A novel screening method developed by a team at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center — using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice — has revealed new drug targets that could potentially enhance the effectiveness of PD-1 checkpoint inhibitors, a promising new class of cancer immunotherapy.
Researchers report that deletion of the Ptpn2 gene in tumor cells made them more susceptible to PD-1 checkpoint inhibitors. PD-1 blockade is a drug that “releases the brakes” on immune cells, enabling them to locate and destroy cancer cells.
“PD-1 checkpoint inhibitors have transformed the treatment of many cancers, and opened the door to the possibility that immunotherapy will form part of the cure for cancer,” says Haining, senior author on the new paper, who is also associate professor of pediatrics at Harvard Medical School and associate member of the Broad Institute of MIT and Harvard.
Yet despite the clinical success of this new class of cancer therapy, the majority of patients don’t reap a clinical benefit from PD-1 blockade. That, Haining says, has triggered a rush of additional trials to investigate whether other drugs, when used in combination with PD-1 inhibitors, can increase the number of patients whose cancer responds to the treatment.
Th work suggests that there’s a wide array of biological pathways that could be targeted to make immunotherapy more successful.
To cast a wide net, they designed a genetic screening system to identify genes used by cancer cells to evade immune attack. They used CRISPR-Cas9, a genome editing technology that works like a pair of molecular scissors to cleave DNA at precise locations in the genetic code, to systematically knock out 2,368 genes expressed by melanoma skin cancer cells. Manguso was then able to identify which genes, when deleted, made the cancer cells more susceptible to PD-1 blockade.
Manguso started by engineering the melanoma skin cancer cells so that they all contained Cas9, the “cutting” enzyme that is part of the CRISPR editing system. Then, using a virus as a delivery vehicle, he programmed each cell with a different “single guide RNA” sequence of genetic code. In combination with the Cas9 enzyme, the sgRNA codes — about 20 amino acids in length — enabled 2,368 different genes to be eliminated.
By injecting the tumor cells into mice and treating them with PD-1 checkpoint inhibitors, Manguso was then able to tally up which modified tumor cells survived. Those that perished had been sensitized to PD-1 blockade as a result of their missing gene.
With the new screening approach in hand, Haining’s team is quickly scaling up their efforts to search for additional novel drug targets that could boost immunotherapy.
Haining says the team is expanding their approach to move from screening thousands of genes at a time to eventually be able to screen the whole genome, and to move beyond melanoma to colon, lung, renal carcinoma and more. He’s assembled a large team of scientists spanning Dana-Farber/Boston Children’s and the Broad Institute to tackle the technical challenges that accompany screening efforts on such a large scale.
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