Chimeric antigen receptor (CAR) T cell therapy has found great success in the treatment of blood cancer. But when it comes to solid tumors, therapy often misses the mark. In solid tumors such as sarcomas, the tumor microenvironment suppresses CAR T cells, making them less effective.
Using synthetic biology, biomedical engineer Gabriel Kwang of the Georgia Institute of Technology and Emory University has developed a technique to control T cell therapy by heat and make cancer cells more sensitive to chemotherapy. New technology could turn the tables for the success of CAR T therapy in solid tumors.
“The idea of spatially controlling the function of cell therapy is a really important and emerging idea,” said Mikhail Shapiro, a chemical engineer at the California Institute of Technology who was not involved in the research. “This work is a very important step forward in demonstrating that it works in vivo in a real cancer scenario.”
Ali Zamat (left) and Gabe Kwang (right) combine heat treatment with CAR T cell therapy to shrink tumors in mice.
Jerry Grillo, Georgia Tech
As an engineer, Kwang has a unique philosophy. Instead of building a gadget and then trying to find the best application, Kwang first tries to identify the main bottlenecks in an area, then he works to design a solution. In the new research, he wanted to control when and where CAR T cell therapy is turned on and keep cells everywhere.
He and his team were inspired by the field of optogenetics, which uses light to control cell activity. Light, however, is not the best stimulus for cancer treatment as it scatters through healthy tissue and can only penetrate up to 1 centimeter of tissue. Conversely, heat can be stored at very precise locations in the body.
Kwang and his team used gold nanoparticles that can take the energy of near-infrared light and convert it into heat in a spatially controlled fashion. They engineered a gene switch in CAR T cells that enables the cells to respond to a temperature increase of about three to five degrees Celsius, much milder than drinking hot coffee or other hot liquids.
The researchers administered gold nanoparticles, which passively accumulated into tumors, via IV injection into mice with hind limb tumors that had received engineered CAR T cells. They then irradiated the tumor with near-infrared light to raise the temperature.
Compared to mice that received only heat treatment or CAR T cells, tumors in mice that received heat treatment and engineered CART cells shrank faster, Kwang and his team report. Nature Biomedical Engineering.
“where we can spatially control [CAR T cell] Activity inside a tumor can actually significantly improve antitumor responses,” Kwang said.
The treatment also prevented recurrence in the mice. Mice that received heated phototherapy treatment remained tumor-free for more than 45 days, whereas tumors returned in the cohort treated with specific CAR T cells.
“This is the beginning of this revolution in medicine, and there are many cool new ways to attack the problem,” Kwang said. “We need more big brains to work together on this problem.”
I. Miller et al., “Increased intratumoral activity of CAR T cells engineered to produce immunomodulators under photothermal control,” Nat Biomed Engg, 1-12, 2021.