Receptor may reduce the need for chemo and radiation pre-T cell therapy

According to a team led by UCLA 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.

The findings of the research were published in the journal 'Nature'.

Before a patient can undergo T-cell therapy designed to target cancerous tumours, the patient's entire immune system must be destroyed with chemotherapy or radiation. The toxic side effects are well known, including nausea, extreme fatigue and hair loss.

T cells engineered with the synthetic IL-9 receptor, designed in the laboratory of Christopher Garcia, PhD, at Stanford, were potent against tumours in mice.

"When T cells are signalling through the synthetic IL-9 receptor, they gain new functions that help them not only outcompete the existing immune system but also kill cancer cells more efficiently," Kalbasi said. "I have a patient right now struggling through toxic chemotherapy just to wipe out his existing immune system so T cell therapy can have a fighting chance. But with this technology, you might give T cell therapy without having to wipe out the immune system beforehand."

Kalbasi, a researcher at the UCLA Jonsson Comprehensive Cancer Center and an assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA, began the work while under the mentorship of Antoni Ribas, MD, PhD, a senior investigator in the study. The study was also led by Mikko Siurala, PhD, from the laboratory of Carl June, MD, at Penn, and Leon L. Su, PhD, of the Garcia Lab at Stanford.

"This finding opens a door for us to be able to give T cells a lot like we give a blood transfusion," Ribas said.

Ribas and Garcia collaborated on a paper published in 2018 that focused on the concept that a synthetic version of interleukin-2 (IL-2), a critical T cell growth cytokine, could be used to stimulate T cells engineered with a matching synthetic receptor for the synthetic IL-2. With this system, T cells can be manipulated 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). Intrigued by that work, Kalbasi and colleagues were interested in testing 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, among the synthetic common-gamma chain signals, the IL-9 signal was worth investigating," Kalbasi said, adding that, unlike other common-gamma chain cytokines, IL-9 signalling is not typically active in naturally occurring T cells. The synthetic IL-9 signal made T cells take on a unique mix of both stem-cell and killer-like qualities that made them more robust in fighting tumours. "In one of our cancer models, we cured over half the mice that were treated with the synthetic IL-9 receptor T cells."

Kalbasi said the therapy proved to be effective in multiple systems. They targeted two types of hard-to-treat cancer models in mice -- pancreatic cancer and melanoma -- and used T cells targeted to cancer cells through the natural T cell receptor or a chimeric antigen receptor (CAR). "The therapy also worked whether we gave the cytokine to the whole mouse or directly to the tumour. In all cases, T cells engineered with synthetic IL-9 receptor signalling were superior and helped us cure some tumours in mice when we couldn't do it otherwise."