TABLE 1.

Strategies for overcoming anti-PD1/PDL1 resistance.

Mechanism	Type of strategy	Example	Phase	Tumor type	Effect	Trial number	References
Enhancing T cell priming	Chemotherapy	Pembrolizumab plus carboplatin and paclitaxel	III	Metastatic squamous NSCLC	Improving overall survival and progression-free survival	NCT02775435	Paz-Ares et al., 2018
		Pemetrexed and a platinum-based drug plus pembrolizumab	III	Metastatic non-squamous NSCLC	Improving overall survival and progression-free survival	NCT02578680	Gandhi et al., 2018
	Oncolytic virus	T-VEC plus pembrolizumab	III	Stage IIIB-IV melanoma	Ongoing	NCT02263508	Long et al., 2016
	vaccine	Multi-peptide vaccine plus nivolumab	I	HLA-A*0201 positive, HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors	Tolerated	NA	Gibney et al., 2015
		Neoantigen vaccine plus pembrolizumab	I	Stage IIIB/C and IVM1a/b melanoma	Tumor regression	NCT01970358	Ott et al., 2017
	Radiotherapy	Previous radiotherapy plus pembrolizumab	I	NSCLC	Longer progression free and overall survival	NCT01295827	Shaverdian et al., 2017
	TLRs agonist	TLR3-specific RNA agonist (ARNAX) plus anti-PDL1 antibody	In vivo experiments	EG7 cell line	Tumor regression	NA	Takeda Y. et al., 2017
		TLR9 agonist lefitolimod plus anti-PD1 or anti-PDL1 antibody	In vivo experiments	A20 and CT26 cell lines	Tumor regression	NA	Kapp et al., 2019
	IFN-α	IFN-α-anti-PDL1 fusion protein	In vivo experiments	A20, MC38, B16F10, and L929 cell lines	Tumor regression	NA	Liang et al., 2018
Reversing T cell exhaustion	Other ICBs	Anti-TIM3 blocking antibody plus Nivolumab	In vitro experiments	NSCLC	Reversing resistance to anti-PD-1 in PBMC from lung cancer patients	NCT02281214	Limagne et al., 2019
		Anti-TIGIT plus anti-PD1 antibody	In vivo experiments	GBM	Improving overall survival	NA	Hung et al., 2018
	Costimulatory agonist	Agonistic anti-CD40 antibody plus anti-PD1 antibody	In vivo experiments	BALB/c Renca renal carcinoma	Downregulating PD-1 expression Tumor regression	NA	Ngiow et al., 2016
Increasing T cell infiltration	Costimulatory agonist	Antibody-guided LIGHT fusion protein plus anti-PDL1 antibody	In vivo experiments	C57BL/6 AT3 mammary adenocarcinoma	Increasing T cell infiltration Tumor regression	NA	Tang et al., 2016
Improving immunosuppressive microenvironment	TGF-β blockade	TGF-β blockade plus anti-PDL1 antibody	In vivo experiments	EMT6 and MC38 cell lines	Facilitating T-cell penetration Tumor regression	NA	Mariathasan et al., 2018
Improving the immunosuppressive microenvironment	TGF-β blockade	TGF-β1 blockade SRK-181-mIgG1 plus anti-PD1 antibody	In vivo experiments	EMT6, Cloudman S91 and MBT2 cell lines	Facilitating T-cell penetration Tumor regression	NA	Martin et al., 2020
	Chemokine/cytokine receptor blockade	CSF1R blockade plus anti-PD-1 antibody	In vivo experiments	Pancreatic ductal adenocarcinoma	Tumor regression	NA	Zhu et al., 2014
		Anti-CCR4 mAb	In vitro experiments	Melanoma	Depletion of effector Tregs	NA	Sugiyama et al., 2013
		Anti-CXCR2 mAb plus anti-PD1 antibody	In vivo experiments	Mouse rhabdomyosarcoma	Tumor regression	NA	Highfill et al., 2014
	PI3K inhibitor	Selective PI3K inhibitor plus anti-PD1 antibody	In vivo experiments	B16 cell line	Tumor regression	NA	De Henau et al., 2016
	Epigenetic modulators	DZNep and 5-AZA-dC plus PD1 blockade	In vivo experiments	Moue ovarian cancer	Slowing down tumor progression	NA	Peng et al., 2015
	IDO inhibitor	IDO inhibitor INCB23843 plus anti-PDL1 and anti-CTLA4 antibody	In vivo experiments	B16 cell line	Tumor regression	NA	Spranger et al., 2014
	Adenosinergic pathway inhibitor	A2AR antagonist ciforadenant plus anti-PDL1 antibody	In vivo and in vitro experiments	MC38 cell line	Tumor regression Improving survival	NA	Willingham et al., 2018
		A2AR antagonist ciforadenant plus atezolizumab	I	Renal cell carcinoma	Tumor regression	NCT02655822	Fong et al., 2020
		CD73 inhibitor MEDI9447 plus anti-PD1 antibody	In vitro and vivo experiments/I	Mouse 4T1 cell line and human MDA-MB-231 cell line	Tumor regression in preclinical study	NCT02503774 (Ongoing)	Hay et al., 2016
Combination with other therapies	Oncogenic pathway inhibitor	BRAF inhibitor vemurafenib plus anti-PD1 or anti-PDL1 antibody	In vivo experiments	Mouse BRAF mutated tumor	Tumor regression Prolonged survival	NA	Cooper et al., 2014
		Dabrafenib and trametinib plus pembrolizumab	I	BRAF V600-mutated metastatic melanoma	Durable response	NCT02130466	Ribas et al., 2019
	Commensal microbiota	Oral administration of Bifidobacterium plus anti-PDL1 antibody	In vivo experiments	Melanoma	Tumor regression	NA	Sivan et al., 2015
		Fecal transplant plus anti-PDL1 antibody	In vivo experiments	Melanoma	Tumor regression	NA	Matson et al., 2018