Robust In Vitro Pharmacology of Tmod, a Synthetic Dual-Signal Integrator for Cancer Cell Therapy

Abstract

Progress toward improved solid-tumor treatment has long been hindered by the lack of truly tumor-specific targets. We have developed an approach to T cell therapy based on a dual-receptor system called Tmod™ that addresses this problem. The Tmod system exploits one of the few common genetic differences between tumor and normal cells: loss of heterozygosity (LOH). It utilizes the basic mechanistic logic that evolved in early vertebrates to mediate self vs. non-self discrimination, where an activation stimulus is blocked by self-ligands. Tmod constructs employ a chimeric antigen receptor (CAR) or T cell receptor (TCR) as activator component and a modified LIR-1 inhibitory receptor (blocker) to achieve high selectivity based on expression of the blocker antigen (Ag). Here we explore the in vitro pharmacology of a blocker directed at the HLA-A*02 Ag paired with either a mesothelin CAR or an HLA-A*11-restricted KRAS peptide TCR. While more sensitive to receptor expression changes on effector cells, we show that Tmod response is well-buffered against variations in Ag levels on target cells. In addition, the data reveal at least two distinguishable pharmacologic mechanisms of Tmod blocker function: (1) reducing activator sensitivity and (2) decreasing activation magnitude.

TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

“…In “A NOT B” logic gates, normal cells that express an antigen B absent on tumor cells, in addition to the targeted antigen A, are protected ( 112 ). This approach is more challenging for TCRs compared to CARs, especially for the A AND B gates, but inhibitory signaling platforms have recently been developed (A NOT B gates) ( 113 ). Suicide gene systems aiming at creating a kill switch in engineered T cells as a safeguard mechanism are also an efficient strategy to stop unanticipated adverse events ( 114 ).…”