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`T cells attacking a tumor cell. STEVE GSCHMEISSNER/SCIENCE SOURCE
`Why a powerful cancer drug only helps some patients
`
`By Jocelyn Kaiser Mar. 12, 2015 , 2:00 PM
`
`A new type of drug that unleashes the immune system on tumors has been a remarkable success,
`but only for some cancer patients. Now researchers have found a genetic signature within lung
`tumors that seems to predict whether this immunotherapy drug will work—and who will benet
`most.
`
`Tumor cells can hide from the immune system by activating a receptor, called PD-1, on the surface
`of the immune cells known as T cells. Instead of attacking the tumor cells, the T cells leave them
`alone. The new drug is an antibody that inhibits PD-1, blocking this “checkpoint” and freeing the T
`cells to wipe out the tumor cells. In clinical trials, PD-1 blockers and other checkpoint inhibitors have
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`Why a powerful cancer drug only helps some patients | Science | AAAS
`extended the lives of patients with several cancer types for years, far longer than conventional
`treatments. The U.S. Food and Drug Administration has approved several of these drugs for
`melanoma and one of them, nivolumab, became the rst to win approval for lung cancer last week.
`But checkpoint inhibitors work only for some people—PD-1 inhibitors shrink tumors in about 20% to
`30% of lung cancer patients—and researchers are scrambling to gure out why.
`
`One hypothesis is that checkpoint inhibitors are more likely to work on tumors that have more
`mutations. These mutations are not necessarily those that allow tumor cells to divide uncontrollably
`or spread to other places; instead, they may simply encode abnormal proteins that do nothing for
`the cancer cell. But they can matter for immunotherapies because the aberrant molecules may act
`as antigens—foreign molecules in the body that trigger an immune response. The more mutations in
`a patient’s tumor, the more of these so-called neoantigens, and hence a stronger response from T
`cells in patients taking a checkpoint inhibitor, the thinking goes.
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`Some recent studies support this view. Melanoma patients with more neoantigen-coding mutations
`in their tumors, for example, were more likely to respond to a checkpoint inhibitor that blocks a
`protein called CTLA-4.
`
`Now, the same seems to hold true for lung cancer. Timothy Chan of Memorial Sloan Kettering
`Cancer Center in New York City, who led the melanoma study, and co-workers sequenced the exome
`—the protein-coding DNA—of tumors from 34 people with non-small cell lung cancer who had been
`treated with a PD-1 inhibitor called pembrolizumab. They found that patients were much more likely
`to respond to the drug if their tumor had more of the type of mutation that results in an altered
`protein. For example, 13 of 18 (72%) patients with at least 178 mutations responded for 6 months or
`longer, compared with one of 13 (8%) of those with fewer mutations. Moreover, the 16 lung cancer
`patients who had a distinctive pattern of mutations caused by smoking were more likely to
`respond than the presumed nonsmokers, who had fewer, different mutations, Chan’s group reports
`online today in Science.
`
`The correlation between mutations and therapeutic response to the cancer drugs is “eye-popping,”
`says cancer researcher Drew Pardoll of Johns Hopkins University School of Medicine in Baltimore,
`Maryland, who was not involved with the study but has collaborated with Chan’s group. “It’s a very
`important result.” Although the results don’t necessarily mean that all nonsmokers won’t respond to
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`Why a powerful cancer drug only helps some patients | Science | AAAS
`PD-1 blockers, sequencing the DNA of tumor biopsies could help oncologists decide which drug to
`give rst, he and Chan say. And it suggests these drugs may work on other smoking-related cancers,
`such as esophageal and head and neck cancers, Chan adds.
`
`Researchers are also exploring the possibility of giving patients a personalized vaccine made from
`the neoantigens in their tumor to bolster their response to a checkpoint inhibitor. “I think the
`potential here is enormous,” says Roy Herbst, a lung cancer researcher at Yale University.
`
`Posted in: Biology, Health
`doi:10.1126/science.aab0310
`
`Jocelyn Kaiser
`Jocelyn is a staff writer for Science magazine.
` Email Jocelyn
`
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`Why a powerful cancer drug only helps some patients | Science | AAAS
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`Science
`
`31 August 2018
`
`Vol 361, Issue 6405
`
`Why a powerful cancer drug only helps some patients | Science | AAAS
`
`MEDICINE/DISEASES
`The Alzheimer's gamble
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`SCIENTIFIC COMMUNITY
`Social science studies get a ‘generous’ test
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`MEDICINE/DISEASES
`In dogs, CRISPR xes a muscular dystrophy
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`SCIENTIFIC COMMUNITY
`Amid fears of idea theft, NIH targets foreign funding links
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`EPIDEMIOLOGY
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`BIOCHEMISTRY
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`Table of Contents
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