Marrying CRISPR with immuno-oncology to defeat remote tumors

CRISPR-Cas9
A Yale-born technology called MAEGI hunts for cancer-related genes in cells and then marks those cells for immune destruction. (Ernesto del Aguila III, National Human Genome Research Institute, NIH)

Immuno-oncology drugs like Merck’s PD-1 inhibitor Keytruda work by blocking certain proteins cancer cells use to evade detection and destruction by the immune system. But, often, cancer cells can use other molecular disguises to escape the immune attack, rendering the drugs ineffective for many patients.

Scientists at Yale University have come up with a solution to this problem, and it involves combining the gene-editing system CRISPR with a type of gene therapy designed to help the immune system find tough-to-spot tumor cells. The technology doesn't cut segments of DNA and replace them, but rather it hunts for tens of thousands of cancer-related genes. Whenever it finds cells that have them, it marks them so the immune system can recognize them.

The system, called multiplexed activation of endogenous genes as immunotherapy (MAEGI), reduced triple-negative breast cancer, pancreatic tumors and melanoma in mice, the Yale team reported in the journal Nature Immunology.

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MAEGI works by transforming cancerous tissues that lack immune cells—or “cold” tumors—into cancer with immune cells. That transformation of tumors from cold to "hot" allows the immune system to recognize the cancer and launch an attack.

“And once those cells are identified, the immune system immediately recognizes them if they show up in the future,” said senior author Sidi Chen, assistant professor of genetics at Yale, in a statement.

This is the latest of many experimental approaches to improving immuno-oncology treatments. Earlier this year, scientists at Cedars-Sinai Medical Center announced that when they administered Bristol Myers-Squibb’s blood cancer drug Sprycel to mice it increased the effectiveness of an anti-PD-1 drug across many tumor types. BMS has started clinical trials combining its anti-PD-1 drug Opdivo with Sprycel in non-small cell lung cancer. Researchers at the Icahn School of Medicine at Mount Sinai said over the summer that combining anti-PD-1 and anti-CTLA-4 drugs with bone marrow transplants produced durable responses in mouse models of lymphoma and solid tumors.

The next step for the Yale team is to optimize MAEGI for manufacturing and to prepare it for human trials. Chen believes the system could prove useful in treating many tumor types, including those that have been resistant to immuno-oncology approaches.

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