Stem cell-based therapies for cancer treatment: separating hope from hype

Abstract

Stem cell-based therapies are emerging as a promising strategy to tackle cancer. Multiple stem cell types have been shown to exhibit inherent tropism towards tumours. Moreover, when engineered to express therapeutic agents, these pathotropic delivery vehicles can effectively target sites of malignancy. This perspective considers the current status of stem cell-based treatments for cancer and provides a rationale for translating the most promising preclinical studies into the clinic.

Figure 1. Using stem cells (SCs) to promote tumour cell death

SCs can be modified in various ways to generate antitumour capabilities. a | SCs can be engineered to secrete therapeutic proteins that function directly on tumour cells or indirectly on cells of the tumour microenvironment. For example, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), epidermal growth factor (EGF) agonists or interferons (IFNα or IFNβ) can be secreted to function on death receptor 4 (DR4) and DR5, EGF receptor (EGFR) or IFN receptors (IFNRs), respectively. Alternatively, SCs can secrete stromal, immune or blood vessel effectors. b | SCs can be engineered to express a suicide gene encoding an enzyme (such as cytosine deaminase (CD), carboxylesterase (CE) or herpes simplex virus thymidine kinase (HSV-tk)) that converts a prodrug into a cytotoxin. This induces suicide of the SC, and cancer cells are killed by the bystander effect, a phenomenon that describes the movement of cytotoxin from the SC to adjacent cancer cells via a paracrine mechanism or gap junctions. The distant bystander effect describes the recruitment of host immune cells in response to death or inflammatory signals released from dying cells. c | SCs can be loaded with nanoparticles containing chemotherapy or imaging agents that are released in the vicinity of the tumour, either passively or in response to external stimuli. d | SCs can be infected with oncolytic viruses (OVs). OVs replicate within the SCs, which then rupture and release OV progeny that can infect cancerous cells and amplify infection. aaTSP1, anti-angiogenic thrombospondin 1; IL, interleukin; NK, natural killer; PEX, a fragment of matrix metalloproteinase 2.

Figure 2. Potentiating stem cell (SC) efficacy

Multiple strategies have been used to enhance the therapeutic potential of SCs. a | Immunoevasive and migratory properties can be enhanced using genetic and non-genetic approaches. For example, SCs can be genetically modified to decrease the expression of human leukocyte antigen (HLA) class I to reduce antigen presentation to T cell receptors (TCRs), cytotoxic T lymphocyte antigen 4 (CTLA4)–immunoglobulin (Ig) can be secreted to block T cell co-stimulation by CTLA4, and upregulation of programmed cell death 1 ligand 1 (PDL1) can also inhibit T cell stimulation. Non-genetic approaches to deliver immune-cell modifying proteins include conjugation of peptides to a cell-penetrating peptide (CPP) and delivery in microparticles or nanoparticles. Enhancing tumour tropism of SCs can be achieved by overexpressing chemokine receptors, upregulating gene expression using epigenetic modifiers, altering SC characteristics using cationic peptides and irradiating tumours. b | The efficacy of SC-delivered therapeutic payloads can be enhanced by engineering bispecific molecules that simultaneously target multiple receptors; for example, epidermal growth factor receptor (EGFR)-specific nanobody (ENb) bound to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), or a CD20 specific single chain Fv antibody fragment (scFvCD20) bound to TRAIL. Alternatively, bimodal SCs can be created that express a combination of two or more secreted therapeutics, suicide and/or reporter genes. c | SCs that secrete therapeutic agents (for example, interleukin 12 (IL 12), TRAIL or oncolytic herpes simplex virus (oHSV)) can be encapsulated in synthetic extracellular matrix (sECM) to increase their therapeutic effectiveness. DR, death receptor.