CAR T therapy has been transformative in the battle against deadly cancers. Scientists extract a patient’s own immune cells, genetically engineer them to target a specific type of cancer, and infuse the boosted cells back into the body to hunt down their prey.
Six therapies have been approved by the FDA for multiple types of blood cancer. Hundreds of other clinical trials are in the works to broaden the immunotherapy’s scope. These include trials aimed at recurrent cancers and autoimmune diseases, such as lupus and systemic sclerosis, in which the body’s immune system destroys its own organs.
But making CAR T cells is a long and expensive process. It requires genetic tinkering in the lab, and patients need to have mutated blood cells wiped out with chemotherapy to make room for healthy new ones. While effective, the treatment takes a massive toll on the body and mind.
It would be faster and potentially more effective to make CAR T cells inside the body. Previous studies have tried to shuttle genes that would do just that into immune cells using viruses or fatty bubbles. But these tend to accumulate in the liver rather than target cells. The approach could also result in hyper-aggressive cells that spark life-threatening immune responses.
Inspired by Covid-19 vaccines, a new study tried shuttling a different kind of gene expression into the body. Instead of gene editors, the method turned to mRNA, a biomolecule that translates DNA instructions into cellular functions. The new method is now more targeted—skipping the liver and heading straight to immune cells—and doesn’t change a cell’s DNA blueprint, potentially making it safer than previous approaches. In rodents and monkeys, a few jabs converted T cells to CAR T cells within hours, and these went on to kill cancer cells. The effects “reset” the animals’ immune systems and lasted for roughly a month with few side effects.
“The achievement has implications for treating” certain cancers and autoimmune disorders, and moves “immunotherapy with CAR T cells to wider clinical use,” wrote Vivek Peche and Stephen Gottschalk at St. Jude Children’s Research Hospital, who were not involved in the study.
Immune Civil War
Our immune system is a double-edged sword. When working in tandem, immune cells fight off bacteria and viruses and nip cancer cells in the bud. But sometimes one immune-cell type, called a B cell, goes rogue.
Normally, B cells produce antibodies to ward off pathogens. But they can also turn into multiple types of aggressive blood cancer and wreak havoc. Cancerous versions of these sneaky cells develop ways to escape the body’s other immune cell types—like T cells, which are constantly on the lookout for unwanted intruders.
Cancer cells aren’t completely invisible. Tumors have unique proteins dotted all over their surfaces, a sort of “fingerprint” that separates them from healthy cells. In classic CAR T therapy, scientists extract T cells from the patient and genetically engineer them to produce protein “hooks”—dubbed chimeric antigen receptors (CAR)—that grab onto those cancer cell proteins. When infused back into the patient, the cells readily hunt down and destroy cancer cells.
CAR T therapy has saved lives. But it has drawbacks. Genetically engineering cells to produce the hook protein could damage their genome and potentially trigger secondary tumors. The manufacturing process also takes time—sometimes too long for the patient to survive.
In My Blood
An alternative is to directly convert a person’s T cells into CAR T cells inside their body with a shot. There have already been successes using DNA-carrying viruses.
The team wondered if they could achieve the same results with mRNA. Unlike DNA, mRNA molecules don’t integrate into the genome, reducing “the risk of damaging DNA in T cells,” wrote Peche and Gottschalk. The idea is similar to how mRNA vaccines for Covid work. These vaccines are loaded with mRNA instructions to fight off the virus. Once inside cells, these mRNA snippets direct the cells to produce proteins that trigger an immune defense. But mRNA can help cells battle other intruders too, like bacteria, or even cancer.
There’s a problem, though. The fatty shuttles used to deliver the mRNA cargo—known as lipid nanoparticles—tend to collect in liver cells, not T cells. In the new study, the team tweaked the shuttles so they would be drawn toward T cells instead. Compared to conventional nanoparticles, these ones rarely stayed inside the liver and more often found their targets.
Each shuttle contained a soup of mRNA molecules encoding a CAR—the “super soldier” protein that helps T cells seek and destroy cancer cells.
When injected into the bloodstreams of mice, rats, and monkeys, the shot converted T cells into CAR Ts in their blood, spleen, and lymph nodes in a few hours, suggesting that the mRNA instructions worked as expected. The therapy went on to destroy cancers in mice with B cell leukemia and lowered B cell levels in monkeys, with effects lasting at least a month.
The shots also seemed to “reset” the body’s immune system. In monkeys, doses of CAR T initially tanked their B cell levels as expected. But these levels eventually rebounded to normal within weeks—with no signs of the new cells turning cancerous.
Compared to clinical studies that used CAR T cells manufactured in labs, these results “should be sufficient to bring about substantial therapeutic benefits,” wrote Peche and Gottschalk.
Not Throwing Away My Shot
The study is the latest to engineer CAR T cells inside the body. But there are caveats.
Compared to directly tinkering with T cell DNA, mRNA is theoretically safer as it doesn’t change the cell’s genetic blueprint. But the method requires functional T cells with the metabolic capability to integrate the added molecular instructions—which isn’t always possible in certain types of cancer or other diseases because the cells break down.
However, the system has promise for a myriad of other diseases. Because mRNA doesn’t last long inside the body, it could lower the risk of side effects while still having long-term impact. And because of the B cell “reset,” it’s possible for the immune system to rebuild itself and once again fight off pathogens.
The team is planning a Phase 1 clinical trial to test the therapy. A similar method could also be used to strengthen other immune cell types or ferry other kinds of therapeutic mRNA into the body. It’s “engineering immunotherapy from within,” wrote Peche and Gottschalk.
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