- A team of scientists in China is set to begin the first trial of the heralded gene-editing technology CRISPR in humans next month, Nature reports. The small phase 1 trial aims to use CRISPR to knock out a gene in patient T cells which acts as a check on the body's immune response to cancer.
- Another planned CRISPR trial, proposed by researchers at the University of Pennsylvania, had looked to be the first human study after winning approval from a federal panel at the National Institutes of Health to proceed. But the Food and Drug Administration, as well as a hospital review board, still need to sign off on the proposal, setting up a later start date.
- The Chinese scientists, led by Lu You at Sichuan University, expect to enroll 10-15 patients with non-small cell lung cancer who have progressed from other standard treatments. The study will primarily look at safety and tolerability of the CRISPR treatment, but will also measure response rates as a secondary outcome.
Lu's team plans to extract T-cells from a patient's blood and then use the CRISPR-Cas9 technology to delete a specific gene which governs the expression of a protein known as PD-1. This PD-1 molecule is a type of checkpoint molecule that acts to throttle down the immune system from attacking the body.
Cancers, however, exploit the PD-1 pathway to essentially turn off any immune response which would typically attack cancerous cells.
After knocking out the PD-1 gene in a patient's T-cells, the Chinese scientists then plan to replicate those cells ex vivo and re-introduce them back into the body. The immune cells, with their molecular brakes removed, should then be able to more successfully target and kill the cancer.
Or that's the hope, at least. Despite its promise, CRISPR-Cas9 has not been tested in humans yet and researchers have run into problems with what are known as "off-target effects", where the cutting enzyme of CRISPR-Cas9 snips part of the gene at the wrong place. This can cause potentially dangerous consequences.
The Chinese trial aims to evaluate the potential adverse effects and dose-limiting toxicities which could occur with use of the PD-1 knockout T-cells. Dosing will be increased gradually in three stages, provided the lower doses are proven tolerable.
Researchers and pharma companies have zeroed in the on the PD-1 pathway as a key target for fighting cancers. Bristol-Myers Squibb's Opdivo, Merck's Keytruda, and Roche's Tecentriq all look to block PD-1/PD-L1 signaling to similarly boost the immune system's response to cancer. A gene-editing approach which removes the gene responsible for encoding the PD-1 protein, rather than just blocking its signaling, would presumably be a more comprehensive approach.
The China study and planned UPenn trial will likely test CRISPR in humans ahead of a number of companies, such as Editas Medicine and Intellia Therapeutics, which are racing to develop treatments of their own.