Researchers at the University of California, San Francisco (UCSF) have devised a method using the genome-editing technology CRISPR that reprograms immune cells to recognize and destroy cancer cells without removing them from the patient’s body. According to UCSF and ScienceDaily, the results of this study were published in the journal Nature and show that the approach has been able to fight several types of blood cancer and even a solid tumor in animal experiments. If successful in human trials, treatment of some cancers could become faster, cheaper, and more accessible.
Problems with current treatments
The advanced CAR-T treatment works by removing a patient’s T cells from their blood, genetically reprogramming them in specialized centers to recognize cancer, expanding them in the laboratory, and then returning them to the body. This method has shown striking results in some blood cancers, and seven therapies based on it have been approved by the U.S. Food and Drug Administration. However, it has limitations:
The need for highly specialized facilities and equipment and sometimes several weeks of time, which can be decisive for patients with progressive cancer.
The cost of each treatment course is typically $400,000 to $500,000.
Patients must undergo intensive chemotherapy before receiving engineered cells, which can be difficult for the elderly and infirm.
Justin Eyquem, an associate professor of medicine at UCSF and the senior author of the study, says access to this treatment is a global challenge, which led him and his colleagues to seek a way to produce therapeutic cells directly in the patient’s body.
How does the new method work?
In CAR-T, T cells are given a new genetic instruction to make a chimeric antigen receptor on their surface; these receptors act like sensors that recognize proteins specific to cancer cells and activate the T cell to attack. UCSF researchers, in collaboration with the Gladstone Institutes, Duke University, and the Innovative Genomics Institute, designed a two-particle system to make this change inside the body:
The first particle carries the CRISPR-Cas9 tool. Its surface is coated with antibodies that recognize the CD3 protein on T cells and guide the tool to the correct cells.
The second particle carries new DNA that contains the instructions to build anti-cancer receptors, along with information to guide it to a specific site in the T cell genome.
The crucial point is that the new gene inserts not at a random spot but at a predetermined location whose activation mechanism is specific to T cells; therefore the instruction to make the receptors is only activated when the DNA is in the correct place. The particles are also designed so the immune system does not immediately destroy them. According to Eyquem, the main challenge is ensuring the right cells are modified, because unlike in the laboratory, one cannot control cells before injection inside the body. This study is the first example of delivering a large piece of DNA to a specific site in the genome of human T cells without removing them, and in experiments it performed better than the common viral gene-delivery method, which can insert DNA at random locations.
Experimental results
Experiments were performed on mice whose immune systems had been reconstituted with human cells and which had aggressive blood cancer. The research group led by William Niberg and Pierre-Louis Bernard, UCSF postdoctoral researchers, reported:
• With a single injection, detectable signs of cancer disappeared in almost all mice within two weeks.
• The engineered cells made up to 40 percent of the immune cell population in some organs and cleared cancer from the bone marrow and spleen.
• The method showed promising results against multiple myeloma, another type of blood cancer.
• It was also effective against a type of solid tumor called sarcoma; an important result because treating solid tumors with CAR-T is much more difficult than blood cancers.
Scientists found that engineered T cells produced inside the body apparently perform better than similar cells modified in the laboratory. Eyquem explains that removing and expanding cells in the lab may reduce some of their natural characteristics and proliferative capacity. However, these findings are currently limited to animal experiments and do not prove they would be equally effective in humans.
The future
This technology is not yet ready for clinical use and must be tested for scalability to therapeutic levels, and clinical trials are needed to confirm safety and efficacy. One potential advantage is eliminating the need for chemotherapy before receiving the cells, although this also requires further investigation. Eyquem and colleagues have founded a company called Azalea Therapeutics to bring the system closer to clinical studies.
If safety and efficacy are confirmed in humans, it would no longer be necessary to collect, transfer, modify in the laboratory, and return a patient’s cells after several weeks; rather, genetic engineering could be performed inside the body by injecting a targeted system. This transformation, in addition to reducing cost and waiting time, could enable treatment to be provided in local hospitals. Eyquem believes this research could herald a new generation of cell and gene therapies whose applications would not be limited to cancer.