Advances in cellular immunotherapy that stimulate genetically modified T cells to attack cancer cells have revolutionized the treatment of certain blood cancers. Six of these CAR-T cell therapies are approved by the Food and Drug Administration to treat certain types of leukemia, lymphoma and multiple myeloma. Still, some patients’ tumors don’t respond well to these therapies, and many patients who initially do well see their cancer come back.
Now, a new study by researchers at Washington University School of Medicine in St. Louis shows that additional treatment with an immunity-boosting protein called interleukin 7 (IL-7) after an infusion of these genetically engineered T cells causes cancer-fighting CAR -T cells multiply and become more efficient at killing tumor cells.
The mouse study -; published on June 13 in the journal Nature Communication -; suggests the promise of a Phase 1 clinical trial at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. The clinical trial studies a type of long-acting genetically modified IL-7 in conjunction with CAR-T cells targeting CD19, a B cell antigen in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Siteman is the coordinating center and one of four sites across the country participating in the trial.
“Many researchers are trying different strategies to improve CAR-T cell function in the treatment of blood cancers,” said lead author John F. DiPersio, MD, PhD, Virginia E. & Sam J. Professor of Medicine. Golman and director of the Division of Oncology. “We are interested in IL-7 because we know it is a major driver of T-cell expansion. The body naturally makes IL-7 to increase the number of T-cells when a person becomes ill, for example.When we give a long-acting type of IL-7 to immunodeficient tumor-bearing mice soon after treatment with CAR-T cells, we see a dramatic expansion of these CAR-T cells greater than ten thousand times compared to mice not receiving IL-7. T cells also persist longer and show significantly increased anti-tumor activity.”
CAR-T cells are made from the body’s normal T cells, either from the patient or from a donor. CAR-T cells are genetically engineered to specifically target a protein on the surface of cancer cells. Targeting helps CAR-T cells find cancer cells, which are masters at evading immune attack. The therapy can be very effective, but sometimes the CAR-T cells are not able to grow enough to kill all the cancer, or they become overstimulated, “exhausting” their ability to function, resulting in a loss of anti-tumor efficacy . .
With these issues in mind, the researchers -; including first author Miriam Y. Kim, MD, assistant professor of medicine, and co-lead author Matthew L. Cooper, PhD, adjunct assistant professor of medicine -; were interested in whether they could harness the body’s natural way of increasing T-cell counts to improve therapy. But natural IL-7 normally disappears quickly from the body. 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 CAR-T cell expansion.
By studying two different models of B-cell lymphoma in mice, researchers showed that mice receiving CAR-T cells and long-acting IL-7 survived almost six times longer than mice receiving CAR cells. -You alone. Mice treated with CAR-T cells alone survived approximately one month after treatment. All mice that received long-acting IL-7 shortly after CAR-T cell treatment were still alive at the end of a 175-day experimental period. Additionally, tumor size in mice that received CAR-T cells and IL-7 was significantly 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 briefly controlled,” DiPersio said. “But by the third week, the tumor starts to come back. And by the fourth week, they start to look like the control mice that didn’t receive any active treatment. But by adding long-acting IL-7, the number of CAR-T cells explode, and these mice lived beyond the time period we set for our experiment. Our study also suggests that it may be possible to fine-tune CAR-T cell expansion by controlling the number of doses of IL-7 we give.”
Research from the University of Washington has laid the groundwork for using IL-7 to boost the immune system to treat disease, including its use with CAR-T cells. Additionally, Richard S. Hotchkiss, MD, professor of anesthesiology, medicine, and surgery, and his team investigated IL-7 for its use in stimulating T cells to combat sepsis, a life-threatening response to the infection. Research from Siteman’s Brain Tumor Center has also shown promise for the use of long-acting IL-7 to enhance T cells in the treatment of glioblastoma, an aggressive brain cancer.
This work was supported by the National Cancer Institute of the National Institutes of Health (NIH), grant numbers R35 CA210084 and P50 CA171963; the Siteman investment program; Alex’s Lemonade Stand Foundation with a Northwestern Mutual Young Investigator Award; University of Washington Leukemia Developmental Research SPORE Award; and a Dean’s Scholars Award from the Washington University Division of Physician-Scientists.
DiPersio, Kim, Cooper and co-authors Karl W. Staser, Julie O’Neal and Byung Ha Lee are the inventors of a patent on the use of IL-7 to improve CAR-T cell function.
Kim MY et al. A long-acting interleukin-7, rhIL-7-hyFc, enhances expansion, persistence and anti-tumor activity of CAR-T cells. Communication Nature. June 13, 2022. DOI: 10.1038/s41467-022-30860-0.
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