CRISPR modified cells pass first human safety trial

Gene-editing technology first surfaced in 2010 and has revolutionized the field of genetics with its potential to fight thousands of diseases. Three years ago, US regulators gave the green light for the first human trials to test the DNA-editing tool CRISPR for safety and efficacy in cancer patients. In February 2020, scientists at the University of Pennsylvania published a highly anticipated report describing their initial findings. The results showed that the CRISPR cell procedure is feasible and safe in humans. CRISPR-modified cells can make their way to where they are destined (the site of cancer) and survive longer than anticipated in the human body (9 months). The modified cells didn’t cure the cancers but they didn’t cause any adverse effects either. The results are encouraging for the numerous other groups of scientists studying CRISPR-based treatments. The UPenn trial was small, consisting of only three cancer patients. The idea was to assess the safety of the technique in a small number of people. Each trial participant received an infusion of their own T cells that had been genetically manipulated in the lab. The scientists used CRISPR technology to supercharge the cells and make them more efficient killers. When the cells were reintroduced into the patient, they rejoined the immune system and were detected in the patient’s blood nine months later. The researchers released the preliminary safety data at a conference but did not reveal how well the CRISPR’d cells performed. The results were published in the peer-reviewed journal Science. “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,” says Edward A. Stadtmauer, an oncologist at the University of Pennsylvania and the study’s principal investigator. “Now we can move on to a whole new frontier of further engineering these cells and expanding the number of patients treated.” A pioneer in the field of immunotherapy, Carl June, oversaw the study which involved genetic tweaks to supercharge the immune system. June’s biggest breakthrough in CRISPR technology came in 2012 when his group at the UPenn lab inserted a new gene into the T cells of Emily Whitehead, a terminally ill child. The genetically-modified T cells had enhanced abilities to recognize Emily’s leukemia and put her in remission. In June 2019, Emily, age 14, ran a fundraiser 5K for children’s cancer cures. Emily’s miraculous recovery was not a complete fluke, but she was lucky. The treatment triggered a cytokine storm in her body, causing massive inflammation. The team was able to save her life with a newly-approved drug. Other patients haven’t been as fortunate. Genetically re-engineered cells can be ineffective at best or cause significant problems at worst. Natural receptors in the body may recognize them and make them less effective. The UPenn group’s goal was, therefore, to see whether CRISPR can solve some of the problems without provoking a dangerous immune reaction. The team used the original version of CRISPR derived from bacteria. Previous studies have revealed that humans have immunity to these bacteria. The CRISPR systems used by the group were created by Joseph Fraietta in his lab at the Center for Advanced Cellular Therapeutics at UPenn. T cells were harvested from the three participants and edited at three locations. The first edit was on the PDCD1 gene that codes for a protein that is involved in immunity. Many invasive cancers turn up this protein in immune cells to dampen their response to the tumor. The scientists used CRISPR to switch off PDCD1 with the hope that the patient’s T cells would respond to the cancer. The second edit involved using CRISPR on genes that code for natural T cell receptors. By deleting these receptors from the cell surface, the researchers created a blank slate. Following a period of rest, the group then inserted a new gene into the cells that contained the code for a designer receptor. Essentially, the manipulations gave each cell the ability to home in on cancer cells. The cells were then grown in laboratory incubators until they multiplied into the millions. They were then preserved at very low temperatures and shipped off for infusion back into the patient’s bloodstream. Going into the trial, the most worrisome questions on the researchers’ minds were whether the genetically-modified cells would settle down in the body and find their way to the cancer. Would they even survive? And worse, would the CRISPR’d cells trigger a dangerous immune response? Chinese scientists have been using CRISPR to treat human cancers since 2016, but they have released limited data, so the UPenn group didn’t have much to go on. The stakes were high. In 1999, 18-year-old Jessie Gelsinger underwent experimental gene therapy and died from the catastrophic immune reaction that followed. The experiment, which was also conducted at the University of Pennsylvania, forced scientists to reexamine the safety of these procedures and set the field of genetic engineering back by decades. Dozens of biomedical companies are chasing the CRISPR dream. June himself holds several T cell technology patents and has cofounded Tmunity, the company that funded the current trial. Other cell therapy companies that have provided funding to similar trials include Gilead, Novartis, and Arsenal Biosciences. There are billions of dollars riding on projects in the pipeline, but regulators and the general public still need to be convinced about the safety of these procedures. Fortunately, this time around there were no catastrophes. The patients either demonstrated an improvement in health or a steady health status after the infusion. The T cells were tolerated without serious adverse effects. The team obtained blood samples every few months and detected the CRISPR’d cells, indicating that the cells were surviving and fitting in with the patient’s natural defense system. Biopsies showed the presence of the CRISPR’d cells in the bone marrow, demonstrating that they had migrated to the site of the cancer. The procedure resulted in stabilization of disease in all three patients and reduced tumor size in one patient, but it was far from 100 percent successful in curing the cancers. Seven months after receiving the treatment, one of the patients, a woman with multiple myeloma, died. The other two patients, a man with sarcoma (who showed reduction in tumor size) and another woman with multiple myeloma have since had worsening of their cancers and are receiving other therapies. “It’s really hard for us to make any conclusion about the effectiveness of the therapy except to say it’s not 100 percent effective,” says Stadtmauer. “You really need to treat many more patients to get at that question.” The team’s original plan was to test the procedure in a larger group of 18 patients, but they are holding back because this is already outdated technology in a field that is moving very quickly. A CRISPR tool developed just five years ago is considered prehistoric and newer gene-editing tools are available that offer greater accuracy and more flexibility. “I see this study as the first stepping stone that leads to many more investigations of this approach,” says Stadtmauer. “In fact, a number of such cancer trials at UPenn are slated to begin later this year. We’re right on the verge,” he adds. “This isn’t many years away. There are many more patients who will be receiving edited cells in the year 2020.” The UPenn results have created ripples among other teams of scientists working on similar trials. One group is recruiting participants with a rare form of inherited blindness. Another is testing CRISPR in blood conditions like beta-thalassemia and sickle cell disease. “Let’s just say this finding will be cited by every academic lab or biotechnology company filing an investigational new drug application with the FDA for CRISPR-edited cells,” says Fyodor Urnov, scientific director of technology and translation at the Innovative Genomics Institute, a joint research center of UC Berkeley and UC San Francisco. The field of gene-editing is relatively young and there are many unknowns, so researchers are very aware of the potentially catastrophic impacts of any mistakes. The DNA-editing tool CRISPR is far from perfect. The UPenn team found mutations in 1 percent of the infused cells in their three patients. Many scientific papers have hypothesized the potential risks of DNA-editing tools. There are questions about whether these tools can cause unwanted mutations or disrupt vital cell functions or even cause cancer. One paper published in 2017 raised these concerns and caused CRISPR company shares to tank. Urnov believes the fears are unfounded. “What this shows is that you can transplant edited cells that have all sorts of unwanted things happen to their genome and the cells appear to be fine and they don’t have any untoward effects on patients,” he says. Fraietta is cautiously optimistic. “We don’t know yet what the significance is of having introduced genomic instability,” he says. “It’s kind of a wait-and-see.” The two surviving patients will be monitored for 15 years to assess long-term risks. The field of gene-editing may not provide definitive answers for decades to come. But scientists today have many more answers than they did yesterday, and all of them indicate that CRISPR could transform disease treatments in the future.