Table 4.

The promising strategies to overcome drug resistance with cancer vaccines to NSCLC.

Mechanisms to improve resistance	Target population	Target	Promising Strategies for resistance	Clinical Trial number	Reference
Reduce circulating EGF levels and decrease its binding to EGFR on cancer cells	Stage IIIB/IV NSCLC patients following front-line CTP	EGF	CIMAvax-EGF vaccine	RPCEC00000161	(273, 340)
Augment tumor-specific CD8+ T cell proportions and, activate their cytotoxic action	NSCLC patients without response to ICIs	MUC1	Combination of TG4010 and nivolumab	NCT02823990	(329)
Induce antigen-specific T cell immune response and increase anti-tumor activity of CD8+ T cells	Stage III/IV NSCLC patients	Patient-specific neoantigen peptides	FRAME-001	NCT04998474	(332)
By activating DC cells (via cytokine GM-CSF) and enhancing CD40L expression, the vaccine aims to increase DC activity in local vaccine sites.	Patients with refractory lung adenocarcinoma	CD40L, GM-CSF	DNA vaccine	NCT00601796	(336)
Recruit lymphocytes and antigen-stimulated DCs, leading to increased infiltrates of CD4, CD8, and CD11c+DEC205+ dendritic cells in the tumor, creating a lymphoid-like microenvironment and facilitating cognate T cell activation.	Stage IIIB/IV NSCLC patients	CCL21	DC vaccine	NCT01574222	(337)
Inducing antigen-specific cellular and/or humoral immune responses via targeting specific tumor-associated antigens (TAAs)	Stage IV NSCLC patients	6 non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1)	mRNA vaccine (CV9202)	NCT01915524	(338)
	Patients with stage IIIB/IV NSCLC who have achieved at least stable disease following first-line chemotherapy or chemoradiation	5 non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein	mRNA vaccine (CV9201)	NCT00923312	(339)
Stimulates T cell priming and infiltration, triggers local immune responses, and counteracts cancer-induced immune evasion within the tumor microenvironment.	Stage I/II NSCLC patients	MAGE-A3	MAGE-A3 vaccine with ICBs	NCT02879760	(341)
Stimulates the immune system to generate antibodies that specifically produce antibodies against hTERT and attack against hTERT-expressing cancer cells.	Patients with resistance to immune checkpoint inhibitors (ICIs) and non-immunogenic cold NSCLCs	TERT (TElomerase Reverse Transcriptase)	Vx-001	NCT01935154	(342, 343)