Removing Regnase-1 'immune brake' improves CAR T-cell therapy for osteosarcoma
核心洞察
Scientists at St. Jude Children's Research Hospital found that deleting the Regnase-1 (搜索) gene from CAR T cells improves their ability to control osteosarcoma (搜索) and prevent lung metastasis in preclinical models.
Nearly all mice treated with Regnase-1 (搜索) knockout CAR T cells survived, whereas untreated mice and those receiving conventional B7-H3 (搜索)-targeting CAR T cells succumbed to disease.
The modified CAR T cells remodeled the tumor microenvironment, activating other immune cells while reducing immunosuppressive signaling, supporting a broad anticancer immune response.
Scientists at St. Jude Children's Research Hospital have discovered that removing the gene for Regnase-1 (搜索) from engineered immune cells makes them more effective at treating relapsed osteosarcoma (搜索). There is great clinical need for new therapies for childhood osteosarcoma, where there are very few effective treatments for relapsed disease. The approach improved the cell's ability to control osteosarcoma growth and prevent metastasis to the lung in preclinical models. The findings, which support the development of an early-phase clinical trial, were published in Cell Reports Medicine.
Chimeric antigen receptor (CAR) T-cell therapy reprograms a patient's own immune cells to recognize and attack cancer. The treatment has shown success in some relapsed childhood leukemias, but it has not worked as well against solid tumors, including osteosarcoma (搜索). One major reason is that the tumor microenvironment, the local area around the tumor, can suppress anticancer immune activity and cause CAR T cells to become less functional.
To overcome these barriers, the St. Jude group removed the gene for Regnase-1 (搜索), which normally acts as a "brake" on immune function, from CAR T cells, then tested the modified cells in mouse models of osteosarcoma (搜索).
"We saw that CAR T cells without Regnase-1 (搜索) controlled tumors and prevented lung metastasis in models of osteosarcoma (搜索)," said Stephen Gottschalk, MD, St. Jude Department of Bone Marrow Transplantation & Cellular Therapy chair. "Those results are particularly promising, as the cancer spreading to the lungs is a primary cause of mortality from relapsed disease and has historically been difficult to address."
Gottschalk is also co-Director of the St. Jude Center of Excellence for Pediatric Immuno-Oncology (CEPIO) with Hongbo Chi, PhD, St. Jude Department of Immunology chair. Chi's initial work on Regnase-1 (搜索) and the collaboration between the Gottschalk and Chi labs through CEPIO led to the study's findings, on which Gottschalk and Chi are co-corresponding authors.
"We are extremely excited by these promising preclinical results for Regnase-1 (搜索) knockout CAR T cells," said Chi. "We have brought a fundamental research discovery into preclinical models that performed so well, and we are now developing it into a clinical trial." The St. Jude team is developing an early-phase clinical trial to test the approach through CEPIO.
Durable tumor control and prevention of metastasis
In preclinical osteosarcoma (搜索) models, nearly all mice treated with human Regnase-1 (搜索) knockout CAR T cells survived. In contrast, untreated mice and mice treated with conventional CAR T cells targeting the same cancer-related protein, B7-H3 (搜索), succumbed to disease. Months later, when researchers reintroduced osteosarcoma cells into the survivors, they still rejected the tumor, suggesting that Regnase-1 knockout enabled human CAR T cells to produce durable, long-term effects.
Remodeling the tumor microenvironment
The scientists believe that the improvement may come from more than improved CAR T-cell function — the modified cells also altered their surroundings.
"We found that our modified CAR T cells had a global impact on the tumor microenvironment," said first author Adeleye Adeshakin, PhD, Department of Bone Marrow Transplantation & Cellular Therapy. "They not only kept themselves from being suppressed but also activated other immune cells to enter the tumor."
In addition to increasing immune cell numbers, the therapy led to elevated levels of chemical signals that activate the immune system. At the same time, it reduced immunosuppressive cell numbers and signaling. Together, these changes represented a broad anticancer immune activation within the tumor microenvironment, which may help this approach overcome previous limitations of the therapy.
"In the past, many of us, including myself, thought of cancer as one diseased organ that can simply be targeted and destroyed," Gottschalk said. "Our study supports the notion that cancer is a systemic disease. Regnase-1 (搜索) knockout CAR T cells remodel the entire immune system and lead to a much more effective anticancer response, demonstrating how we need to find systemic solutions to improve these immunotherapies for children facing these diseases."
Study support
The study was supported by grants from the National Cancer Institute (P30CA021765, T32CA272387, R35CA253188, U01CA281868, R01AI140761, R01CA292466 and R01CA288967), the National Institute of Allergy and Infectious Diseases (U01AI176470), the St. Jude Collaborative Research Consortium on Novel Gene Therapies for Sickle Cell Disease and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.