. 2019 Oct 3;12(2-3):119–132. doi: 10.1007/s12307-019-00232-2

Table 1.

Therapeutic strategies to target tumor microenvironment

Strategy	Target	Agent	Biological function	Disease	Refs
Immune activation	CTLA-4	Ipilimumab	T-cell activation	Melanoma* Preclinical trials: NSCLC, breast cancer	[125–128]
	PD-1	Nivolumab	T-cell activation	Metastatic melanoma, NSCLC and RCC*	[129–133]
		Pembrolizumab		Metastatic HNSCC, Hodgkin lymphoma	[124]
		Cemiplimab		Advanced and metastatic cutaneous SCC*	[134, 135]
	PD-L1	Atezolizumab	T-cell activation Amplify anti-tumor immunity	Metastatic NSCLC* and UC*	[136, 137]
		Avelumab		Metastatic Merkel-cell* and UC*	[138]
		Durvalumab		Advanced bladder cancer*	[139]
	TIM3	Sym023 TSR-022 LY3321367 MBG453	T-cell activation	Phase I trials: advanced solid tumors and lymphomas	[124]
	LAG3	Sym022 TSR-033	T-cell activation	Phase I trials: advanced solid tumors and lymphomas	[124]
	LAG3	BMS-986016	T-cell activation	Phase I trials: recurrent GBM and hematologic neoplasms	[124]
Re-education	CD40	CD40 mAb	APCs and T-cell activation Re-educating cytotoxic myeloid cells	Lymphoma, melanoma, pancreatic carcinoma	[142]
Re-education	T cells	CAR-T	Ex vivo genetic modification of T cells	Leukemia, large B cell lymphoma, neuroblastoma, sarcoma	[144–147]
Macrophage-targeting	CSF-1R	PLX3397	Macrophage infiltration reduction	Breast and prostate cancer, melanoma, GBM	[118, 149–151]
	CCR2	CCX872-B MLN1202 BMS-813160	Macrophage infiltration reduction	Phase I/II trials: PDAC, CRC and bone metastasis	[118, 149]
	PI3Kγ in M2-like TAMs	IPI-549 TG100–115	T-cell activation	HNSCC, PDAC, lung and breast cancer, melanoma	[118, 152]
	HRG	–	Macrophage polarization and angiogenesis	Fibrosarcoma, pancreatic and breast cancer	[118, 155]
	HDAC	TMP195 inhibitor	Repolarizes TAMs. Synergizes with PD-1	Breast cancer	[118, 156]
MDSCs-targeting	Class I HDAC	Entinostat	Inhibition of MDSC activity	LLC and RCC	[119–121]
	STAT3	AZD9150	Inhibition of MDSC activity	Phase I trials: advanced HCC Phase II trials: pancreatic cancer, HNSCC, NSCLC and CRC	[119]
	CXCR2	SX-682	Blockade of MDSC recruitment	Oral cancer and LLC	[119, 122]
T_reg-targeting	CD25	Daclizumab	T_reg depletion	Breast cancer and melanoma	[123]
	CCR4	Mogamulizumab	T_reg depletion	Leukemia, lymphoma, lung and oesophageal cancer	[123]
	OX40	PF-04518600 MEDI6383	Reduction of immuno-suppressive activity	Melanoma, RCC, B cell lymphoma, advanced HNSCC and metastatic breast cancer	[123]
	GITR	MEDI1873 TRX518 MK-1248	Reduction of immuno-suppressive activity	Advanced solid tumors	[123]
	PI3Kδ	Parsaclisib	Increased CD8⁺ T-cell activity	Phase I trial: advanced solid tumors	[123]

*, FDA-approval; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; HNSCC, head and neck squamous cell carcinoma; UC, urothelial carcinoma; GBM, glioblastoma; PDAC, pancreatic ductal adenocarcinoma; CRC, colorectal cancer; LLC, Lewis lung carcinoma; HCC, hepatocellular carcinoma