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T cells
Researchers say they have developed biodegradable nanoparticles that can be used to genetically reprogram T cells while they are still in the body.
The nanoparticles were able to program T cells with genes encoding leukemia-specific chimeric antigen receptors (CARs).
The resulting CAR T cells were able to eliminate leukemia or slow the progression of disease in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL).
Researchers reported these results in Nature Nanotechnology.
“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Matthias Stephan, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.
“The reprogrammed cells begin to work within 24 to 48 hours and continue to produce these receptors for weeks. This suggests that our technology has the potential to allow the immune system to quickly mount a strong enough response to destroy cancerous cells before the disease becomes fatal.”
Dr Stephan and his colleagues designed their nanoparticles to carry genes that encode for CARs intended to target and eliminate B-ALL. The nanoparticles are coated with ligands that make them seek out and bind to T cells.
When a nanoparticle binds to a T cell, the cell engulfs the particle. The nanoparticle then travels to the cell’s nucleus and dissolves.
The CAR genes integrate into chromosomes housed in the nucleus, making it possible for the T cells to begin decoding the new genes and producing CARs within 1 or 2 days.
Once they determined their CAR-carrying nanoparticles reprogrammed a noticeable percentage of T cells, the researchers tested the T cells’ efficacy in a mouse model of B-ALL.
The team infused the nanoparticles into 10 mice and found the treatment eradicated tumors in 7 of the animals. The other 3 mice “showed substantial regression” of leukemia, the researchers said.
On average, mice that received CAR-carrying nanoparticles had a 58-day improvement in survival compared to control mice.
Mice that received the nanoparticles also had “dramatically reduced” B-cell numbers in their spleens. The researchers noted that this is consistent with the reversible B-cell aplasia observed in patients who receive conventional CD19 CAR T-cell therapy.
Dr Stephan and his colleagues also tested conventional CAR T-cell therapy in the B-ALL mouse model. The mice received cyclophosphamide followed by CAR T cells created ex vivo.
These mice had significantly better survival than controls, but their survival was comparable to that of the mice that received the CAR-carrying nanoparticles.
Although these nanoparticles are several steps away from the clinic, Dr Stephan said he imagines a future in which nanoparticles transform cell-based immunotherapies into easily administered, off-the-shelf treatments that are available anywhere.
“I’ve never had cancer, but if I did get a cancer diagnosis, I would want to start treatment right away,” Dr Stephan said. “I want to make cellular immunotherapy a treatment option the day of diagnosis and have it able to be done in an outpatient setting near where people live.”
