Study shows how T cells therapy in solid tumours can be improved

PENNSYLVANNIA [US]: 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 tumours".

The results, which were reported in the Proceedings of the National Academy of Sciences (PNAS), demonstrated that focusing on two regulators that manage gene activities linked to inflammation caused T-cell expansion in models to be at least ten times higher, increasing antitumor immune activity and durability.

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 tumours", such as lung cancer and breast cancer.

"We want to unlock CAR T cell therapy for patients with tumours", which include the most commonly diagnosed cancer types," said June, the new study's senior author.

"Our study shows that immune inflammatory regulator targeting is a worth additional investigation to enhance T cell potency." One of the challenges for CAR T cell therapy in 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 as well.

Previous observational studies hinted at the inflammatory regulator Regnase-1 as a potential target to indirectly overcome the effects of T cell exhaustion because it can cause hyperinflammation when disrupted in T cells -- reviving them to produce an antitumor response.

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.

"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 starting to get closer to strategies that seem to be promising in the solid tumour context."

The team used CRISPR-Cas9 gene editing to knock out Regnase-1 and Roquin-1 individually and together in healthy donor T cells with two different immune receptors that are currently being investigated in Phase I clinical trials: the mesothelin-targeting M5 CAR (mesoCAR) and the NY-ESO-1-targeting 8F TCR (NYESO TCR).

Neither engineered T cell product targets CD19, the antigen targeted by most approved CAR T cell therapies, as this antigen is not present in tumours".

After CRISPR editing, the T cells were expanded and infused in solid tumour mice models, where researchers observed the double knockout led to at least 10 times as many engineered T cells compared to disabling Regnase-1 alone, as well as increased antitumor immune activity and longevity of the engineered T cells.

In some mice, it also led to the overproduction of lymphocytes, causing toxicity.

"CRISPR is a useful tool for completely ablating the expression of target genes like Regnase and Roquin, resulting in a clear phenotype, however, there are other strategies to consider for translating this work to the clinical setting, such as forms of conditional gene regulation," Sheppard said.

"We're certainly impressed by the antitumor potency that was unleased by knocking out these two non-redundant proteins in combination. In solid tumour studies, we often see the limited expansion of CAR T cells, but if we're able to make each T cell more potent, and replicate them to greater quantities, we expect T cell therapies to have a better shot at attacking tumours".