Cheating death: a Fas-41BB immunomodulatory fusion protein obviates a death signal to enhance T cell function and adoptive therapy targeting leukemia and solid tumors

Abstract

Abstract Fas/FasL signaling plays a significant role in the generation and persistence of tumors. We and others have detected FasL expression in the tumor microenvironment (TME) of human ovarian, pancreatic, and other cancers, where it can function to protect tumor cells from tumor-infiltrating lymphocytes. Adoptive immunotherapy, a promising treatment option, uses genetically modified T cells to eliminate tumors. However, efficacy of T cell immunotherapy is dampened by limited costimulation as well as increased inhibitory and death signals in the TME. We previously showed enhanced therapeutic efficacy by engineering T cells to express an immunomodulatory fusion protein (IFP) to convert the inhibitory CD200R signal to a costimulatory CD28 signal and questioned if IFPs could use a 4-1BB signal to enhance in vivo persistence and memory formation. 4-1BB forms a trimer when binding its ligand, that is requisite for an effective costimulatory signal. We and others engineered T cells to express 4-1BB with an ectodomain that dimerizes, however this IFP did not improve T cell function. We hypothesized a Fas IFP with a 4-1BB signal would effectively replace Fas signaling and provide costimulation, as Fas also trimerizes when engaged by ligand. T cells transduced with the Fas-4-1BB IFP exhibited enhanced accumulation and function in vitro. In a model of leukemia, Fas-4-1BB-transduced T cells eradicated otherwise lethal disease and exhibited increased persistence. Preliminary data in the autochthonous KPC pancreatic and ID8 ovarian cancer models support increased efficacy. We describe for the first time that an IFP can generate an effective 4-1BB signal to overcome obstacles in the TME and enhance T cell immunotherapy of solid and liquid malignancies.