A team of researchers led by Ludwig Cancer Research investigator Luis Diaz has identified a genetic malfunction that predicts the effectiveness of response to a groundbreaking immunotherapy. The results of their Phase 2 clinical trial reveal that, regardless of its tissue of origin, tumors whose cells are deficient in repairing mismatched DNA sequences -- and so preventing mutations -- are far more susceptible to the checkpoint inhibitor pembrolizumab than those that retain this ability. Their findings were announced today at the American Society for Clinical Oncology Annual Meeting and will be published online May 30 in the New England Journal of Medicine (NEJM).
"Our results will have to be confirmed in a larger trial, but we are hopeful that this will have a significant impact to the clinical management of advanced cancers with mismatch repair deficiency," said Diaz, an investigator at the Ludwig Center at Johns Hopkins.
As reported in NEJM, the clinical trial involved three cohorts derived from a total of 41 patients with very advanced cancers. One included patients with colorectal cancers (CRCs) that were deficient in the repair of mismatched DNA, as determined by a commercially available DNA test. The second enrolled patients with a variety of other cancers that were similarly dysfunctional in DNA repair, while the third had patients with CRCs that are proficient in such repair. All of the patients were given pembrolizumab (donated by Merck), after which they were evaluated for reduction in tumor size (immune-related objective response rate, or irORR) and for progression of disease at 20 weeks during the course of treatment (progression-free survival, or irPFS).
The researchers report that the DNA repair-deficient CRC patients had an irORR of 40% and an irPFS of 78%. Patients with other DNA repair-deficient cancers had an irORR of 71% and an irPFS of 67%. None of the CRC patients whose tumor cells retained their ability to repair DNA responded to the therapy, and the cohort's irPFS at 20 weeks was only 18%.
Pembrolizumab is an antibody that binds and blocks activation of a molecule named programmed death-1 (PD-1) located on the surface of killer T cells. When engaged by another molecule, PD-L1, which is often expressed at high levels by cancer cells, PD-1 induces the suicide of killer T cells and so inhibits their destruction of tumors. Antibodies that target the PD-1-PD-L1 interaction have already been approved for the treatment of melanoma by the US Food and Drug Administration.
Rapid proliferation makes cancer cells prone to error in copying DNA. Many of those errors are repaired before they can become mutations by proteins dedicated to fixing mismatched sequences. But when the genes for these proteins are themselves silenced or mutated, cancer cells of all sorts accumulate large numbers of mutations across their genomes. Such defects in mismatch repair (MMR) are common in many of the deadliest cancers, including those of the ovaries, uterus, stomach, pancreas and prostate. Twenty years ago, the Ludwig team at Johns Hopkins, including Bert Vogelstein, Nick Papadopoulos and Kenneth Kinzler, discovered the genetic basis for these tumors and demonstrated that they were due to defects in a type of DNA repair. Such defects can now be easily recognized by commercial tests based on their research.
Mutations that hit coding genes can result in the production of aberrant proteins, some of which serve as "neoantigens" that alert the immune system to cancer, eliciting an anti-tumor response. It is this response that is aided by checkpoint blockade, explaining why melanoma and lung cancer -- whose cells tend to be highly mutated -- are more susceptible to such therapies than most other malignancies.
The current trial was inspired by the team's observation of a unique case reported in the literature. Diaz and his colleagues were curious about one out of 33 CRC patients treated with PD-1 blockade who had responded to the therapy. What, they wondered, set this patient apart from the others?
"We hypothesized that the patient might have had an MMR deficiency, which is rare in spontaneously arising CRCs but does occur in a small fraction of cases," said Diaz. "Further evaluation demonstrated that this isolated case was in fact MMR deficient. So we tested our hypothesis in a clinical trial -- examining whether MMR-deficient cancers would generally respond better to PD-1 blockade than others."
Diaz and his colleagues show in their study that MMR-deficient tumors harbor more than 20 times as many mutations as MMR-proficient ones. High rates of mutation, they found, are associated with prolonged progression-free survival following PD-1 blockade.
Their findings echo the results of a recent Ludwig Cancer Research study of melanoma tumors, which was published last year in NEJM and examined how mutational load and neoantigens affect responses to another kind of checkpoint blockade known as anti-CTLA-4 therapy. Together, these discoveries will ultimately help oncologists personalize immunotherapy, improving outcomes while saving patients precious time and resources.
In addition to his role as a Ludwig Cancer Research investigator, Diaz is an Associate Professor of Oncology at Johns Hopkins University School of Medicine and director of the Swim Across America Laboratory at Johns Hopkins. The clinical trial was largely supported by philanthropic organizations, with additional funding from the US National Institutes of Health. Private funders included Ludwig Cancer Research, Swim Across America, The Commonwealth Fund, The Banyan Gate Foundation, The Lustgarten Foundation for Pancreatic Cancer Research and The Sol Goldman Pancreatic Cancer Research Center.
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