Researchers at the Perelman School of Medicine at the University of Pennsylvania have been working on a preclinical study that focuses on a novel strategy that uses a “one-two punch” to assist T cells in attacking solid tumours. The results demonstrated that focusing on two regulators that manage gene activities linked to inflammation caused T cell expansion in models to be at least 10 times higher, increasing anti-tumour immune activity and durability.
The new study’s senior author, June, said, “We want to unlock CAR T cell therapy for patients with solid tumours, which include the most commonly diagnosed cancer types. Our study shows that immune inflammatory regulator targeting is worth additional investigation to enhance T cell potency.”
CAR T cell therapy was pioneered at Penn Medicine by Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy at Penn and director of the Center for Cellular Immunotherapies (CCI) at Abramson Cancer Center, whose work led to the first approved CAR T cell therapy for B-cell acute lymphoblastic leukaemia in 2017. Since then, personalized cellular therapies have revolutionized blood cancer treatment but remained stubbornly ineffective against solid tumours, such as lung and breast cancer.
One of the challenges for CAR T cell therapy in solid tumours is a phenomenon known as T cell exhaustion, where the persistent antigen exposure from the solid mass of tumour cells wears out the T cells to the point that they aren't able to mount an antitumor response. Engineering already exhausted T cells from patients for CAR T cell therapy results in a less effective product because the T cells don't multiply enough or remember their task.
The research team, including lead author David Mai, a Bioengineering graduate student in the School of Engineering and Applied Science, and co-corresponding author Neil Sheppard, DPhil, head of the CCI T Cell Engineering Lab, hypothesized that targeting the related but independent Roquin-1 regulator at the same time could boost responses further.
Mai said, “Each of these two regulatory genes has been implicated in restricting T cell inflammatory responses, but we found that disrupting them together produced much greater anticancer effects than disrupting them individually. By building on previous research, we are starting to get closer to strategies that seem to be promising in the solid tumour context.”
