Table 1.

Preclinical and clinical studies utilizing various iNKT cell immunotherapy strategies.

Strategy	Therapy Regimens	Preclinical Models or Clinical Trials	Outcome	References
Free glycolipids
	α-GalCer (i.v.)	Multiple cancer models	Activation of iNKT, NK, T cells, increased IFN-γ and IL-12	[97,98]
	α-GalCer (i.p.)	Multiple cancer models	NK and iNKT mediated tumor cell elimination, elevated IFN-γ	[99,100]
Adoptive transfers
	Tumor cells irradiated and loaded with α-GalCer	A20 lymphoma, Meth A sarcoma, VK*Myc model, Eµ-myc model	iNKT cells and effector T cells promote anti-tumor immunity, elevated IFN-γ and IL-12	[101]
	α-GalCer loaded dendritic cells	Multiple cancer models	Activation of iNKT cells	[51,52,102]
	α-GalCer loaded -APCs	Myeloma, NSCLC, and Head and neck cancer	Increased iNKT expansion and IFNγ production leading to stable disease	[103,104,105]
	Ex-vivo expanded iNKT cells	Multiple cancer models	Increased iNKT cytotoxicity, tumor regression and overall survival. Was model dependent	[17,52,106,107]
CAR-NKT cells
	GD2 CAR NKT	Melanoma and neuroblastoma models	Cytotoxicity against GD2 positive tumors, increased Th1 cytokines and localization to tumor site	[108,109,110]
	CD62L+ CD19 CAR NKT cells	B cell lymphoma model	Prolonged persistence in vivo	[96,111]
	CSPG4 CAR NKT cells	Melanoma	Increased iNKT pro-inflammatory cytokine production	[112]
CD1d-antibody fusion proteins
	Anti-HER2	Melanoma and Colon carcinoma	Increased iNKT pro-inflammatory cytokine production and cytotoxicity. Increase DC, NK, and CD8 T cells recruitment Increased tumor regression. Limited off-target effects.	[113,114]
	Anti-CEA	Colon carcinoma	Increased iNKT pro-inflammatory cytokine production and cytotoxicity. Increased tumor regression.	[113]
	Anti-CD19	Melanoma and Colon carcinoma	Increased iNKT pro-inflammatory cytokine production and cytotoxicity. Increased tumor regression.	[115]
Combination therapies
	α-GalCer-loaded DCs + expanded iNKT cells	Head and neck cancer	Increased circulating iNKT cell number and IFNγ production.	[17,116]
	α-GalCer -loaded DCs + anti-PD-1 or anti-PD-L1 mAbs	Melanoma metastasis, Colon cancer, Hepatoma model	Prevented iNKT cell anergy and enhanced anti-tumor function overcomes CD8 T cell exhaustion in PD-1 resistant tumors	[117,118,119]
	α-GalCer + anti-4-1BB, anti-CD40, or anti-DR5	Renal and breast cancer models	Stimulate robust anti-tumor immunity	[120,121]
	α-GalCer + IL-12 or IL-21	Melanoma and breast cancer models	Increased tumor regression and overall survival, increased iNKT cell cytotoxicity	[122,123]
	Vector bound α-GalCer	B16 melanoma models	Increased iNKT cell expansion and cytokine release, prevented NKT cell anergy	[124,125,126,127,128,129,130]
	α-GalCer + Cisplatin	Mesothelioma Model	Increased pro-inflammatory cytokine gene expression and tumor regression	[131]
	α-GalCer + 5-FU	Colon cancer model	Increased NK cell cytotoxicity and coreceptor expression	[132]
	α-GalCer loaded APCs and lenalidomide	Multiple myeloma patients	Decreased cancer cell proliferation, angiogenesis. Increased T cell, NK cell and iNKT cell activation and expansion. Elevated iNKT cell cytokine production. Well tolerated in patients.	[133,134]
	α-GalCer loaded APCs and anti-DEC205 nanoparticles	B16-F10 melanoma model	iNKT cell-mediated activation of NK cells, DCs, and γδ T cells	[92]
	α-GalCer-loaded APCs and oncolytic VSV	4T1 breast cancer and ID8 ovarian cancer models	Induced immunogenic cell death and lead to increased overall survival	[134,135]
	α-GalCer + iPSC-iNKT cells	EL4 T cell lymphoma	Enhanced anti-tumor activity and tumor regression	[136,137]

i.v., intravenous; i.p., intraperitoneal.