Immunotherapy’s next horizon: cancer prevention
MD Anderson researchers hope to lower odds of lung disease for those at high risk
Teresa Powell learned she remained at high risk for lung cancer three years ago, after doctors removed an early-stage malignancy but testing still showed pre-disease growths.
Powell, who’d smoked on and off for 39 years before quitting nearly a decade ago, had only one seeming medical option: “watch and wait” for the development of a tumor, at which point doctors perform surgery or give radiation, the standard therapies for the disease’s early stages.
“It doesn’t do any good to worry about things outside your control, but it was hard not to just before each six-month screening,” says Powell, 70, a retired school teacher in Houston. “Odds are, the cancer could return anytime.”
MD Anderson Cancer Center scientists are hoping to reduce the odds for Powell and ultimately for all patients at high risk of lung cancer under a new clinical trial just launched at the Houston research hospital. The trial’s lofty aim: prevent the disease from developing.
The trial represents the next horizon for drugs that unleash the immune system, the approach that won MD Anderson scientist Jim Allison the 2018 Nobel Prize and has joined surgery, radiation and chemotherapy as a mainstay of cancer treatment. The approach, known as checkpoint blockade immunotherapy, involves releasing a brake on the immune system that’s necessary to keep the body’s defenses in check but is often exploited by cancer.
Allison’s discovery of the brake, a protein that researchers until then thought acted as a gas pedal, revitalized the field of cancer immunotherapy, which had tantalized researchers since the 1960s but had become seen as a lost cause. After determining the protein inhibited the proliferation of T cells, the immune system’s foot soldiers, Allison developed the first drug to block the protein — in essence taking the brake off so the system can attack cancer. The breakthrough led to the identification of other brakes and the development of other drugs that also free the immune system to go after tumors.
The result: cures in some cancers, those of the lung foremost among them, that historically have meant death sentences.
Still, the treatment works only in a subset of patients, so scientists are constantly conducting research to extend the benefits to more people. The effort to apply it to those who don’t have the disease is potentially the most impactful use yet.
“It’s exciting to think that introducing checkpoint blockade immunotherapy earlier in care may prove to be an effective way to prevent cancer development or its recurrence after treatment,” says Jill O’DonnellTormey, CEO and director of scientific affairs at the Cancer Research Institute, an immunotherapy advocacy group. “While immunotherapy has made a positive impact treating many different types of cancer, an ultimate goal would be to prevent cancer from developing in the first place.”
The trial will measure whether checkpoint blockade drugs can destroy precancerous nodules in the lung as a way to prevent the development of lung cancer, much as precancerous polyps in the colon are surgically removed to prevent the development of colon cancer. It targets high-risk people who have either never had lung cancer or were successfully treated but remain highly vulnerable to the disease returning. Tens of thousands of Americans annually would fit the two criteria.
Powell fits the second category. A breast cancer survivor, she was diagnosed with Stage 1A lung cancer after her oncologist learned she previously smoked and recommended she get screened at the same time as her next scheduled mammogram. Doctors surgically removed the tumor in her lung, but nodules detected in follow-up screenings meant there was a good chance of disease recurrence.
Research to prevent cancer is nothing new. Initially known as chemoprevention, a word first used in a 1976 journal article, the effort has enlisted a number of different chemical agents, from vitamins to aspirin to approved cancer drugs. The main beneficiary has been breast cancer, whose risk drops significantly if the patient takes raloxifene or tamoxifen.
Lung cancer chemoprevention has proved a much more elusive target, despite years of efforts. An MD Anderson slide presentation given this year said there is “no clear evidence of benefits from chemoprevention” for the disease.
No. 1 cancer killer
No other type of cancer is in such need of prevention. Lung cancer remains by far the nation’s No. 1 cancer killer, accounting for more deaths than the second, third and fourth most lethal cancers combined. Estimates call for it to be diagnosed in more than 228,000 people in 2019 and to kill more than 142,000. It is usually diagnosed only in the most advanced stages, when it is most difficult to treat.
Checkpoint blockade immunotherapy represents a next option to prevent the disease, partly because of the success it already has shown treating lung cancer. It is now given to all latestage lung cancer patients, of whom at least 20 percent get lasting benefits. As many as 30 percent have received such a benefit in trials using combinations of immunotherapies.
More than that, says the leader of the MD Anderson trial, immunotherapy is a logical tool to try to prevent lung cancer based on his research that proved the disease becomes more sophisticated as it progresses.
“From normal tissue to pre-cancer to cancer to metastatic cancer, malignant cells become smarter, more complicated, harder to treat,” says Dr. Jianjun Zhang, an MD Anderson lung cancer medical oncologist and cancer geneticist. “They acquire additional mutations, learn how to trick the immune system, better withstand whatever treatment the patient is given.”
Zhang’s laboratory research showed that precancerous lung cancer cells already have started engaging the immune system brake to escape detection, which is why he thinks drugs to unleash it will work. His research also showed that the immune response is much stronger early in the process, before cancer’s growth has beat it down.
The approach worked in Zhang’s trials with mice with precancerous growths in their lungs. The mice that received checkpoint blockade had a significantly lower rate of developing cancer than those that didn’t get the therapy.
The clinical trial aims to enroll 81 patients, 54 of whom will get the drug Keytruda and 27 of whom will act as an observation arm and receive no intervention. The patients subsequently will be rescreened at regular intervals, initially every three months, then every six, then every year. Keytruda targets another brake found to interfere with the immune response, not the one Allison identified.
Enrollment thus far has been slow, partly because the criteria are strict. Candidates must obtain a precancerous cells screening score high enough to be considered at risk but not so high they may have active cancer. Numerous candidates with particularly high scores have been rejected from the trial because they turned out to already have cancer, still a benefit for them because they then go in for treatment when the disease is more curable.
Others, mostly those who would have come from a long distance, rejected the trial because they didn’t want to travel just to end up in the observation arm. Zhang thinks he may need to open up the trial to centers besides MD Anderson in the hope of speeding recruitment.
Trial criticism
Dr. Robert Homer, a Yale pathologist, criticized the trial in a tweet that said “we can’t predict who responds (to immunotherapy) now so we would be forced to give (it) to many people who would not get cancer, and of those who would otherwise get cancer, most would not benefit. All get financial and clinical toxicity.” The latter refers to the drug’s high cost and side effects, which typically involve inflammation at the site of the disease.
Zhang downplayed concerns about the side effects, noting that Keytruda has been shown to be generally safe and that the short-term dosage — every three weeks for 12 weeks, compared with every three weeks for two years when it is used to treat lung cancer — makes it highly unlikely there would be any serious issues. He did not address the cost, which would be set by drug companies if the intervention is shown to be effective. Trial participants get the drug free.
Under the protocol, there must be a 30 percent reduction in lung cancer occurrence in patients getting Keytruda compared with those getting nothing for the trial to reach its goal. For the strategy to be approved by the Food and Drug Administration, Zhang figures, the approach ultimately needs to cut the risk by 50 percent.
“What we know is that lung cancer is killing more than 140,000 Americans a year and we have something that may be able to prevent it in those at high risk, perhaps saving more than 10,000 lives a year,” says Dr. John Heymach, chairman of thoracic, head and neck cancer at MD Anderson. “It works in mice. Hopefully, it’ll work in people as well.”
The early returns have been promising for Powell, who says she’s happy to be a human lab rat. Seven months after she got her first dose of Keytruda, some of the growths that showed up in previous screenings have disappeared.
“What we know is that lung cancer is killing more than 140,000 Americans a year and we have something that may be able to prevent it in those at high risk.”
Dr. John Heymach, chairman of thoracic, head and neck cancer at MD Anderson