Overcoming cell therapy barriers in the suppressive tumor microenvironment with engineered proteins

Adoptive cell immunotherapy (ACT) with genetically-modified T cells has shown impressive efficacy against some cancers, particularly CD19+ leukemias. However, ACT efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs), with increased inhibitory signals, reduced T cell infiltration/accumulation, and inadequate metabolic substrates. FasL is a death receptor ligand that is overexpressed in the majority of human TMEs and can protect tumor cells from immunity. To overcome this particular barrier, engineered immunomodulatory fusion proteins (IFPs), combining the Fas receptor ectodomain with the 4-1BB costimulatory signaling domain, thereby converting a negative signal into a positive one. T cells engineered with the Fas-4-1BB IFP exhibited enhanced proliferation and anti-tumor function, and reduced exhaustion in vitro. Fas-4-1BB T cells displayed characteristics consistent with 4-1BB signaling, including altered metabolism, increased mitochondrial density, and expression of pro-survival signaling molecules. In vivo, Fas-4-1BB T cells exhibited improved persistence and eradicated lethal murine leukemia. In the autochthonous KPC pancreatic tumor model, IFP ACT resulted in increased T cell accumulation in the tumor and significantly improved survival. The Fas-4-1BB IFP also enhanced primary human T cell expansion and anti-tumor function in vitro, supporting clinical translation.

Learning Objectives:

1. Identify 3 barriers to immune cell response to cancer

2. List 3 approaches to overcome immunosuppressive barriers to bolster the immune response to cancer

3. Explain how fusion proteins can convert a negative signal to a positive boost for T cells