Engineered stem cells targeting multiple cell surface receptors in tumors

Abstract

Multiple stem cell types exhibit inherent tropism for cancer, and engineered stem cells have been used as therapeutic agents to specifically target cancer cells. Recently, stem cells have been engineered to target multiple surface receptors on tumor cells, as well as endothelial and immune cells in the tumor microenvironment. In this review, we discuss the rationales and strategies for developing multiple receptor-targeted stem cells, their mechanisms of action, and the promises and challenges they hold as cancer therapeutics.

Keywords: adult stem cells; cancer; cell death; cell surface receptors; signal transduction.

Figure 1.. Engineered receptor targeted stem cells promote tumor cell death:

SCs can be modified in a variety of ways to generate an anti-tumor response by targeting cell surface receptors. SC engineered to express therapeutic proteins or antibodies that function directly on tumor cells (TRAIL, EGF agonists, anti-CD20, CD33, CD19) or that act on the tumor microenvironment to elicit an immune response (IL-10, IL-18, IFNα/β) or on surround cells (stromal effectors or blood vessel effects (aaTSP-1). SCs loaded with oncolytic virus amplify within the SC eventually leading to its rupture and release of viral progeny. These viral particles will go on to infect tumor cells, killing them and inducing an immune response at the tumor site. Abbreviations: SC- stem cell, TRAIL- tumor necrosis factor-related apoptosis inducing ligand, IL- interleukin, IFN- interferon, EGF- epidermal growth factor, aaTSP-1- anti-angiogenic thrombospondin,

Figure 2.. Potentiating stem cell efficacy through bifunctional SCs:

The efficacy of engineered SCs can be improved by targeting multiple cell surface receptors with a single bifunctional SC, increasing specificity and overcoming resistance. Bifunctional SCs 1) release a single molecule, such as TRAIL, that simultaneously targets two cell surface receptors (DR4 and DR5); 2) release two different molecules that target distinct cell surface receptors, such as TRAIL and aaTSP-1, or release a bifunctional fusion protein to target two different cell surface receptors, such as ENb-TRAIL or scFv-CD20-TRAIL 3) release bifunctional fusion proteins to target and recruit immune cells from the tumor microenvironment such as T cells (anti-CD33-antiCD3 and anti-CD19-anti-CD3) bsAbs fusion proteins. Abbreviations: SC- stem cell, TRAIL-tumor necrosis factor-related apoptosis inducing ligand, 3TSP-1- anti-angiogenic thrombospondin, ENb- epidermal growth factor receptor nanobody, bsAb-bispecific antibody