Researchers at the University of Pennsylvania’s Perelman School of Medicine are working on a preclinical study that focuses on a novel strategy that uses a “one-two punch” to help T cells attack solid tumors. The results, reported in the Proceedings of the National Academy of Sciences (PNAS), showed that focusing on two regulators that manage gene activity associated with inflammation led to at least a tenfold increase in T-cell expansion in models, increasing antitumor immunity. activity and stability.
CAR T Cell Therapy in Pain Medicine Carl H. June, MD, Richard W. of Immunotherapy in Pain It was pioneered by the obscure professor and director of Cellular Immunotherapy (CCI) at the Abramson Cancer Center, whose work led to the first approval. CAR T cell therapy for B-cell acute lymphoblastic leukemia in 2017. Since then, personalized cellular therapies have revolutionized blood cancer treatment, but have remained stubbornly ineffective against solid tumors such as lung cancer and breast cancer.
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“We want to unlock CAR T cell therapy for patients with solid tumors, including the most commonly diagnosed cancer types,” said Jun, senior author of the new study. “Our study shows that targeting immune inflammatory regulators to enhance T cell capacity is worth additional investigation.”
One of the challenges for CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion, where continuous antigen exposure from a solid mass of tumor cells exhausts T cells to the point that they are no longer able to mount. Antitumor response. Engineering that has already depleted T cells from patients for CAR T cell therapy results in a less effective product because the T cells do not multiply enough or even remember their function.
Previous observational studies pointed to the inflammatory regulator regnase-1 as a potential target to indirectly overcome the effects of T cell exhaustion because inhibition of T cells can cause hyperinflammation—reviving them to produce an antitumor response. The research team, 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 to target a related, but independent. The Roquin-1 regulator can further promote responses at the same time.
“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,” Mai said. “By building on previous research, we are moving closer to strategies that appear promising in the solid tumor context.”
The team used CRISPR-Cas9 gene editing to isolate regnas-1 and roquin-1 in T cells from two different immune receptors that are currently being investigated in phase I clinical trials: the mesothelin-targeting M5 CAR (mesoCAR). ) and NY-ESO-1-targeting 8F TCR (NYESO TCR). None of the engineered T cell products target CD19, the antigen targeted by most approved CAR T cell therapies, as this antigen is not present in solid tumors.
After CRISPR editing, the T cells were expanded and infused into solid tumor mice models, where the researchers showed that the double knockout generated at least 10 times more engineered T cells than inactivating Regnes-1 alone, as well as increased antitumor immune activity. Longevity of engineered T cells. In some mice, it also caused an overproduction of lymphocytes, leading to toxicity.
“CRISPR is a useful tool to completely eliminate the expression of target genes such as Regnase and Roquin, resulting in a pronounced phenotype, however, there are other strategies that can be considered to translate this work into a clinical setting, such as forms of conditional gene regulation,” said Shepard. said “We are certainly impressed by the antitumor potential that was elicited by knocking down these two non-redundant proteins in combination. In solid tumor studies, we often see limited expansion of CAR T cells, but if we are able to make each T cell more powerful, and make them bigger Repeatedly, we expect T cell therapies to have a better shot at attacking solid tumors.” (ANI)
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