Definition

A mRNA-based cancer vaccine that targets the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO; IDO1) and the tumor-associated antigen (TAA) and immune checkpoint molecule programmed cell death-1 ligand 1 (PD-L1), with potential immunostimulatory and antineoplastic activities. Upon intramuscular administration, the mRNA-derived IDO/PD-L1-targeted vaccine mRNA-4359 is taken up and translated by antigen presenting cells (APCs). Following translation, the epitopes are presented via major histocompatibility complex (MHC) molecules on the surface of the APCs. This leads to an induction of cytotoxic T-lymphocyte (CTL)-mediated immune response that specifically targets and destroys tumor cells and immunosuppressive cells expressing IDO and PD-L1. This may restore the proliferation and activation of various immune cells, and may eradicate tumor cells expressing IDO and PD-L1. IDO, a cytosolic enzyme responsible for tryptophan catabolism and conversion of tryptophan into kynurenine, is overexpressed on multiple tumor cell types as well as on APCs. Tryptophan depletion inhibits T-lymphocyte proliferation and activation, and subsequently suppresses the immune system. PD-L1 is overexpressed on many tumor cell types as well as on APCs and immunosuppressive cells in the tumor micro-environment (TME), such as regulatory T-cells (Tregs). PD-L1 binding to its cognate receptor programmed cell death protein 1 (PD-1; PDCD1; CD279) on T cells suppresses the immune system and results in increased immune evasion and decreased CTL activation.