A new lab study shows additional treatment with interleukin 7 (IL-7) after CAR-T cell infusion makes the therapeutic cells grow in number and become more effective at tumor killing.
The Washington University School of Medicine in St. Louis team’s report was published today in Nature Communications.
“Many researchers are trying different strategies to enhance the function of CAR-T cells in treating blood cancers,” said senior author John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine and director of the Division of Oncology.
Different approaches have included injecting a hydrogel with specialized signaling proteins to improve delivery.
“We’re interested in IL-7 because we know it is a major driver of T cell expansion. The body makes IL-7 naturally to ramp up the number of T cells when a person gets sick, for example. When we give a long-acting type of IL-7 to tumor-bearing immunodeficient mice soon after CAR-T cell treatment, we see a dramatic expansion of these CAR-T cells greater than ten-thousandfold compared to mice not receiving IL-7. These CAR-T cells also persist longer and show dramatically increased anti-tumor activity,” he added.
CAR-T cells are manufactured using the body’s normal T cells, either from the patient or a donor. These cells are genetically modified to specifically target a protein on the surface of the cancer cells. The targeting helps the CAR-T cells find the cancer cells, which are masters at evading immune attack. The therapy can be highly effective, but sometimes the CAR-T cells aren’t able to expand enough to kill all of the cancer, or they become overstimulated, exhausting their ability to function, resulting in their loss of anti-tumor effectiveness.
With these problems in mind, these researchers were interested in whether they could harness the body’s natural way of boosting T cell numbers to enhance the therapy.
Natural IL-7 normally disappears from the body quickly. Therefore, DiPersio and his team tested a modified form of IL-7 that circulates in the body for weeks, making it much more effective at supporting the CAR-T cell expansion.
Investigating two different models of B cell lymphoma in mice, the researchers showed that mice receiving CAR-T cells and long-acting IL-7 survived almost six times longer than mice receiving CAR-T cells alone. Mice treated with CAR-T cells alone survived for about one month after therapy. All mice that received long-acting IL-7 soon after the CAR-T cell treatment were still living at the end of an experimental time frame of 175 days. Further, tumor sizes in the mice that had received CAR-T cells and IL-7 were dramatically reduced, to the point of being undetectable in the majority of mice by day 35.
“In mice that received the CAR-T cells alone, the disease is controlled briefly,” DiPersio said. “But by week three, the tumor starts to return. And by week four, they start to look like the control mice that didn’t receive any active therapy. But by adding long-acting IL-7, the numbers of CAR-T cells just explode, and those mice lived beyond the time frame we set for our experiment. Our study also suggests that it may be possible to fine-tune the expansion of the CAR-T cells by controlling the number of IL-7 doses that we give.”
