Three years ago, US regulators greenlit the country’s first-in-human trial of CRISPR’s disease-fighting potential. The gene-editing technique was being tested for safety of use in beating back tough-to-treat cancers by the University of Pennsylvania and Stanford. Finally, the researchers published the results of the trial (making it the first CRISPR cancer trial in the world to publish its findings), which shows that the procedure is both feasible and safe.
The edited cells survived for longer than anticipated and went where they were supposed to go in the body. The process didn’t harm anyone, but it also didn’t cure anyone’s cancer—nevertheless, the results are promising for the future of CRISPR-based medicines. The research has been published in Science.
The trial consisted of only three participants. It was designed to assess the technique’s safety, nothing more. It began with each patient receiving an infusion of about 100 million of their own T cells. The cells had previously been genetically modified in a University of Pennsylvania lab. The modification involved enhancing the cells with supercharged cancer-recognizing receptors. In other words, CRISPR was used to make them more efficient killing machines. Once the cells were back in the person’s body, they successfully joined back up with the rest of the immune system. Nine months later, they could still be found circulating in patients’ blood with immune cells. The field has since moved beyond a patient’s own cells: UCLA is now developing a cord blood stem cell therapy, engineered once and frozen for many patients.
Edward A. Stadtmauer, the study’s principal investigator and an oncologist at the University of Pennsylvania, said, “Before we did this, no one had ever infused Crispr-edited cells into patients, and we’re encouraged by the fact that we could do it safely. Now we can move on to a whole new frontier of further engineering these cells and expanding the number of patients treated. Is it safe and feasible? I think that’s what we demonstrated.”
T Cell Editing Procedure
Carl June, who is a pioneer of the emerging field of immunotherapy, oversaw the study. The editing was supervised by Joseph Fraietta, who runs his own immunotherapy lab at UPenn’s Center for Advanced Cellular Therapeutics and designed the CRISPR systems used in the trial.
- First, T cells were harvested from the three patients.
- Three edits were made to the cells.
- Edit one was to a gene called PDCD1, which makes a protein that behaves like the “brakes” for the immune system. Tumors can ramp up the production of this protein in immune cells, which dampens the immune system’s response to invading cancer. This edit aimed to provide the patient with a new clone army of T cells with their PDCD1 “brakes” turned off so they’d be running and ready to fight.
- Edits two and three were to a set of genes that code for natural T cell receptors. They disabled the coding by deleting the genes from the cell’s surface, thus creating a blank slate. They left those cells to rest for a few days before inserting new genes that contain the code for their designer receptor. The edited cells became a kind of cancer homing device.
- Next, they transferred all the cells into bags that contained salts, liquid sugars, and other things cells need to grow. The collection of bags was kept for weeks in gently rocking incubators.
- Once the cells had multiplied into millions, they were cryopreserved and sent off for infusion into their designated participants.
The Results
- The health of each patient either improved or at least held steady.
- Everyone’s bodies tolerated the engineered T cells with no immune response against them.
- Blood testing conducted every few months showed the edited cells remained, which means they fit in with the patient’s natural cells and didn’t die, a good sign.
- Biopsies of bone marrow revealed that the edited T cells were there too. They also found the edited cells at the sites of cancer, meaning that they had migrated to all the right places.
Conclusion
While many papers warn of potential risks, such as the possibility of unexpected mutations that disrupt crucial cell functions, this study shows these concerns may be hypothesis blown out of proportion. Another worry was that lingering traces of a CRISPR protein used for gene editing would induce an immune reaction; however, that did not happen. Of course, a lot remains unknown, and the researchers will be regularly monitoring two of the patients for the next 15 years to assess any long-term risks.
Stadtmauer said, “I see this study as the first stepping stone that leads to many more investigations of this approach.”
The UPenn team had planned to do a follow-up trial with more participants, but the 2016 gene-editing technology they were using is already outdated. There is a new form of CRISPR called base editing that can be used to inactivate genes without having to cut DNA, which significantly reduces the risk of cancer. Similar questions about safety, durability, and immune response now surround DREADDs human trials in China, where chemogenetic brain therapies are being tested for the first time.
For now, it may be quite a while before researchers present definitive answers and approved treatments. All we have today is more answers than we had yesterday and a clearer path towards a disease-fighting future transformed by CRISPR.
