Genetic Engineering Publications - GEG Tech top picks

One of the challenges of CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion. Previous studies have alluded to the inflammatory regulator Regnase-1 as a potential target to indirectly overcome the effects of T-cell exhaustion, as it can cause hyperinflammation when disrupted in T cells, reviving them to produce an antitumor response. The research team hypothesized that targeting the related but independent Roquin-1 regulator at the same time could boost responses further. 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 studied in Phase I clinical trials: the mesothelin-targeting M5 CAR (mesoCAR) and the NY-ESO-1-targeting 8F TCR (NYESO TCR). Following CRISPR editing, the T cells were expanded and infused into solid tumor mouse models, where the researchers observed that the double knockout resulted in at least a 10-fold increase in modified T cells compared to knocking down Regnase-1 alone, as well as increased anti-tumor immune activity and longevity of modified T cells. In some mice, this also led to an overproduction of lymphocytes, causing toxicity.

A chimeric antigen receptor (CAR) T-cell therapy that targets the protein mesothelin showed no evidence of major toxicity and had antitumor activity in patients with malignant pleural disease from mesothelioma, according to new results.

According to the results of the phase 1 trial published in Cancer Discovery, the combination of CAR T cell therapy and pembrolizumab, an anti-PD-1 therapy, appeared safe and feasible for patients with malignant pleural mesothelioma. 83% of patients who received the regimen remained alive 1 year after CAR-T infusion. The investigators reported no cases of high-grade cytokine release syndrome or neurotoxicity. This study was done with the use of a dose escalation of autologous CAR T cells that target the mesothelin protein on the surface of cancer cells and express an iCaspase-9 gene that serves as a "safety switch" to shut down the activity of the engineered T cells.

The investigators chose a locoregional CAR-T dosing strategy because this type of cancer does not typically metastasize outside the chest cavity.  A Phase 2 study using a fixed dose of mesothelin-directed CAR T cells followed by pembrolizumab is already underway. Four patients have been treated to date.