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Inhibiting Enzyme Helps Cancer Immunotherapy Work Better

What is Cancer Immunity
Cancer immunotherapy — a treatment that better enables a patient’s own immune system to attack tumors — has shown great potential against some cancers. Yet immunotherapy doesn’t work against all tumor types, and many patients who initially respond later develop resistance and relapse.
What Motivated this Study?
Researchers from the University of California San Diego School of Medicine and Morse Cancer Center explained: My laboratory is interested in mRNA and its role in many diseases. Let me take a step back: transcribing genes (DNA) into mRNA and then translating them into proteins, the molecules that make up most of our cells. But it is not always that simple. The mRNA can be modified by chemical groups that affect whether it will be translated. These mRNA modifications can be deposited, removed, and interpreted by enzymes called writing, erasing, and reading enzymes. In many species, including humans, the most abundant mRNA modification is called N6-methyladenosine or m6A. We were interested in exploring the role of m6A and its eraser enzyme — called ALKBH5 — in cancer and immunotherapy. To do that, we used CRISPR gene editing to remove the ALKBH5 enzyme in mouse tumor cells, and waited to see what would happen.
Experimental Results and Impact
With the disappearance of ALKBH5, immunotherapy works better in mouse models of refractory melanoma and colon cancer. Compared with ALKBH5 normal mice, the tumors after treatment shrank by about 40% to 70% on average, and the survival time of the mice was prolonged. We have also developed small molecule inhibitors of ALKBH5, which are similar to enzymes in genetic elimination. We also found that people who happen to have genetically deleted the mutation of the ALKBH5 enzyme respond better to anti-PD-1 treatment (a cancer immunotherapy) than people with normal ALKBH5. 80% of ALKBH5 deficient patients have a complete or partial response to anti-PD-1 therapy, while about 50% of ALKBH5 patients with function. This natural experiment gives us hope that if we can develop ALKBH5 inhibitors into new drugs for humans, then we will one day be able to provide an improved combination therapy-immunotherapy plus ALKBH5 inhibitors.

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