UCSF researchers have shown they can turn immune cells into cancer fighters directly inside the body, clearing aggressive cancers in mice. The approach could slash the cost and wait time for CAR-T therapy and bring it to far more patients.
For patients with certain blood cancers, CAR-T cell therapy can be a lifeline — but it is often painfully slow, punishing and out of reach. A new study from UC San Francisco points to a future where those same cancer-fighting cells could be created inside the body with a single injection.
In experiments in mice with human-like immune systems, UCSF scientists and collaborators used a gene-editing delivery system to reprogram T cells in the bloodstream so they could recognize and destroy cancer. The approach cleared aggressive leukemia, multiple myeloma and even a solid tumor in the animals, while avoiding the complex manufacturing process that today makes CAR-T therapy so expensive and hard to access.
Senior author Justin Eyquem, an associate professor of medicine at UCSF, noted the work signals a turning point for cell and gene therapy.
“I think this is just the beginning of a big wave of new therapies that will be truly transformational and save a lot of lives,” he said in a news release. “I’m incredibly excited to be part of it.”
CAR-T cell therapy works by taking a patient’s own T cells — white blood cells that act as the immune system’s soldiers — and giving them new genetic instructions. Scientists add a chimeric antigen receptor, or CAR, that acts like a sensor on the T cell’s surface. When that sensor recognizes a matching protein on a cancer cell, it triggers the T cell to attack.
Seven CAR-T therapies are currently approved in the United States for blood cancers. But each treatment is custom-made from a patient’s cells in specialized facilities. The process can take weeks and costs hundreds of thousands of dollars, and patients must usually undergo intensive chemotherapy beforehand to make room in the bone marrow for the engineered cells.
“It’s become a global access issue; many patients who would benefit from CAR-T cells either can’t afford them or can’t get them fast enough,” Eyquem added. “There has been a big push in the field to try to move to directly producing these cells in the body.”
The new work, published March 18 in the journal Nature, is the first to insert a large DNA sequence at a specific spot in human T cells that were never removed from the body. That precise, targeted editing not only worked, the researchers report, but also outperformed the more common method of randomly inserting DNA into cells using viruses.
To pull this off, Eyquem and colleagues at UCSF, the Gladstone Institutes, Duke University and the Innovative Genomics Institute built a two-part delivery system designed to home in on T cells and rewire them safely.
One particle carried CRISPR-Cas9 gene-editing machinery — often described as molecular scissors — and was coated with antibodies that recognize CD3, a protein found only on T cells. That coating helped ensure the editing tools latched onto the right cells as they circulated in the bloodstream.
The second particle carried a stretch of DNA encoding the cancer-fighting CAR, along with instructions to tuck that DNA into a particular location in the T cell genome. That site includes a molecular on switch that is naturally active only in T cells, so the new CAR is turned on only when it lands in the correct place. The particles were also engineered to avoid being quickly destroyed by the immune system.
“When you manufacture these cells outside the body, you can do a lot of quality control to make sure you only end up with re-engineered T cells,” added Eyquem. “Inside the body, we can’t do that post-manufacturing quality control, so we really needed to optimize the approach upfront to avoid altering any other cells.”
In mice engrafted with aggressive leukemia, a single injection of the dual-particle system eliminated all detectable cancer in nearly all animals within two weeks, according to the study. In some organs, the newly engineered CAR-T cells made up as much as 40% of immune cells and were able to clear cancer from both the bone marrow and spleen.
The same strategy worked against multiple myeloma, another blood cancer, and against a solid sarcoma tumor. Solid tumors have historically been difficult to treat with CAR-T therapies, so the sarcoma result is especially encouraging for researchers hoping to extend the technology beyond blood cancers.
The team also found that T cells engineered inside the body appeared to be stronger than those made in the lab.
“What was especially remarkable was that the cells we’re generating in vivo actually look better than what we make in the lab,” Eyquem added. “We think that when cells are taken out of the body and grown in the lab, they lose some of their ‘stemness’ and proliferative capacity and that doesn’t happen here.”
If the approach can be translated to people, it could address several of the biggest barriers to CAR-T treatment. In-body, or in vivo, manufacturing could eliminate the need to ship cells to centralized facilities, shorten the time from diagnosis to treatment and potentially remove the requirement for harsh preparatory chemotherapy. That could make the therapy safer for older and frailer patients.
It could also dramatically cut costs and open the door for community hospitals, not just major cancer centers, to offer advanced cell therapies.
“If we can translate this to humans, we could dramatically reduce costs, eliminate waiting times, and potentially allow community hospitals — not just major cancer centers — to offer these life-saving therapies,” concluded Eyquem. “That would truly democratize access to CAR-T cell therapy.”
For now, the work remains in the preclinical stage. The technology must be scaled up and rigorously tested for safety and effectiveness in humans. Eyquem and his collaborators have launched a company, Azalea Therapeutics, to move the dual-particle platform toward clinical trials.
More broadly, the study showcases how precise gene editing inside the body could reshape medicine. The ability to insert large DNA sequences at exact locations in specific cell types could eventually be used not only for cancer, but also for inherited disorders and autoimmune diseases.
For patients and families facing cancer today, that future cannot come soon enough. The new findings do not change current treatment options yet, but they offer a glimpse of a world where powerful cell therapies are faster, gentler and available far beyond a handful of specialized centers.