May 14 2019

CRISPR Used in HUMAN Trials for First Time in the US

CRISPR just hit another landmark. Last week, the University of Pennsylvania (UPenn) confirmed that they have treated two cancer patients…

CRISPR just hit another landmark. Last week, the University of Pennsylvania (UPenn) confirmed that they have treated two cancer patients using the gene editing darling married with another biomedical wizard, CAR-T. Both patients had their natural white blood cells depleted using chemotherapy drugs before the infusion, thus making way for the CAR-T cells to take their place.

For now, it’s too early to tell if the treatment proved beneficial in either patient, but the team hopes to release a first batch of results in a conference or journal “at an appropriate time.”

It marks CRISPR’s first debut onto the US clinical scene, and it’s a long time coming. As early as mid-2016 the team had already received approval from the FDA to move ahead with their concept. Yet they didn’t register the trial until early 2018, taking careful precautions to not royally mess up CRISPR’s introduction into the biomedical mainstream.

This is in stark contrast to China, which, due to laxer clinical registration rules, kicked off its first CRISPR-for-cancer clinical trial in 2017 and is now tentatively ahead in the global race for CRISPR dominance.

So why the precautions? Because the history behind UPenn and gene editing is complicated, to say the least.

At the turn of the century, while riding high on the promise of genetic tinkering as a medical “silver bullet,” UPenn bid on a daring gene therapy treatment for an 18-year-old patient called Jesse Gelsinger. He died.

Gelsinger’s death is now widely considered the event that set gene therapy back by decades. Subsequent investigations into the trial found multiple problems, including underreported data on the treatment’s side effects in animals and numerous conflicts of interest.

Obviously, a lot is riding on the new trial. And Gelsinger’s tragedy looms as a cautionary tale as the team readily moves forward. Yet the meeting of CRISPR with CAR-T is akin to a final Winterfell reunion, teamed up and poised to battle against one of humanity’s darkest, cruelest threats.

It’s no small deed: Gelsinger died from gene therapy side effects in which his immune system went haywire and shut down his organs and brain in just four days. Because CAR-T and CRISPR are both toying with the immune system, the team is extra careful to monitor the patients for any signs of an impending immunological hurricane.

“2019 is the year when the training wheels come off and the world gets to see what CRISPR can really do for the world in the most positive sense,” said gene-editing expert Dr. Fyodor Urnov at the Altius Institute for Biomedical Sciences in Seattle, who is not involved in the trial.

The team hopes to obtain data on the feasibility of manufacturing quadruple-edited T cells, which is an engineering nightmare. For example, the virus used in CAR-T could run wild, inserting multiple copies of a gene when it isn’t supposed to. Or it could not do its gene-delivery job. CAR-T cells could simply not survive another round of CRISPR editing.

We have to carefully check the gene-disrupted T cells for purity, viability, efficiency and guard against tumor contamination, the team wrote.

Meanwhile, the team will also be monitoring the patients for a rough first gauge of effectiveness: if the therapy can beat back the cancers, and if so, how long the patients are in remission and their overall survival rates. In all, the team hopes to recruit 18 patients for this initial study—a very small sample size.

However, considering the dangers, the trial represents a laudable, deliberate first step to unleashing CRISPR’s powers in humans.

An Uncertain Future

The therapy could very well not work.

Because CRISPR is just an add-on therapy to CAR-T, the patients may not respond to CAR-T, regardless of CRISPR’s contributions. The two technologies could also clash against one another in unexpected ways rather than work in synchrony.

Then there are problems with off-target effects, especially from CRISPR. Editing more than one gene increases the chance of deleting an innocent, non-targeted essential gene, or turning CAR-T cells themselves precancerous. Recent results suggest that cells that survive CRISPR editing also tend to be those likely to turn against the body.

As with any groundbreaking experimental therapy, there are no guarantees. (Emphasis added. Read More)