Gastrointestinal cancer stem cells as targets for innovative immunotherapy

Table 1 Gastrointestinal cancer stem cells markers

Tumor type	Cancer stem cell phenotype	Ref.
Esophageal	CD44+, CD90, CD133+, ALDH1+	[10,11]
Gastric	CD44+, ALDH1+	[9,12]
Pancreatic	CD24+, CD44+, CD133+, EpCAM+, ALDH+	[13-15]
Liver	CD44+, CD90+, CD133+, EpCAM+	[16-19]
Colorectal	CD24+, CD44+, CD49f, CD133+, EpCAM+, ALDH1	[16,20,21]

Table 2 Targeting gastrointestinal cancer stem cell surface markers by monoclonal antibodies

Targeting approach	Cancer model	Effects	Ref.
RG7576 mAb against CD44	Solid tumors	Inhibited tumor growth and induced activation of macrophages	[23-26]
SWA11 against CD24	Colorectal cancer	Reduced tumor cell proliferation and angiogenesis	[27,28]
G7 mAbs against CD24	Liver cancer	Suppressed tumor growth	[29-31]
Catumaxomab (Removab®) mAb targeting EpCAM (CD326)	Gastric, colon cancers, pancreas	Activated immune cells (NK cells, macrophages, and T cells); prolonged survival period	[32-35]

NK: Natural killer; mAb: Monoclonal antibodies.

Table 3 Targeting gastrointestinal cancer stem cell by natural killer cells, chimeric antigen receptor expressed on T cells and dendritic cells based vaccines

Targeting approach	Cancer model	Ref.
CIK cells via NKG2D ligands expressed on CSC	Hepatocellular carcinoma	[56]
NK cells via NKG2D ligands expressed on CSC	Pancreatic cancer	[57]
CAR-T for CSC antigen ASB4	Colon cancer	[59]
CAR-T for EGFR and CAR-T for CSC antigen CD133	Cholangiocarcinoma	[60]
CAR-T for CSC antigen CD24	Pancreatic adenocarcinoma	[61]
DC loaded with Panc-1 CSC lysate	Pancreatic cancer	[62]
DC loaded with total mRNA from gastric CSC	Gastric cancer	[63]

CIK: Cytokine-induced killer; CSC: Cancer stem cells; NK: Natural killer; CAR-T: Chimeric antigen receptor expressed on T cells; EGFR: Epithelial growth factor; DC: Dendritic cells.

Table 4 List of approved drugs targeting immune checkpoints for gastrointestinal cancers

Target	Drug	Commercial name	Indication
PD-1	Nivolumab	Opdivo	Hepatocellular carcinoma, colorectal cancer with MSI-H
PD-1	Pembrolizumab	Keytruda	Gastric cancer, hepatocellular carcinoma, colorectal cancer, solid tumors with MSI-H
CTLA-4 and PD-1	Ipilimumab plus nivolumab	Yervoy plus Opdivo	Colorectal cancer with MSI-H

PD-1: Programmed death 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; MSI-H: High microsatellite instability.