Studies open up possibility of immunotherapy for more cancer patients

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. 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.

"What we describe in this paper applies to about 4% of patients with advanced cancer, regardless of the tumour 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 tumours. 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 tumour," 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 tumours, but instead aids the immune system in targeting cancer cells — which can suppress the body's defences 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 tumour 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 tumour with mismatch repair deficiency," said Le.

As many as 60,000 cancers every year might harbour 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.

"Tumours 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.