|A new study has identified a receptor that may reduce the need for chemo and radiation pre-T cell therapy.|
A team of researchers demonstrated that a synthetic IL-9 receptor allows cancer-fighting T cells to function without the use of chemotherapy or radiation.
Before undergoing T cell therapy to target cancerous tumors, the patient's entire immune system must be destroyed with chemotherapy or radiation. The toxic side effects, which include nausea, extreme fatigue, and hair loss, are well known.
Now, a team led by UCLA's Anusha Kalbasi, MD, in collaboration with scientists from Stanford and the University of Pennsylvania, has demonstrated that a synthetic IL-9 receptor allows cancer-fighting T cells to do their job without the use of chemo or radiation. T cells engineered with the synthetic IL-9 receptor, developed in the laboratory of Christopher Garcia, Ph.D., at Stanford, were effective against tumors in mice, according to a study published in Nature on Wednesday.
"When T cells signal through the synthetic IL-9 receptor, they acquire new functions that allow them not only to outcompete the existing immune system but also to kill cancer cells more efficiently," Kalbasi explained. "I currently have a patient undergoing toxic chemotherapy in order to wipe out his existing immune system so that T cell therapy can have a fighting chance. However, with this technology, T cell therapy could be administered without first wiping out the immune system."
Kalbasi, a researcher at the UCLA Jonsson Comprehensive Cancer Center and an assistant professor of radiation oncology at UCLA's David Geffen School of Medicine, began the work while working under the supervision of the study's senior investigator, Antoni Ribas, MD, Ph.D. Mikko Siurala, Ph.D., of Carl June, MD's laboratory at Penn, and Leon L. Su, Ph.D., of the Garcia Lab at Stanford also led the study.
"This discovery opens the door for us to be able to give T cells similar to how we give blood transfusions," Ribas said.
Ribas and Garcia worked together on a paper published in 2018 that explored the idea of using a synthetic version of interleukin-2 (IL-2), a critical T cell growth cytokine, to stimulate T cells engineered with a matching synthetic receptor for the synthetic IL-2. T cells can be manipulated using this system even after they have been given to a patient by treating the patient with the synthetic cytokine (which has no effect on other cells in the body). Kalbasi and colleagues were intrigued by that work and wanted to test modified versions of the synthetic receptor that transmit other cytokine signals from the common-gamma chain family: IL-4, -7, -9, and -21.
"It was clear early on that the IL-9 signal was worth investigating among the synthetic common-gamma chain signals," Kalbasi said, adding that, unlike other common-gamma chain cytokines, IL-9 signaling is not typically active in naturally occurring T cells. The synthetic IL-9 signal caused T cells to develop a unique combination of stem-cell and killer-like properties, making them more effective in fighting tumors. "We cured more than half of the mice treated with synthetic IL-9 receptor T cells in one of our cancer models."
According to Kalbasi, the therapy was effective in a variety of systems. They used T cells targeted to cancer cells via the natural T cell receptor or a chimeric antigen receptor to treat two types of difficult-to-treat cancer models in mice: pancreatic cancer and melanoma (CAR). "The therapy was also effective whether the cytokine was administered to the entire mouse or directly to the tumor. T cells engineered with synthetic IL-9 receptor signaling were superior in all cases and helped us cure some tumors in mice that we couldn't cure otherwise."
Anusha Kalbasi, Mikko Siurala, Leon L. Su, Mito Tariveranmoshabad, Lora K. Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah V. Kremer, Amy L. Sun, Sofia Castelli, Sangya Agarwal, John Scholler, Decheng Song, Philipp C. Rommel, Enrico Radaelli, Regina M. Young, Warren J. Leonard, Antoni Ribas, Carl H. June, K. Christopher Garcia. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature, 2022; DOI: 10.1038/s41586-022-04801-2