Table 2.

Summary of agents with potential to overcome acquired resistance to immune checkpoint inhibitors

Category	Agent	Target	combinational therapies	Tumor type (s)	Phase	References
Targeting neoantigen depletion	Neo-PV-01	Personalized neoantigen-based vaccine	Nivolumab	Melanoma NSCLC Bladder Cancer	Phase Ib (NCT02897765)	[98]
	ISA 101	Synthetic long-peptide HPV-16 vaccine	Nivolumab	HPV-16-positive cancer	Phase II (NCT02426892)	[99]
	T-VEC	Oncolytic virus	Pembrolizumab	Melanoma	Phase Ib (NCT02263508)	[102]
	T-VEC	Oncolytic virus	Ipilimumab	Melanoma	Phase II (NCT01740297)	[103]
	T-VEC	Oncolytic virus	Ipilimumab; Nivolumab; Pembrolizumab	Melanoma	Retrospective	[104]
Targeting defects in antigen processing and presentation	LCL161	The cIAP1/2 antagonist	Anti-PD-L1 and/or anti-CTLA4	Pancreatic ductal adenocarcinoma	Preclinical
	Trametinib	The mall molecule MEK inhibitor	Anti-PD-L1	HNSCC	Preclinical	[106]
	Chloroquine	Inhibiting autophagy	Anti-PD1 and anti-CTLA4	PDAC	Preclinical	[107]
	ASPIRE nanovaccine	Specific pMHC-I, anti-PD1 antibody and B7 are simultaneously anchored by a programmed process	NA	Melanoma Colon carcinoma Lewis lung carcinoma	Preclinical	[108]
Targeting IFN‐γ/JAK signaling pathway	BO-112	A nanoplexed formulation of Poly I: C coupled to polyethylenimine	Anti-PD-L1	Melanoma	Preclinical	[110]
	BO-112	A nanoplexed formulation of Poly I: C coupled to polyethylenimine	Pembrolizumab; Nivolumab	Solid tumor	Phase I (NCT02828098)	[111]
	Overexpression of NLRC5	Upexpressing NLRC5	ACT	Melanoma	Preclinical	[112]
Targeting alternate ICI activation	F38-2E2	Anti-TIM-3 antibody	Nivolumab	Lung cancer	Preclinical	[55]
	Ieramilimab	The LAG-3 inhibitor	Spartalizumab	Advanced malignancies	Phase I/II (NCT02460224)	[115]
	MIH63	Anti-VISTA antibody	Anti-PD-1 and anti-CTLA-4	Squamous cell carcinoma	Preclinical	[116]
	Anti-murine BTLA antibody	Anti-BTLA antibody	Anti-PD-1	Glioblastoma	Preclinical	[117]
	Tiragolumab	Anti-TIGIT antibody	Atezolizumab	NSCLC	Phase II (NCT03563716)	[118]
Targeting suppressive tumor microenvironment	anti-CD25 antibody	Anti-CD25 antibody	Anti-PD-1	Sarcoma, colon adenocarcinoma, melanoma, and colorectal carcinoma	Preclinical	[119]
	Mogamulizumab	Anti-CCR4 antibody	Nivolumab	Solid tumors	Phase I (NCT02476123)	[121]
	PLX3397	CSF-1R kinase inhibitor	Oncolytic viruses, and anti-PD-1	Colon cancer	Preclinical	[123]
	BLZ945	CSF-1R kinase inhibitor	Anti-PD-1 and anti-PD-L1	Control spontaneous neuroblastoma	Preclinical	[124]
	ATRA	Targeting MDSCs	Anti-PD-1	NSCLC	Preclinical	[125]
	ATRA	Targeting MDSCs	Ipilimumab	Melanoma	Phase II (NCT02403778)	[126]
	BMS-211	Targeting MDSCs	anti-CTLA-4	Lung carcinoma, colon carcinoma, breast carcinoma and lymphoma	Preclinical	[127]
	Epacadostat	The IDO1 enzyme inhibitor	Pembrolizumab	Solid tumors	Phase I/II (NCT02178722)	[128]
	Epacadostat	The IDO1 enzyme inhibitor	Pembrolizumab	Melanoma	Phase III (NCT02752074)	[129]
	Linrodostat mesylate	The IDO1 enzyme inhibitor	Nivolumab	Bladder cancer	Phase I/II (NCT02658890)	[130]
	CD39 knockout	Blocking CD39	anti-PD1	HCC	Preclinical	[131]
	Oleclumab	Anti-CD73 monoclonal antibody	Durvalumab	NSCLC	Phase II (NCT05221840)	[132]
	NIR178	The A2AR antagonist	Immunotherapy	NSCLC	Phase II (NCT02403193)	[133]
	TGFβ-blocking	Inhibiting TGFβ	Anti-PD-L1	Urothelial cancer	Preclinical	[134]
	Mithramycin		Anti-PD-L1	Chronic lymphocytic leukemia	Preclinical	[135]
	Pegilodecakin	The PEGylated form of IL10	Pembrolizumab or nivolumab	Solid tumors	Phase IB (NCT02009449)	[136]
Targeting epigenetic modification	Decitabine	The DNMT inhibitor	anti-CTLA-4	Ovarian Cancer	Preclinical	[142]
	Azacitidine	The DNMT inhibitor	Nivolumab	Acute Myeloid Leukemia	Phase II (NCT02397720)	[148]
	Panobinostat	The HDAC inhibitor	Anti-PD-L1	Melanoma	Preclinical	[143]
	Romidepsin	The HDAC inhibitor	Anti-PD-L1	Lung Adenocarcinoma	Preclinical	[144]
	HBI-8000	The HDAC inhibitor	PD-1, PD-L1, or CTLA-4,	Colon carcinoma and B-cell lymphoma	Preclinical	[145]
	Vorinostat	The HDAC inhibitor	Pembrolizumab	NSCLC	Phase I/Ib (NCT02638090)	[149]
	Entinostat,	The HDAC inhibitor	Pembrolizumab	Melanoma	Phase Ib/II NCT02437136	[150]
	Entinostat	The HDAC inhibitor	Pembrolizumab	NSCLC	Phase Ib/II NCT02437136	[151]
	GSK503	The EZH2 inhibitor	Anti-PD1, anti-CTLA-4 and IL-2	Melanoma	Preclinical	[146]
Targeting gut microbiome Dysbiosis	Bifidobacterium	Regulating gut microbiota	Anti-PD-L1	Melanoma	Preclinical	[153]
	Bacteroides fragilis	Regulating gut microbiota	Anti-CTLA-4	Melanoma	Preclinical	[94]
	Lactobacillus johnsonii, Bifidobacterium pseudolongum, and Olsenella	Regulating gut microbiota	Anti-CTLA-4	Colorectal cancer, bladder cancer, and melanoma	Preclinical	[154]
	EDP1503	Regulating gut microbiota	Pembrolizumab	Solid tumors	Phase I/II (NCT03775850)	[155]
	MRx0518	Regulating gut microbiota	Pembrolizumab	Bladder cancer, NSCLC, RCC, and Melanoma	Phase I/II (NCT03637803)	[156]
	FMT	Regulating gut microbiota	Anti-PD-1	Epithelial tumors	Preclinical	[89]
	FMT	Regulating gut microbiota	Nivolumab	Melanoma	Phase I NCT03353402	[157]
	FMT	Regulating gut microbiota	Pembrolizumab	Melanoma	Phase II NCT03341143	[158]
Other emerging combination strategies	STING-LNP	Stimulating the STING pathway	Anti-PD-1	Melanoma	Preclinical	[159]
	MUSIC platform	Stimulating the STING pathway	Anti-PD-1	Breast cancer	Preclinical	[160]
	iTPNCs	Activating inflammatory signaling	Anti-CTLA-4	Melanoma, colon cancer, and breast cancer	Preclinical	[161]
	177Lu-PSMA-617	Delivering beta-particle radiation	Pembrolizumab	Prostate cancer	Phase II NCT03805594	[162]
	BNT111	RNA vaccine	Anti-PD-1	Melanoma	Preclinical	[163]
	8FNs	Nanovaccine	Anti-PD-1	Melanoma	Preclinical	[164]