Gene removal makes engineered immune cells more effective against osteosarcoma

Scientists at St. Jude Children's Research Hospital have discovered that removing the gene for Regnase-1 from engineered immune cells makes them more effective at treating relapsed osteosarcoma. 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 support the development of an early-phase clinical trial and were published today 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. 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 (which normally acts as a "brake" on immune function) from CAR T cells, then tested the modified cells in mouse models of osteosarcoma.

We saw that CAR T cells without Regnase-1 controlled tumors and prevented lung metastasis in models of osteosarcoma. 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."

Stephen Gottschalk, MD, St. Jude Department of Bone Marrow Transplantation & Cellular Therapy chair

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 and the collaboration between the Gottschalk and Chi labs through CEPIO led to the Cell Reports Medicine study's findings, on which Gottschalk and Chi are co-corresponding authors.

"We are extremely excited by these promising preclinical results for Regnase-1 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.

Modified CAR T cells remodel the tumor microenvironment

In preclinical osteosarcoma models, nearly all mice treated with human Regnase-1 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, 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.

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. They not only kept themselves from being suppressed but also activated other immune cells to enter the tumor."

Adeleye Adeshakin, PhD, first author, Department of Bone Marrow Transplantation & Cellular Therapy

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 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."