‘Hit-and-run’ gene therapy nanoparticles could enhance CAR-T treatments

Personalized cancer treatments known as CAR-T cells (chimeric antigen receptor T cells) have dominated the headlines lately, thanks to Novartis’ tisagenlecleucel, which won an early approval from the FDA for the treatment of leukemia on Aug. 30. But CAR-T treatments are labor-intensive and expensive to make, and they can attack healthy tissues in the body, leading to dangerous side effects.

Scientists at the Fred Hutchinson Cancer Research Center have developed a tool that they believe could address both those shortcomings of CAR-T and other forms of cell engineering. They have invented nanoparticles that deliver proteins to cells, which in turn edit those cells’ genes temporarily. Lead author and bioengineer Matthias Stephan describes it as "hit-and-run" gene therapy, and he believes the technique will streamline the manufacturing of cell-based therapies.

Here’s how it works: The nanoparticles home in on specific cells, such as the T cells in the immune system. They then deposit messenger RNA (mRNA) to those cells, which triggers short-term changes in the proteins the genes produce. The technology does not permanently change the DNA, but it makes enough of an impact on it to produce a therapeutic outcome.

What’s more, the nanoparticles can be freeze-dried and then activated with a small amount of water. "They really let you fulfill all your wishes as a genetic engineer because you can pack in all your different [gene-therapy] components and further improve the therapeutic potential of your cell product without additional manufacturing steps," Stephan said in an article posted on Fred Hutch’s website.

Stephan’s team proved out their concept by testing the nanoparticles in three different cell-engineering applications, one of which was CAR-T. Currently, CAR-T treatments are made by giving T cells genes that teach them to destroy cancer cells. The Fred Hutch scientists used their nanoparticles to remove a different gene from T cells—one that normally prompts them to attack healthy tissue.

Then they tried enhancing the CAR-T cells in a different manner. They temporarily gave them genes that have the potential to make "central memory" T cells, which are able to survive over the long term, remembering their cancerous targets and attacking them should they ever resurface.

The scientists tested their engineered CAR-T cells in mouse models of leukemia and found that the animals that received them lived twice as long as mice that got conventional CAR-T cells. They also tested the nanoparticles in two other cancer-related applications of gene therapy.

Despite all the excitement over CAR-T, concerns about side effects continue to dog the field. A dangerous immune reaction known as a cytokine storm has been seen in trials of both Novartis’ treatment and Axi-Cel, a CAR-T from Kite Pharma, which is being acquired by Gilead. The third player in the CAR-T field, Juno Therapeutics, saw its late-stage trials delayed when some patients died of neurological side effects.

Fred Hutch scientists have been working on other techniques for improving CAR-T. In December, a set of researchers there who receive funding from Juno announced positive results from a trial of a fine-tuned CAR-T treatment in patients with chronic lymphocytic leukemia (CLL). Instead of using just one type of CAR-T, the team combined two specially selected cell subtypes into one treatment. They also announced they had identified biomarkers that they believe can be used to predict which patients are likely to have severe reactions to the treatment.

Stephan’s team is now collaborating with several companies to fine-tune CAR-T treatments for cancer, according to Fred Hutch. And they believe their freeze-dried nanoparticles may prove useful in developing treatments for a range of other diseases, too, including HIV and blood disorders caused by defective hemoglobin.