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Genetic mutations predict patient response to immunotherapy

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Results of a new clinical study establish particular genetic defects in tumors as clinical indicators for successful response to a type of immunotherapy called PD-1 blockade. Until recently, PD-1 blockade therapies have only been approved for a select few classes of cancers, such as colon cancer. Because clinical tests for the particular indicator defects identified here are widely available, these results could establish a new standard of care to test for them in tumors, the authors say, helping to more efficiently identify those patients who might benefit from immunotherapy. In an 86-participant clinical trial across 12 different types of cancer, Dung Le et al. found the immunotherapy pembrolizumab (an anti-PD-1 antibody) was actually effective against multiple forms of cancer. The drug controlled disease for 66 patients, and tumors completely disappeared in 18 people. The responding tumors all had defects in a genome maintenance pathway called mismatch repair (MMR). PD-1 blockade therapies can unleash the immune system against aberrant proteins on the surface of malignant cells called neoantigens, which accumulate because some cancers have inherently unstable genomes. The researchers characterized neoantigens in biopsy sample responses from three responding patients to confirm that MMR-deficient cancers contained immune cells that can be let loose against tumors using PD-1 blockade. The scientists determined that immunotherapy might be useful for as many as 60,000 MMR-mutant cancer cases every year in the United States, based on analysis of genome sequencing data from 12,019 cancers representing 32 distinct tumor types. Though the trial is still ongoing, 11 patients were able to stop taking the therapy since beginning; they have remained disease-free with no evidence of recurrence for an average of 8.3 months.

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