A new strategy to overcome T-cell exhaustion could help make T-cell therapies more effective against solid tumors.
In a study published March 15 in Proceedings of the National Academy of Sciences, researchers from the University of Pennsylvania described how they knocked out the genes for two inflammatory regulator proteins in chimeric antigen receptor T cells (CAR-Ts) and T-cell receptor T cells (TCR-Ts). While there’s more work to be done to refine the strategy—especially considering that the approach boosted the immune response so much that it was toxic to some of the mice—the results suggest it could be a good path to take for using T-cell therapies against solid tumors.
“We want to unlock CAR-T therapy for patients with solid tumors, which include the most commonly diagnosed cancer types,” lead author Carl June, M.D., one of the scientists who pioneered CAR-T cell therapy, said in a press release sent to Fierce Biotech Research. “Our study shows that immune inflammatory regulator targeting is worth additional investigation to enhance T cell potency.”
T-cell exhaustion happens when T cells—white blood cells that kill foreign invaders or abnormal cells like cancer cells—lose the ability to do their job. While it’s not quite clear why T-cell exhaustion happens, it is thought to be one of the main reasons TCR-Ts and CAR-Ts don’t work against solid tumors. Researchers have tried several different approaches to combating T-cell exhaustion in the context of solid tumors, like targeting a family of proteins called Nr4a transcription factors.
In this case, the June lab’s strategy centered on increasing the potency of T-cell therapies to overcome T-cell exhaustion. To regulate the immune response, they focused on Regnase-1 and Roquin-1, a pair of proteins that break down mRNA that would otherwise encode inflammatory molecules and activate T cells. Previous studies showed that inhibiting Regnase-1 and Roquin-1 independently could improve T-cell responses against cancer, as could interrupting the interaction between them.
Building on those findings, the team used CRISPR-Cas9 to knock out one or both of the Regnase-1 and Roquin-1 genes in CAR-Ts targeting the antigen mesothelin and TCR-Ts targeting the antigen NY-ESO-1. Seeing that the cells had heightened expression of genes associated with a greater inflammatory response, they then tested out their tumor-fighting potential in mouse models with different types of cancer. Both the Regnase-1 single knockout and double knockout CAR-Ts and TCR-Ts were effective against the tumors and generated many more T cells than in controls—even after the tumors were completely cleared. Some of the mice developed toxicity as a result.
Given that a similar type of toxicity is already seen in the clinic among patients who receive CAR-Ts with the Regnase-1 and Roquin-1 genes intact, “[knockout] CAR-T[s] may have greater potential for neurotoxicity due to both increased cytokine function and expansion,” the researchers wrote.
“It will be important for translational efforts to evaluate these safety considerations, which may be done using emerging preclinical safety models,” they added.
Future projects stemming from this study will continue to evaluate Regnase-1 and Roquin-1 as potential therapeutic targets, along with other regulators of T cell-based inflammation. Given how important the proteins are to preventing out-of-control inflammation and autoimmune disease in other contexts, it might be useful to consider ways to disrupt them transiently rather than permanently, the researchers noted. CRISPR-Cas9 may not be the best approach, as co-corresponding author Neil Sheppard, D.Phil., pointed out in the Penn press release.
“CRISPR is a useful tool for completely ablating the expression of target genes … however there are other strategies to consider for translating this work to the clinical setting, such as forms of conditional gene regulation,” he said.