Table 3.

Preclinical/clinical trials of combination therapies targeting CSC markers.

Preclinical Studies
Experimental Model	Target	Immunotherapy	Combined Therapy	Cancer Type	Refs
In vitro (cell line)	CD47	5F9 mAb	AZA (cytotoxic analogue of the nucleoside cytidine, inhibitor of DNA methyltransferase)	AML	[251]
In vivo (cell-line derived xenograft)
In vivo (patient-derived xenograft)	ROR1	Cirmtuzumab	Ibrutinib (Bruton’s tyrosine kinase (BTK) inhibitor)	CLL	[253]
In vitro (cell line)	EGFR	CAR NK-92	Cabozantinib (VEGFR-2 inhibitor)	Renal cell carcinoma	[114]
In vivo (cell-line derived xenograft)
In vitro (cell line)	Carbonic Anhydrase IX (CAIX)	CAR T	Sunitinib (multi-targeted receptor kinase inhibitor)		[131]
In vivo (cell-line derived xenograft)
In vitro (cell line)	HER2	HER2 CAR NK-92	Apatinib (VEGFR-2 inhibitor)	Gastric cancer	[256]
In vivo (cell-line derived xenograft)
In vitro (cell line)	IL-6	Tocilizumab	MK-0752 (γ-secretase inhibitor)	Breast cancer	[257]
In vivo (cell-line derived xenograft)
In vivo (patient-derived xenograft)
In vivo (cell-line derived xenograft)	EpCAM	CAR-NK-92	Regorafenib (multitargeted kinase inhibitor)	Colorectal cancer	[258]
In vivo (syngeneic models)	ALDHHigh CSCs	ALDHHigh-DC vaccine	Anti PD-L1 antibody	D5 murine melanoma and 4T1 murine breast cancer	[247]
In vivo (syngeneic models)	ALDHHigh CSCs	ALDHHigh-DC vaccine	Anti PD-L1 antibody; Anti CTLA-4 antibody	B16-F10 murine melanoma tumors	[248]
In vivo (cell-line derived xenograft)	CD133	CAR-T	Cisplatin (DNA-binding cytotoxic drug)	Gastric cancer	[259]
In vitro (Cell line)		CAR NK-92		Ovarian cancer	[260]
In vivo (cell-line derived xenograft)	CD44+/CD24− CSCs	CD44+/CD24− CSC-pulsed DC vaccine		Ehrlich carcinoma	[250]
In vitro (patient-derived cell line)	OAcGD2	8B6 mAb	Temozolomide (alkylating agent)	GBM	[261]
In vivo (Patient-derived xenograft)
In vivo (cell-line derived xenograft)	CD105	TRC105	Conventional fractionated RT (5 × 2 Gy)	Prostate cancer	[262]
In vivo (Cell-line derived xenograft)	CD47	Anti-CD47 mAb	Conventional fractionated RT (1 × 5 Gy; 4 × 5 Gy; 1 × 10 Gy)	Small cell lung cancer, colon cancer	[263]
In vitro (3D model)	CD98	UniCAR T + CD98 TM	Conventional fractionated RT (2 × 2 Gy)	HNSCC	[246]
In vivo (Cell-line derived xenograft)	CD25	Anti-CD25 mAb	Conventional fractionated RT		[264]
Clinical trials
NCT number	Target	Immunotherapy	Combined therapy	Cancer type	Refs
NCT03248479	CD47	Magrolimab (Hu5F9-G4)	AZA	AML/MDS	[252]
NCT03088878	ROR1	Cirmtuzumab	Ibrutinib	CLL	[254]
NCT02259582	DLL4	Demcizumab	Carboplatin + pemetrexed	Non-squamous NSCLC (DENALI)	[265]