Using an intermediate adaptor cell gives clinicians more control over dosage and reverses a potentially fatal side effect of CAR T-cell therapy.
While cell therapy has proven it can recruit the body’s immune system to fight diseases, it can also trigger runaway immune responses that harm and or even kill patients. Now, preclinical evidence presented at a recent conference shows that “adaptor” molecules could enable clinicians to fine tune the immune response and eventually reverse the fatal side effects.
The most advanced immunotherapy, CAR T-cell therapy, has shown repeated success in clinical trials tackling blood cancers that have stopped responding to treatment. Some adults and children who received this treatment have had their blood cancer go into remission for years. To develop the therapy, the immune cells are engineered to attack a specific site on a cancer cell. This works by extracting T-cells from a patient’s blood, then modifying them in the lab to attach a receptor that recognizes a specific protein on the surface of a cancer cell.
This receptor, called a chimeric antigen receptor (CAR), connects to a portion of protein dangling inside the T-cell. When the external receptor binds to a cancer cell, the internal portion of the CAR activates the T-cell to recruit an army of immune cells that kill abnormal cells.
But sometimes CAR T-cells overstimulate a patient’s immune system. The resulting storm of chemical messengers, called cytokines, causes high fever, shock, and in some clinical trials, death. To harness the power of CAR T-cells for cancer treatment, academic and industrial researchers are looking for ways to temper or quickly reverse an overstimulated immune response.
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Endocyte, a biopharmaceutical company based in Lafayette, IN, has developed a strategy to control CAR T-cells. It draws on the company’s 20 years of experience producing molecules to deliver chemotherapy or imaging agents to cancer cells. It believes its CAR T-cell adaptor molecules, or CAMs, will enable them to fine tune the amount of CAR T-cell activation in the body.
To make a CAM, company researchers first identify a molecule that binds to a receptor on the surface of a cancer cell. For example, the first CAM they hope to test in clinical trials uses folate as the cancer-specific recognition molecule.
Then the researchers attach a green fluorescent dye called fluorescein to folate. Finally, they introduce CAR T-cells carrying receptors engineered to recognize fluorescein, instead of a protein on the surface of a cancer cell. By controlling the CAM dose, the researchers tailor the amount of sites available for CAR T-cells to attach to cancer cells.
Endocyte presented data from preclinical tests of folate-containing CAM at the American Association for Cancer Research conference in April. Fluorescein-targeted CAR-T cells shrunk a breast cancer tumor in mice only when the folate CAM was also present in the blood. The CAM and CAR T treatment also shrunk other tumors that display folate receptors, including bone and blood cancers in mice.
To reduce side effects from an overstimulated immune system, the researchers controlled the timing and amount of CAM delivered to the mice before injecting the CAR T-cells. Injecting the CAM 24 hours before a dose of CAR-T cells helped prevent severe cytokine storms in mice. “Pre-painting” the tumors with the CAM helped direct the CAR T-cells only to the cancer and not to healthy cells as well.
Displacing the CAM from cancer cells also provides a way to stop a runaway cytokine storm. The researchers induced a severe cytokine storm in mice by injecting them with CAR T-cells followed by the CAM the next day. After the CAR T-cell injection, the mice’s fur turned greasy and they became inactive.
Then the researchers injected them with a dose of sodium fluorescein, a water-soluble version of the fluorescein dye attached to the CAM (which is also used by ophthalmologists to visualize tiny blood vessels). The sodium fluorescein bound to the CAR T-cells, displacing them from the cancer cells and deactivating their immune response, says Chris Leamon, vice president of research at Endocyte.
“Within hours, an animal with a cytokine storm gets better,” Leamon says. “The next day, you’d never know the animal had a problem.” The company is collaborating with Seattle Children’s Hospital to use CAM in clinical trials for bone cancer, he said.
Leamon believes CAM could be a “universal” platform for CAR T-cell therapy, one that could efficiently target multiple proteins on a cancer cell. This multi-protein targeting can be used to more precisely direct CAR T-cells to cancer cells and also to attack rapidly mutating surface proteins.
Today, researchers must engineer many different T-cells so that each recognize a surface protein on a cancer cell. With the CAM platform, the company only needs to produce CAR T-cells that recognize the CAM’s green dye—a much faster and simpler process because CAM molecules are easier to modify and propagate than live cells.
Melissae Fellet is an independent technology writer based in Missoula, MT.
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