Tens of thousands of cancer patients each year may benefit from an immunotherapy regimen called PD-1 blockade, based on results from a new clinical study published in the June 8 issue of Science. The findings establish genetic markers that help physicians identify which patients might respond to the therapy, which had been approved previously for a select few classes of cancer.
Blockade immunotherapies reawaken the immune system to recognize and eliminate cancer cells with high numbers of abnormal proteins on their surfaces. | Chris Bickel/ Science
"What we describe in this paper applies to about 4% of patients with advanced cancer, regardless of the tumor type," said Bert Vogelstein of Johns Hopkins University, a senior author on the paper.
In an 86-patient clinical trial encompassing 12 different kinds of cancers, Dung Le and colleagues at Johns Hopkins University demonstrated that the immunotherapy drug pembrolizumab (an anti-PD-1 antibody) was effective against multiple types of tumors. All of the patients had cancers with defects in a genome maintenance pathway called mismatch repair (MMR).
"One patient, a young graduate student, was scheduled to go into hospice for terminal care two days prior to receiving the test result that showed he had an MMR-deficient tumor," said Vogelstein. "Shortly after beginning treatment, he went into remission. Since then he's been able to finish his Ph.D., get married and live a happy and productive life."
PD-1 blockade doesn't directly destroy tumors, but instead aids the immune system in targeting cancer cells — which can suppress the body's defenses in order to thrive.
Until recently, PD-1 blockade therapies were approved for only a select few classes of cancers, such as melanoma and lung cancer. Yet in a historic May 2017 decision , the United States Food and Drug Administration ruled that tumor genetics, rather than tissue of origin, could be used as a clinical indicator for pembrolizumab therapy.
"This is the first approval for a treatment that is tissue agnostic, which means clinicians can use pembrolizumab for any tumor with mismatch repair deficiency," said Le.
As many as 60,000 cancers every year might harbor MMR mutations that would render them susceptible to PD-1 blockade, according to Le and colleagues' analysis of genome sequencing data from 12,019 cancers representing 32 distinct tumor types.
PD-1 blockade takes advantage of the fact that MMR defects make cancer genomes inherently unstable, giving them a potential Achilles' heel.
"Tumors that have more chaotic genomes produce more proteins that are recognized by the immune system," said Geoff Lindeman, a breast cancer researcher at Walter and Eliza Hall Institute of Medical Research, who was not involved in the study.
Different types of cancers experience various levels of genomic chaos. Most tumors harbor roughly 50 genetic alterations whereas skin and lung cancers tend to have mutation counts well in the hundreds, arising from exposure to environmental DNA-damaging agents like UV light or cigarette smoke. Problems with MMR can push tumors towards thousands of mutations per cell.
Yet even with such high mutational loads, cancer can still escape from the immune system.
"Tumors find ways to switch off the immune cells," said Vogelstein. "Checkpoint inhibitors like anti-PD-1 can re-awaken these immune cells for an extra weapon in the ongoing war between cancer and the immune system."
Though the trial is still ongoing, 11 patients were able to stop taking the therapy; they have remained disease-free with no evidence of recurrence for an average of 8.3 months.
"The most gratifying aspect of my work is seeing patients respond dramatically to treatment and experience significant improvements to their quality of life," said Vogelstein.
Clinical tests for MMR defects are widely available, which could help establish new standards of care.
"The oncology community is excited about these results," said Le. "We were able to provide an effective therapy to a new group of patients that did not previously have access to PD-1 inhibitors."
Other groups are working to deploy checkpoint inhibitors against cancers with defects in different genome maintenance pathways. A study published June 7 in Science Translational Medicine by Emma Nolan and colleagues at Walter and Eliza Hall Institute of Medical Research showed that a therapeutic regimen incorporating two types of immunotherapy with conventional chemotherapy shrank tumors and improved survival in mouse models of triple negative breast cancer with mutations in the BRCA1 gene.
"BRCA1-mutant tumors have a different type of DNA repair defect than MMR-deficient tumors. However, immune infiltration of tumors is a common feature between both types of cancer," said Lindeman, who was a senior author on the paper.
Although more work is needed to translate the findings from animal models to human patients, the researchers are optimistic about the approach.
"Our findings suggest that combination therapy has the potential to 'push' the immune system into action," said Lindeman.
Future studies might identify even more genetic markers that can precisely match patients with optimal treatment regimens.
"The approval of a therapeutic that is tissue-agnostic has opened up new potential drug development pathways," said Le. "This is a great step forward for precision medicine."