT scan, but receives no active treatment. This is the standard way of caring for patients with lung nodules. If a CT scan does detect cancer at some point, then we intervene. The second group receives treatment with four doses of the immunotherapy drug pembrolizumab. After six months, we evaluate them to see if their nodules shrunk or disappeared.

The clinical trial has just begun, and it’s too early to draw conclusions. We do know, however, that none of the participants have had any major side effects. That’s a very important point, since we’re giving cancer drugs to people who don’t have cancer.

What are the potential side effects of pembrolizumab?

Immunotherapy drugs like pembrolizumab can cause side effects, many of which happen when the immune system that has been trained to attack cancer also acts against healthy cells and tissues in your body. Common side effects include: fatigue; pain in the muscles, bones, joints and abdomen; decreased appetite; itching; diarrhea; nausea; rash; fever; cough; shortness of breath; and constipation. People interested in joining the clinical trial should weigh these potential risks against the potential benefit of preventing lung cancer.

Will immunoprevention be used to treat other pre-cancers in the future?

We hope so. We’re already talking about designing an immunoprevention clinical trial for colorectal cancer. Take, for example, people with Lynch syndrome – an inherited condition that raises the chance of getting colorectal cancer to more than 50%. By definition, these folks are at very high risk for cancer. Furthermore, colorectal cancers associated with Lynch syndrome tend to carry a lot of mutations. The more mutations a cancer has, the better it responds to immunotherapy. So people with Lynch syndrome would be ideal clinical trial participants.

There’s a great deal of interest in immunoprevention, so look for more studies involving more types of cancer soon. It’s much better to prevent cancer in the first place than to treat it later. As the saying goes, an ounce of prevention is worth a pound of cure.

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