Table 2.

Immunotherapy of lung cancer with MPE

Immunotherapy	Treatment method	Target effect/target medicine	Clinically relevant effects/manifestations	References
Target T cells	Minimally invasive technologies	Specific T cells	Screen patients who are susceptible to T cell-targeted therapies	[35]
	Intrapleural administration of IL-2	CD8+T cells, CD3+T cells	Prolong patients survival, alleviate pleurisy	[129, 130, 132]
Adoptive cell therapy	CAR-T	CEA	Phase I clinical trial: evaluate the efficacy and safety of CAR-T therapy	NCT02349724 NCT04348643
		GPC3	Eliminate GPC-expressing LSCC cells and produce cytokines(IL-2,IL-10,IFN-γ,TNF-α)	[148]
		HER2	Afatinib is a treatment option for HER2 mutation-positive NSCLC	[151]
		/	Exhibit acceptable toxicity in phase I/II studies	NCT01935843
		MSLN	Inject CAR-T cells is better than systemic infusion of T cells	NCT01583686 NCT02414269
		PD-L1	Killing effect enhanced and proliferation rate of tumor cells was low	[156]
		ROR1	Microphysiological 3D models exhibited anti-tumor activity	[160]
		EGFR	Phase I trial: EGFR-CAR-T cells infusion was tested in NSCLC patients	NCT01869166 166
		/	Evaluate CXCR-5-modified anti-EGFR-CAR T cells immunotherapy	NCT04153799
		MUC1	Anti-MUC1-CAR T cells is used in an open Phase I/II clinical trial	NCT02587689
		/	Phase I/II trial: evaluate anti-MUC1 CAR-T cells with PD-1 gene knockout	NCT03525782
		/	MUC1-CAR T cells treatment in phase I/II study	NCT02587689
		/	MUC1-CAR-pNK cells study: implant CAR structure into NK cells	NCT02839954
		/	CAR-T cells target TnMUC1 in a phase I trail	NCT04025216
		FAP	Phase I clinical trial: anti-FAP-Δ-CD28/CD3ζ CAR-T cells with PD-1 inhibition improved survival	NCT01722149 [169]
ICB	CTLA-4	Ipilimumab	Added carboplatin and paclitaxel didn’t prolong NSCLC PFS or OS	[174, 175]
	PD-1/PD-L1	Pembrolizumab	Improve OS (12.7 vs 8.5 months)	[186]
		/	Improves PFS, OS and efficacy rates	[187]
		Nivolumab	Improved efficacy rates (20% vs 9%), PFS (3.5 vs 2.8 months) and 5-year OS (13% vs 3%)	[188, 189]
		Atezolizumab	Median OS prolong 7.1 months and incidence of garde 3/4 adverse events was low	[190]
		Durvalumab	Phase III Pacific trial: the median PFS(16.8 vs 5.6 months) was improved	[191]
		/	4-year median OS (47.5 vs 29.1 months), 4-year OS rate(49.6% vs 36.3%) and 4-year PFS rate (35.3% vs 19.5%) improved	[192]
		Nivolumab + Ipilimumab	Efficacy rates, median survival (17.1 vs 13.9 months), 2-year OS rate (40% vs 32.8%) improved and incidence of adverse reactions (32.8% vs 36%) decreased	[195]
Tregs	CCR4 antagonist	Tregs	CCR4 and CTLA-4 inhibitors increase efficacy greatly	[201]
	IL-1 blockers	CCL22	Inhibit tumor-induced immunosuppression by attracting CCL22	[202]
	Target TNFR2	Tregs	Antitumor activity of CD8+T cells was enhanced remarkablely	[70]
TAMs	PA-MSHA	NKs	Pleural effusion gradually reduced in 12 h	[206, 207]
	mAb, vaccines, antisense oligonucleotides, small molecule inhibitors	TGF-β	Reverse immune suppression using antisense gene	[208]
	Fucoidan	NK-κB	Inhibit tumor cells migration, CCL22 generation and CD4+T cells recruitment	[211]
DCs	DCs are reinfused to thoracic cavity	CD34+stem-cells	The overall response rate was 54%, the median duration of response was 20 weeks	[212]
	DC-CIK	DCs	The overall response rate was 38% and the disease control rate was 70.3%	[215]
	DC vaccine therapy combined with ICB	CD8 + T cells	Show anti-tumor effect	[216]
MDSCs	Peptide-Fc fusion protein	S100A protein family	Eliminate MDSCs	[218]
	CSF-1R	TAMs, PMN-MDSCs	Boost anti-PD-1 immunotherapy efficacy	[225]
	PDE-5 inhibitors	MDSCs	Reinvigorate anti-tumor immune responses and prolong survival in vivo	[227, 228]
	Paclitaxel	MDSCs	Promote MDSCs differentiation into DCs in MPE	[229]
NKs	Intrapleural administration of IL-2	NKs	MPE disappeared and didn’t recurrent more than 2 years	[234–237]
	IL-15	NKs	Antagonize the inhibitory effects of TME and not cause corresponding toxicity	[107]