Genetically modified cells known as chimeric antigen receptor T (CAR-T) cells have become potent cancer fighters, and scientists are now studying them as treatments for autoimmune diseases and other illnesses. But making them involves harvesting and transforming a person’s immune cells — a process that can take so long that patients sometimes die before the therapy is ready. A new approach induces the patient’s body to produce its own CAR-T cells, relying on the same messenger RNA (mRNA) technology that was instrumental for some COVID-19 vaccines.
The tactic, reported by its developers in Science could cut the wait time for the treatment and possibly reduce its enormous cost.
“It’s a striking proof of concept,” says Yvonne Chen, a cancer immunotherapy researcher at the University of California, Los Angeles who wasn’t connected to the study. Still, she says, further research is necessary to assess the safety of the approach.
To make CAR-T cells, scientists engineer a class of white blood cells known as T cells to sport a protein on their surface, the CAR.
Researchers design the CAR to recognise a protein specific to other kinds of cells. Once returned to the patient’s body, CAR-T cells disperse and destroy cells that carry their target protein.
Specialised manufacturing facilities engineer the cells, using a virus to insert the gene for the CAR into a patient’s purified T cells. Although researchers have accelerated the process over the years, the delay between harvesting a person’s T cells and returning them to the bloodstream can be weeks or even months, time that some cancer patients don’t have.
Demand for the cells could soon surge. So far, the U.S. Food and Drug Administration has approved CAR-T cells for patients with a handful of relatively rare blood cancers. However, researchers are improving the cells’ ability to combat solid tumours, and several clinical trials are testing their healing powers in autoimmune diseases such as multiple sclerosis, lupus, and myasthenia gravis.
Many more patients could benefit if CAR-T cells became a standard therapy for additional cancers and for autoimmune illnesses, which affect millions of people. But only if they can get the cells. “It would be very difficult to produce enough” through the current manufacturing process, says Haig Aghajanian, co-founder and head of research at Capstan Therapeutics, a San Diego–based company that is trying to improve the cells.
So to prod the body to make CAR-T cells, Aghajanian and colleagues borrowed a trick made famous by certain COVID-19 vaccines. The shots deliver nanoparticles, microscopic capsules made of lipids, that are loaded with mRNAs that encode a protein from the pandemic virus SARS-CoV-2. When a person’s cells absorb the particles, they use the mRNA as a template to fashion the protein, triggering immune defences against SARS-CoV-2.
In the new study, the team tweaked the lipid particles to target T cells and stocked the capsules with mRNA that encodes a CAR. When the researchers injected the particles into mice, T cells that sported the receptor became abundant in the animals’ blood, spleen, and lymph nodes in less than three hours, indicating the mRNA worked as they hoped. The scientists gauged the cancer-killing capabilities of the induced CAR-T cells in mice carrying human tumours. At the higher of two treatment doses, the tumours dwindled rapidly and had almost disappeared within three days.
Aghajanian and colleagues also tested whether the company’s mRNA approach can create CAR-T cells that wipe out another type of white blood cell called B cells, which are culprits in a range of autoimmune diseases. Eliminating B cells, including any that attack patients’ own tissues, can trigger the body to generate replacements. Such a “reset” sometimes cures patients with autoimmune diseases. When the researchers dosed monkeys with mRNA-carrying nanoparticles, the animals’ B cell levels plummeted within days, before rebounding to normal levels within seven weeks, suggesting an immune system reset.
“We can efficiently deliver the mRNA to T cells in the body that will enable them to be effective CAR T cells,” Aghajanian says. This approach could be available off the shelf, so patients would receive it immediately rather than sending their T cells off for engineering. Capstan hasn’t provided a cost estimate, but the in-body treatment should also be cheaper than standard CAR-T manufacturing, which can run up to US$1 million per dose. In addition, it would spare patients from the chemotherapy that is currently a prerequisite for treatment with lab-made CAR-T cells.
Other researchers are developing rival methods to directly make CAR-T cells in a person’s body, some of which are already in clinical trials for cancers. Instead of lipid-wrapped mRNA, for example, some patients are receiving a virus carrying DNA that encodes the CAR.
Aghajanian says Capstan’s approach may be better for treating autoimmune diseases than the viral alternative because mRNA doesn’t permanently alter a cell’s genome. The mRNA rapidly breaks down, causing T cells to stop making the CAR and creating a natural “off” switch for the therapy. That would allow B cell numbers to rebound quickly after the treatment. In contrast, he says, CAR-T cells induced by DNA-carrying viruses could persist and continue to destroy B cells. “You can live without B cells, but you don’t want to.”
Chen notes that one monkey in the Capstan study became ill with a potentially fatal condition that results in severe inflammation and occasionally afflicts patients treated with labmade CAR-T cells. That side effect highlights the big unknown about the mRNA approach, she says. “Whether it will be therapeutically active at a level that is nontoxic remains to be seen.” A phase 1 safety trial that Capstan has launched is a first step toward addressing that issue.
Report written by Mitch Leslie..
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