Tumor vaccines: Toward multidimensional anti-tumor therapies

Figures & data

Figure 1. Tumor vaccine strategies based on boosting the immune system. Different types of tumor vaccines are inoculated and presented by DC to activate the CD8⁺ T cells, CD4⁺ T cells and B cells to kill tumor cells directly or indirectly. Abbreviations: DC: dendritic cells; ICAM-1: intercellular cell adhesion molecule-1; CTL: cytotoxic T cells; MHC: Major histocompatibility complex; IFN-γ: interferon γ; GzmB: granzyme B; PFN: perforin; TAMs: tumor-associated macrophages.

Table 1. Experimental studies of tumor vaccines based on boosting the immune response.

Vaccine type	Regimen	Adjuvant	Tumor model	Outcome	Ref.
Peptide vaccines	CTP-mediated peptides	—	Mouse Leukemia model (protective and therapeutic immunization strategies).	Induced a more effective cellular immune response.	Yang^Citation13
	NanoSTING-vax (a synthetic cancer nanovaccine)	—	MC38 murine colorectal adenocarcinoma model (protective and therapeutic immunization strategies).	Enhanced the CD8^+ T cell responses to a diversity of peptide antigens.	Shae et al.^Citation19
	SIM2-derived peptides	—	Immunization models.	Induced an effective CD4^+ and CD8^+ T-Cell response.	Kissick et al.^Citation21
	TriVax vaccine (peptide, TLR ligand, and CD40 mAb, administered i.v.)		Mouse model of malignant melanoma (therapeutic immunization strategies).	Induced more robust antigen-specific CD4^+ T-cell responses than conventional adjuvants.	Kumai et al.^Citation36
mRNA vaccines	Lipid nanoparticles containing mRNA coding for the tumor-associated antigens gp100 and TRP2	LPS	Murine melanoma model (therapeutic immunization strategies).	Inducing a strong cytotoxic T cell response. Significantly extended the overall mice survival.	Oberli et al.^Citation23
	A lymph-node – targeting mRNA vaccine based on lipid nanoparticles (113-O12B/mOVA)	LNP	Murine B16F10-OVA melanoma model(protective and therapeutic immunization strategies)	O12B/mOVA Elicited a Robust CD8 T Cell Response and Protective Effect on the B16F10-OVA Tumor Model.	Chen et al.^Citation37
	Circular RNA vaccine(CART-circOVA vaccine)		Murine B16-F10-OVA melanoma model(protective immunization strategies)	Observed potent and persistent T cell responses in mice following immunization. The circRNA vaccine group showed a significant tumor growth inhibition compared to the untreated group	Amaya et al.^Citation38
Cell based cancer vaccines	AFP peptide-pulsed or lenti-AFP-engineered methods dendritic cells	—	Hepatocellular carcinoma (in vitro study).	AFP-specific T cells could efficiently kill HepG2 cells	Liu et al.^Citation22
Viral vector vaccine	Murine CMV to express a modified B16 melanoma antigen gp100	—	Aggressive B16 lung metastatic melanoma model (protective and therapeutic immunization strategies).	Induced a potent gp100-specific CD8^+ T-cell response and strongly protected mice from highly metastatic lung melanoma.	Qiu et al.^Citation27
	Mouse CMV vector expressing RAE-1γ	—	A mouse model for human melanoma (protective and therapeutic immunization strategies).	Promote the induction of KLRG1 CD8^+ T cells with augmented effector functions	Tršan et al.^Citation28
	Genetic vaccines based on adenoviruses derived from nonhuman Great Apes (GAd)	—	Murine MC38 colorectal adenocarcinoma model (therapeutic immunization strategies)	GAd vaccine combined with αPD-1 treatment enhances immunogenicity and expands neoantigen-specific CD8^+ T cells in the tumor	D’Alise et al.^Citation29
	Flt3L-NDV ISV	—	GFP A20 tumor model(therapeutic immunization strategies)	NDV efficiently induced cDC1 activation and tumor Ag cross-presentation, and that Flt3L induced robust amplification of tumor-specific T cell responses and long-term tumor control. Flt3L-NDV ISV therapy efficiently induced CD8 T cells reactive to neoepitopes identified by tumor exome and RNA sequencing.	Svensson-Arvelund et al.^Citation30

CTP: cytoplasmic transduction peptide; AFP: alpha-fetoprotein; LPS: lipopolysaccharide; LNP: lipid nanoparticle; OVA: ovalbumin; CMV: cytomegalovirus; NDV: oncolytic Newcastle disease virus; ISV: in situ vaccination.

Table 2. Clinical trials of tumor vaccines based on boosting the immune response.

Vaccine type	Regimen	Clinical trial identifier	Conditions	Adjuvant	Phases	Outcome	Ref.
Peptide vaccine	CPV S-588410 (a novel CPV comprising five human leukocyte antigens (HLA)-A *24:02-restricted 9–10-mer peptides derived from five cancer testis antigens (DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1))	UMIN000023324	Esophageal cancer (n = 15)	MONTANIDE ISA51VG	Exploratory open‑label clinical study	Densities of CD8^+, CD8^+ Granzyme B^+, CD8^+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue.	Daiko et al.^Citation39
	iNeo-Vac-P01(Neoantigen peptides)	NCT03645148	Pancreatic cancer(n = 7)	GM-CSF	I	Indicated the potential of iNeo-Vac-P01 in inducing the activation of a specific subset of T cells to kill cancer cells	Chen et al.^Citation33
	NEO-PV-01 (consisting of up to 20 synthesized peptides of approximately 14–35 amino acids in length that are derived from an individual patient’s mutated tumor DNA)	NCT03380871	Lung Cancer (n = 38)	Poly-ICLC	Ib	NEO-PV-01 plus chemotherapy and anti-PD-1 induces neoantigen-reactive T cell responses that are neo-epitope specific, persistent, and show cytotoxic potential. A large majority of the vaccine-induced cytotoxic responses were CD4^+ T cells.	Awad et al.^Citation34
	VX-001 (targets the universal tumor antigen TElomerase Reverse Transcriptase (TERT))	NCT01935154	Non-small Cell Lung Cancer (n = 221)		II	Vx-001 could induce specific CD8 immune response but failed to meet its primary endpoint.	Gridelli et al.^Citation40
mRNA vaccines	Autogene cevumeran	NCT04161755	Pancreatic ductal adenocarcinoma (n = 16)	Lipoplex nanoparticles	I	The vaccine induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen.Vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8^+T cells.	Rojas et al.^Citation24
DNA vaccines	pTVG-AR (a DNA vaccine encoding the androgen receptor ligand-binding domain)	NCT02411786	Prostate Cancer (n = 40	GM-CSF	I	pTVG-AR was safe and immunologically active in patients with mCSPC. Association between immunity and PPFS suggests that treatment may delay the time to castration resistance, consistent with preclinical findings.	Kyriakopoulos et al.^Citation25
Cell based cancer vaccines	Sipuleucel-T (an active cellular immunotherapy, a type of therapeutic cancer vaccine, consisting of autologous peripheral-bloodmononuclear cells)	NCT00065442	Prostate cancer (n = 512)		III	Sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer.	Kantoff et al.^Citation8
	GBM6-AD (lysate of an allogeneic glioblastoma stem cell line)	NCT02549833	Low-grade gliomas (n = 17)	Poly-ICLC	I	Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8 T cells in peripheral blood.	Hirokazu et al.^Citation41
	CpG-MCL vaccine	NCT00490529	Mantle cell lymphoma (n = 47)(MCL)		II	CpG-MCL vaccine induce CD8 T cell immune responses that are associated with a superior clinical outcome.	Frank et al.^Citation42
Viral vector vaccines	Nous-209 vaccine(Nous-209 is based on a heterologous prime/boost regimen composed of the Great Ape Adenovirus GAd20–209-FSP used for priming and Modified Vaccinia virus Ankara MVA-209-FSP used for boosting)	NCT04041310	Unresectable or metastatic deficient mismatch repair (dMMR) or MSI-H CRC, gastric, or gastro-esophageal junction (G-E junction) tumors(n = 10)		I	Nous-209 vaccination elicits a strong and broad neoantigen-specific T cell response in patients with dMMR tumors.	Svensson-Arvelund et al.^Citation30
	MEDI5395(a Recombinant Newcastle Disease Virus Encoding genes for GM-CSF)	NCT03889275	Advanced Solid Tumors(n = 39)		I	Unpublished
	MEDI9253(a Recombinant Newcastle Disease Virus Encoding Interleukin-12)	NCT04613492	Solid Tumors(n = 37)		I	Unpublished
	VRP-HER2（based on a novel alphaviral vector encoding a portion of HER2）	NCT01526473	HER2 Expressing Breast Cancer (n = 22)		I	VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies.	Crosby et al.^Citation43

CPV: cancer peptide vaccines; GM-CSF: granulocyte-macrophage colony-stimulating factor; Poly-ICLC: poly-IC containing poly-lysine and carboxymethylcellulose; Poly-IC: a dsRNA mimic that functions as a pattern recognition receptor ligand; CpG: cytosine-phosphate- guanosine.

Figure 2. Tumor vaccine strategies based on overcoming tumor immunosuppression. Tumor vaccines reshape the tumor microenvironment by remodeling, repolarizing, gene silencing or target immunosuppressive cells, turning immunosuppression into immunostimulation. [Figure reproduced from bleve A, durante B, sica A, consonni FM. Lipid metabolism and cancer immunotherapy: immunosuppressive myeloid cells at the Crossroad. Int J Mol Sci. 2020 Aug 14; 21(16): 5845. doi: 10. 3390/ijms21165845. PMID: 32823961; PMCID: PMC7461616] Abbreviations: MDSC: myeloid-derived suppressor cells; TAN: tumor-associated neutrophils.

Table 3. Tumor vaccines based on overcoming tumor immunosuppression.

Study type	Type of tumor	Phase	Substance	Outcome	Ref.
Experimental study	Melanoma	-	HCA587 protein + CpG ODN + ISCOM	The vaccination resulted in enhanced accumulation of TILs with enrichment of conventional CD4+ T cells but a reduced representation of Treg cells.	Chen et al.^Citation75
	HPV	-	HPV16 E7 43–77 peptide + CpG ODN	Increased cellular immunity was mediated by CD4+IFN-γ+ T cells and CD8+IFN-γ+ T cells, while decreased numbers of immunosuppressive cells including Tregs and MDSCs were induced by the vaccine.	Yang et al.^Citation76
	Melanoma	-	Vac + ASOcont + transfected irradiated B16 cell vaccine	This tumor cell vaccine combined with Foxp3 or CTLA4 gene silencing increased the efficacy of antitumor therapy.	Miguel et al.^Citation65
		-	Fragment C (Fc) portion of IgG + Foxp3	The expression of Foxp3-Fc (IgG) in vaccines in tumor therapies for removal of regulatory cells serves as a successful strategy to increase the efficiency of other immunotherapies.	Mousavi et al.^Citation67
	Melanoma	-	Human tyrosinase gene (Tyr) sequences	This vaccine reduced the number of MDSCs in the tumor microenvironment through the downregulation of monocyte chemoattractant protein 1, interleukin-10, CXCL5, and arginase II, which are factors important for MDSC expansion.	Yan et al.^Citation70
	HCC	-	SiPCCl2-hybridized mesoporous silica with coordination of Fe (III)-captopril	This neoantigen nano-vaccine remodels tumor-associated neutrophils to potentiate the anticancer immune response and enhance immunotherapy efficiency.	Wang et al.^Citation71
		-	Mouse A20 small hairpin interfering RNA sequence	This vaccine encodes an A20-specific shRNA to enhance DC function, and targets fibroblast activation protein (FAP) expressed in CAFs and the tumor antigen tyrosine-related protein (TRP)2 (DC-shA20-FAP-TRP2).	Gottschalk et al.^Citation72
Clinical trial	HNSCC	I	Autologous monocyte-derived DCs loaded with selected wt p53 peptides	Two-year DFS was 88%; p53-specific T-cell and IFN-ded with selected wt p53 pept Treg frequency was consistently decreased.	Schuler et al.^Citation77
	GEA	Ib	HER2/neu fusion peptide P467+nontoxic diphtheria protein CRM197	IMU-131 was well tolerated and safe. The vaccine-induced HER2-specific Abs and cellular responses were dose-dependent. The numbers of FOXP3+ Tregs in patients were reduced following tumor regression.	Wiedermann et al.^Citation61
	Esophageal, stomach, or lung cancer	I/II	Cholesterol-bearing hydrophobized pullulan (CHP)+MAGE-A4 protein (CHP-MAGE-A4)	Treg ratios that remained low both before and after vaccination were associated with a good prognosis, and a low Treg/CD4 lymphocyte ratio 7 weeks after the initial vaccination was correlated with a better prognosis.	Wada et al.^Citation62

HPV: human papillomavirus; CpG ODN: CpG-containing oligodeoxynucleotides; HCA587: a cancer-testis antigen; ISCOM: immune- stimulating complex; HCC: hepatocellular carcinoma; HNSCC: head and neck squamous cell carcinoma; GEA: gastroesophageal adenocarcinomas; DC: dendritic cell; TILs: tumor-infiltrating lymphocytes.

Figure 3. Tumor vaccine strategies based on anti-angiogenesis. Tumor vaccines induce cellular and humoral immune responses targeting endothelial cells, and inhibit tumor angiogenesis through CTL-mediated killing of TAMs that secrete pro-angiogenic factors. Abbreviations: MMP-9: matrix metalloproteinase-9.

Table 4. List of animal experimental studies on tumor vaccines based on anti-angiogenesis.

Vaccine types	Vaccine	Model	Adjuvant	Outcome	Ref.
Peptide Vaccines	Nanoliposomal VEGF-R2 peptide vaccine	Murine B16F10 melanoma model (therapeutic immunization strategies)	-	Results represented that VEGFR-2 peptide nanoliposomal formulations (Lip-V1) substantially activated CD4^+ and CD8^+ T cell responses against B16F10 cells and significantly boosted the production of IFN-γ and IL-4. The formulation led to a significant decrease in tumor volume and enhanced survival in mice, which could be a promising therapeutic vaccination approach capable of eliciting strong antigen-specific immunologic and anti-tumor responses.	Zahedipour et al.^Citation92
	MUC1 peptide vaccine	Murine breast cancer model（protective and therapeutic immunization strategies）	mVEGF165b	Co-immunized mVEGF165b with MUC1 peptide vaccine increased the VEGF antibody titers and MUC-1-specific IFN-γ-producing CD8^+ T cells, thus to decreasing the frequency of regulatory T cells (Tregs) in both preventive and therapeutic scenarios. mVEGF165b may be an ideal immunization adjunct to enhance the immune efficacy of peptide-based tumor vaccines by overcoming immune tolerance.	Zhang et al.^Citation99
DNA Vaccines	DNA plasmids encoding MUC1,VEGFR2, GM-CSF	Murine Lewis carcinoma model (preventive strategies)	GM-CSF	The anti-tumor effect of MUC1-VEGFR2 was greater than that of MUC1 or VEGFR2 alone. The anti-tumor effect of MUC1-VEGFR2 combined with GM-CSF was greater than that of MUC1-VEGFR2. The DNA vaccine induced humoral and cellular MUC1-specific immune responses in mice and increased IFN-γ and IL-4 release. The DNA vaccine inhibited the growth of MUC1-expressing tumors and prolonged mouse survival.	Ruan et al.^Citation90
	DNA plasmids encoding HPV 16 E6E7 fusion protein,VEGFR2 (pVAX1-E6E7-F2A-VEGFR2)	Murine TC-1-E6E7 Cervical cancer model (preventive strategies)	-	The plasmid harboring the E6E7 fusion gene and VEGFR2 showed stronger inhibition of tumor growth and angiogenesis than the plasmid expressing E6E7 or VEGFR2 alone by inducing more robust CTLs targeting E6E7 or VEGFR2，Th1 (IFN-γ)and Th2 (IL-4)cell response, which indicated that the combination of E6E7 and VEGFR2 could exert a synergistic antitumor effect.	Gao et al.^Citation91
	CAVE:Semliki Forest Virus (SFV) replicon DNA vaccine expressing murine VEGFR2 and IL12 CAVA: SFV replicon DNA vaccine targeting survivin and β-hCG antigens	Murine B16F10-β-hCG melanoma model (preventive strategies)	-	Compared with CAVE or CAVA vaccine alone, the combined vaccines inhibited the tumor growth and improved the survival rate in B16 melanoma mice model more effectively. The intratumoral microvessel density was lowest in combined vaccines group than CAVE or CAVA alone group.	Yin et al.^Citation89
	SCT-KDR2 DNA: SCT-encoding VEGFR2 antigen peptide and mouse MHC class I heavy chain H-2D^b	Murine B16 melanoma model 3LL Lewis lung carcinoma metastasis mouse model (preventive strategies)	-	SCT-KDR2 DNA was able to successfully break self-immunological tolerance and induce robust cytotoxic T-lymphocyte (CTL) response to VEGFR2, leading to marked suppression of tumor cell-induced angiogenesis and metastasis in murine models of B16 melanoma and 3LL Lewis lung carcinoma.	Chen et al.^Citation88
	DNA plasmids encoding survivin	Murine B16 melanoma model (preventive strategies)	-	Human survivin DNA vaccine delivered by intradermal electroporation (EP) generated Survivin-specific CD8^+ cytotoxic T lymphocyte (CTL) responses against B16 and peptide-pulsed RMA-S cells, cross-reactive with the mouse epitope surv20–28, suppressed angiogenesis in vivo and elicited protection against highly aggressive syngeneic B16 melanoma tumor challenge.	Lladser et al.^Citation87
	DNA plasmids encoding survivin	Murine immune model	GM-CSF	The DNA vaccine induced a survivin-specific humoral through generating IgG2a, as well as cellular immune response in recipient by activating cytotoxic Interferon-gamma (IFN-g) secreting CD8^+ T cells.	Lladser et al.^Citation86
Cell Based Vaccines	4T1 murine mammary cancer cell vaccine (irradiated and infected adenovirus encoding the VEGFR2 gene)	Murine 4T1 breast cancer models (therapeutic immunization strategies)	-	AdVEGFR2-infected whole-cancer cell vaccines inhibited subsequent tumor growth and pulmonary metastasis compared with challenge inoculations. Angiogenesis was inhibited, and the number of CD8^+ T lymphocytes was increased within the tumors.	Yan et al.^Citation95
	Soluble flk1 and IFN-γ fusion gene-transfected DC(DC-sflk1-IFN-γ)	Murine immune model Murine B16 Metastasis Model Lewis Lung Metastasis Model (preventive strategies)	-	DC-sflk1-IFN-γ induced a CD8^+ cytotoxic T cell responses to flk1, leading to profound inhibition of tumor-cell-induced angiogenesis and metastasis.	Pan et al.^Citation94
	Dendritic cells pulsed with a soluble flk1 protein (DC-flk1)	Murine immune model Murine B16 Metastasis Model Lewis Lung Metastasis Model (preventive strategies)	-	DC-flk1 generated flk1-specific neutralizing antibody and CD8^+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. DC-flk1 suppressed tumor-induced angiogenesis and inhibited development of pulmonary metastases in DC-flk1–immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 prolonged the survival of mice challenged with Lewis lung tumors.	Li et al.^Citation93
	DC-VEC:Dendritic cell vaccine (loading VE-cadherin)	Murine 4T1 breast carcinoma and CT26 murine colon carcinoma model (preventive strategies and therapeutic immunization strategies)	-	DC-VEC vaccine exhibited CTLs against VE-cadherin and suppressed angiogenesis. DC-VEC vaccine decreased VEGF-A, TGF-β1 and the percentage of myeloid-derived suppressor cells and regulatory T cells, but increased IL-4, IFN-γ CD4^+ and CD8^+ T cells.	Zhou et al.^Citation101
	VEGF164-modified LL/2 lung cancer cell vaccine (LL/2-VEGF164)	Murine lung cancer model (protective strategies）	-	VEGF164-modified tumor vaccine induced humoral immune response and CTLs against the parental tumor cells. LL/2-VEGF164 vaccine modulated host antitumor immune response via increasing infiltration of CD68-positive monocytes/macrophage and hold therapeutic potential for cancer.	Kan et al.^Citation100
Viral Vector Vaccines	Mannan modified adenovirus encoding VEGFR2	Murine LL/2 (Lewis lung carcinoma), B16 (melanoma) and CT26 (colon carcinoma) modell (preventive strategies and therapeutic immunization strategies) Murine Lewis lung carcinoma metastasis model(preventive strategies)	-	Oxidized mannan-modified adenovirus expressing VEGFR-2 vaccination led to greater IFN-γ and VEGFR-2-specific CTLs to stimulate both protective and therapeutic immune response in a mice model, which resulted in the suppression of angiogenesis and an increase in CD8^+ cells in tumor tissues. The data suggest that the combination of cancer immunity and anti-angiogenesis via modified mannan is a promising strategy in tumor prophylaxis and therapy.	Zhang et al.^Citation97
Attenuated Bacteria Vaccines	Orally administered DNA vaccine encoding FLK1 (pcDNA3.1-FLK1ECD) carried by attenuated Salmonella typhimurium	Murine 3LL Lewis Lung Carcinoma model and pulmonary metastasis model (preventive strategies)	-	pcDNA3.1-FLK1ECD was effective at protective antitumor immunity in Lewis lung carcinoma models in mice by breaking immune tolerance to FLK1 self-antigen and inducing FLK1-specific humoral and cellular immune responses against endothelial cells and FLK1-positive target cells to inhibit tumor neovascularization. pcDNA3.1-FLK1ECD resulted in tumor suppression and prolonged survival and inhibited pulmonary metastases in mice.	Zuo et al.^Citation96
	Orally administered DNA vaccine encoding murine VEGFR-3 carried by attenuated S. typhimurium SL3261	Murine LL/2 (Lewis lung carcinoma) model (preventive strategies)	-	The oral VEGFR-3-based vaccine inhibited lung carcinoma growth and suppressed lymphangiogenesis via increasing the levels of T helper type 1(Th1) cell intracellular cytokine expression (IL-2, IFN-γ, and TNF-α) and VEGFR-3-specific antibody, increasing CD4^+ or CD8^+ T cell numbers.	Chen et al.^Citation102

IL-2: interleukin-2; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor-α; FLK1: fetal liver kinase 1; KDR: kinase insert domain receptor; IL-4: interleukin-4; VEGF-A: vascular endothelial growth factor A; TGF-β1: transforming growth factor beta-1; Tregs: regulatory T cells; MDSCs: myeloid-derived suppressor cells; DC: dendritic cell; VE-cadherin: vascular endothelial-cadherin; GM-CSF: granulocyte macrophage colony stimulating factor; MUC1: melanoma-associated antigen 3 and mucin 1; HPV: human papillomavirus; TEM8: tumor endothelial marker 8; MBD2: murine beta-defensin 2; MUC1: a T-cell epitope dominant peptide vaccine from Mucin.

Table 5. List of clinical trials of tumor vaccines based on anti-angiogenesis.

Vaccine types	regimen	Clinical trial identifier	Conditions	Adjuvant	Phases	Outcome	Ref.
Peptide Vaccines	7 peptides epitopes derived from FOXM1,MELK, HJURP,VEGFR1,VEGFR2,URLC10,HIG-2	UMIN 000003860 UMIN 000003862 UMIN 000003902 UMIN 000003903	Cervical cancer (CC)or ovarian cancer(OC) (n = 66)	Montanide ISA-51VG	II	The vaccination activated CTLs to attack and destroy the tumor cells without severe adverse events, which was safe and effective for disease control. Response rate in OC and CC were 22.9% and 20%, respectively. Further clinical study of peptide vaccines in combination with ICIs and/or an anti-VEGF antibody such as bevacizumab will be mandatory.	Takeuchi et al.^Citation121
	7 peptides epitopes derived from FOXM1,MELK, HJURP,VEGFR1,VEGFR2,RNF43,TOMM34,	UMIN000007801	Colorectal cancer (n = 30)	Montanide ISA-51VG	Ib	The 7-peptide vaccine used with leucovorin (UFT/LV) was safety Patients who exhibited positive CTLs to all seven peptides had longer overall survival. 3 patients showed PR,15 patients showed SD,12 patients showed PD.	Okuno et al.^Citation111
	6 peptides epitopes derived from FOXM1,LY6K, DEPDC1,KIF20A,VEGFR1, VEGFR2	-	High-grade gliomas (HGGs) (n = 10)	Montanide ISA-51VG	Pilot Study	The median overall survival time in all patients was 9.2 months. 2 patients demonstrated SD and 1 patient achieved CR. Six peptides vaccine was well tolerated without any severe systemic adverse events and induced robust glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA)-specific T-lymphocyte responses in recurrent/progressive HGG patients.	Kikuchi et al.^Citation114
	5peptides epitopes derived from RNF43,TOMM34,KOC1,VEGFR1, VEGFR2	UMIN000001791	Colorectal cancer (CRC) (n = 89)	Montanide ISA-51	II	Therapeutic epitope peptides vaccine increased VEGFR1 and 2-specific robust CTLs response, which did not correlate with OS. VEGFR2 IgG responses may be an important immunological biomarker in the early course of treatment for CRC patients.	Kanekiyo et al.^Citation120
	5peptides epitopes derived from RNF43,TOMM34,KOC1,VEGFR1, VEGFR2	UMIN000001791	Colorectal cancer (CRC) (n = 96)	Montanide ISA-51	II	Five therapeutic epitope peptides vaccine appeared to be effective in a subset of patients, and warranted a randomized phase III study. A delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination. RR and the median OS was 62.0%,60.9% and 20.7 months,24.0 months in the HLA-A *2402-matched and -unmatched groups, respectively.	Hazama et al.^Citation119
	5peptides epitopes derived from RNF43,TOMM34,KOC1,VEGFR1, VEGFR2	UMIN000004948	Colorectal cancer (n = 18)	Montanide ISA-51	I	The vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis.	Hazama et al.^Citation110
	5peptides epitopes derived from FOXM1,MELK, HJURP,VEGFR1,VEGFR2	UMIN000003999	Cervical cancer (n = 21)	Montanide ISA-51	I	Five peptides vaccination was safety and induced high T-cell responses to FOXM1 and MELK in patients with cervical cancer, but showed modest clinical efficacy. All vaccine-related adverse events were tolerable.	Hasegawa et al.^Citation112
	4peptides epitopes derived from RNF43,TOMM34,VEGFR1, VEGFR2	UMIN000004452	Colorectal cancer (n = 10)	Montanide ISA-51VG	I	Results showed that 1 patient had PR, 7 patients had SD and 2 patients had PD. The peptide vaccine therapy together with UFT+LV was safe and induced peptide-specific CTLs recognizing RNF43, TOMM34 and VEGFR2 in patients with PR and SD, thus further study is needed. Patients who had a strong CTL reaction had a tendency to have longer progression-free survival and overall survival.	Matsushita et al.^Citation107
	4peptides epitopes derived from URLC10,CDCA1/TTK,VEGFR1, VEGFR2	NCT00633724 NCT00874588	Non-small cell lung cancer (NSCLC) (n = 15)	Montanide ISA-51	I	Peptide vaccine was well tolerated with no severe treatment-associated adverse events and enhanced peptide-specific T cell responses against at least one peptide in 13 of the 15 patients.	Suzuki et al.^Citation109
	4peptides epitopes derived from KIF20A,CDCA1,VEGFR1, VEGFR2	UMIN000004337	Pancreatic cancer (n = 9)	Montanide ISA-51	I	The multi-peptide vaccine was well-tolerated without grade 3 or 4 adverse events, induced robust peptide-specific T-cell responses against KIF20A,CDCA1,VEGFR1,VEGFR2 and showed clinical benefits. Median PFS and OS were 90 and 207 d, respectively.	Okuyama et al.^Citation108
	3peptides epitopes derived from KIF20A,VEGFR1,VEGFR2 (OCV-C01)	UMIN000007991 UMIN000020366	Pancreatic ductal carcinoma (n = 30)	Montanide ISA-51VG	II	OCV-C01 combined with gemcitabine was tolerable and DFS of patients with positive KIF20A expression in resected pancreatic cancer specimen may potentially be prolonged with frequent KIF20A-specific CTL response by receiving this immunotherapy treatment. A randomized controlled trial was essential to demonstrate the clinical benefits of OCV-C01 for surgically resected pancreatic cancer patients	Miyazawa et al.^Citation117
	3peptides epitopes derived from KIF20A,VEGFR1,VEGFR2	UMIN000008082	Pancreatic cancer (n = 68)	Montanide ISA-51	II	The therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions. The patients with peptide-specific CTL induction against either KIF20A or VEGFR1 showed significantly better OS.	Suzuki et al.^Citation118
	2peptides epitopes derived from VEGFR1–1084, VEGFR2–169	UMIN000013381 UMIN000023565	High-grade glioma (WHO grade III or IV) (n = 4)	Montanide ISA-51VG	I and II	VEGFR1 and 2-specific CTLs attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. VEGFR1 and 2 peptide vaccination may possibly enhance the effects of temozolomide (TMZ).	Tamura et al.^Citation116
	2peptides epitopes derived from VEGFR1–1084, VEGFR2–169	UMIN000023565	Schwannomas (n = 7)	-	exploratory clinical study	VEGFR1 and 2-peptide vaccination was safety and induced VEGFR1 and VEGFR2-specific CTLs to directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and VEGFR2-expressing Tregs. Tumor volume reductions of ≥ 20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine.	Tamura et al.^Citation115
	2peptides epitopes derived from VEGFR1–1084, VEGFR2–169	-	Glioblastoma (n = 8)	Montanide ISA-51VG	Pilot Study	This treatment was well-tolerated, safety and induced positive CTLs responses against at least one of the targeted VEGFR epitopes targeting tumor vasculatures in high grade gliomas. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months.	Shibao et al.^Citation113
	2peptides epitopes derived from VEGFR1–1084, VEGFR2–169	UMIN000005007	Gastric adenocarcinoma (n = 22)	Montanide ISA-51VG	I and II	The combination therapy was well tolerated and highly effective in advanced or recurrent gastric cancer. Substantial specific CTL for both peptides was frequently induced even under chemotherapy. Cancer vaccination combined with standard chemotherapy warrants further analysis as a promising strategy for the treatment of advanced cancer.	Masuzawa et al.^Citation106
	VEGFR peptide vaccine	UMIN000013381 UMIN000012774 UMIN000005545	Glioma (n = 13)	-	Pilot Study	1 patient had a Grade 4 pulmonary embolism and 2 patients had Grade 2 cerebral infarctions in the group of bevacizumab (Bev)+ VEGFR peptide vaccine VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.	Tamura et al.^Citation122
	Elpamotide (VEGFR2)	UMIN000001664	Pancreatic cancer (n = 153)	Montanide ISA-51VG	II/III	Combination therapy of elpamotide with gemcitabine was well tolerated and failed to obtain overall survival benefits. Patients who experienced severe injection site reaction might have better survival.	Yamaue et al.^Citation105
	Elpamotide (VEGFR2–169)	UMIN000008336	Advanced refractory solid tumors (n = 10)	-	I	Elpamotide was well tolerated, biologically active and induced an immune response that targets angiogenesis in the clinical setting.	Okamoto et al.^Citation104
	VEGFR2–169	NCT00622622	Pancreatic cancer (n = 21)	Montanide ISA-51VG	I	VEGFR2–169 peptide vaccine in combination with gemcitabine was well tolerated and induced peptide-specific CTL. The proportion of Treg cells after the vaccination was significantly reduced. A randomized, controlled clinical trial will be essential to demonstrate the clinical benefits of the VEGFR2–169 peptide for advanced pancreatic cancer patients treated with gemcitabine.	Miyazawa et al.^Citation103
	Survivin	UMIN000012146	Pancreatic adenocarcinoma (n = 83)	Montanide ISA‐51 VG	II	No significant improvement in PFS was observed. Compared with placebo group, the SVN‐2B plus IFNβ group increased survivin 2B‐specific CTLs and showed better overall survival, significant immunological reaction after vaccination, but did not have improved PFS. A longer SVN‐2B plus IFN-β vaccination protocol might confer survival benefit.	Shima et al.^Citation127
	Survivin	UMIN000000905	Pancreatic cancer (n = 6)	IFA and IFNα	I	More than 50% of the patients had positive clinical and immunological responses. The vaccination protocol of survivin-2B80–88 plus IFA and IFNa was very effective and useful in immunotherapy for this type of poor-prognosis neoplasm.	Kameshima et al.^Citation126
	Survivin	—	Colon cancer (n = 13)	IFA and IFNα	-	The effect of survivin-2B80–88 plus IFA was not significantly different from that with survivin-2B80–88 alone, treatment with the vaccination protocol of survivin-2B80–88 plus IFA and IFNa resulted in clinical improvement and enhanced immunological responses of patients via increasing survivin-2B80–88 peptide-specific CTL The vaccination of colon cancer patients with survivin-2B80–88 plus IFA and IFNa could be considered to be a very potent immunotherapeutic regimen, and that this protocol might work for other cancers.	Kameshima et al.^Citation125
	Survivin	—	Breast cancer (n = 14)	Montanide ISA −51	I	The survivin-2B peptide vaccination was well tolerated. When it mixed with IFA, the frequency of peptide-specific CTL effectively increased, although neither vaccination could induce efficient clinical responses. The addition of another effectual adjuvant such as a cytokine, heat shock protein, etc. to the vaccination with survivin-2B peptide mixed with IFA might induce improved immunological and clinical responses.	Tsuruma et al.^Citation124
	Survivin	-	Colorectal cancer (n = 15)	-	I	No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19–9) decreased transiently during the period of vaccination. One patient revealed an increase in peptide-specific CTL frequency Survivin-2B peptide-based vaccination was safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer.	Tsuruma et al.^Citation123
Attenuated Bacteria Vaccines	VXM01 (Salmonella bacteria carrying an expression plasmid, encoding VEGFR-2)	NCT01486329	Pancreatic cancer (n = 45)	-	I	VXM01 elicited a productive, complex VEGFR2 specific T effector cell response in patients with pancreatic cancer that correlates with anti-angiogenic activity and had a favorable safety profile.	Schmitz-Winnenthal et al.^Citation129
	VXM01 (Salmonella typhi strain Ty21a encoding the human full-length VEGFR-2)	NCT01486329	Pancreatic cancer (n = 45)	-	I	The results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine V×M01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications.	Niethammer et al.^Citation128

FOXM1: forkhead box M1; MELK: maternal embryonic leucine zipper Kinase; HJURP: holliday junction recognition protein; URLC10: up regulating lung cancer 10 gene; HIG-2: hypoxia-inducible gene 2; VEGFR1/2: vascular epithelial growth factor receptor 1 and 2; HLA: human leukocyte antigen; IFA: incomplete Freund’s adjuvant; CTLs: cytotoxic T lymphocytes; ICIs: immune checkpoint inhibitors; VEGF: vascular epithelial growth factor; KOC1: kinase of the outer chloroplast membrane 1; TOMM34: translocase of outer mitochondrial membrane 34; RNF43: ring finger protein 43; OS: overall survival; DFS: disease-free survival; NLR: neutrophil/lymphocyte ratio; PR: partial response; SD: stable disease; PD: progressive disease; DCs: dendritic cells; HUVEC: human umbilical vein endothelial cell; PFS: progression-free survival; TTK: TTK protein kinase; CDCA1: cell division cycle associated gene 1; ORR: objective response rate; CR: complete response; PR: partial response; RR: response rates; LY6K: lymphocyte antigen 6 family member K; DEPDC1: DEP domain containing 1; KIF20A: CT antigens kinesin family member 20A; CDCA1: cell division cycle-associated 1; PFS: progression-free survival; Teff: T effector; Tregs: regulatory T cells.

Figure 4. Multidimensional tumor vaccine strategies versus single-dimensional therapy. Tumor growth inhibition is more potent when tumor vaccines mediate antitumor effects through two mechanisms, while maybe the inhibition is even the most potent when three mechanisms used. The three mechanisms of the multidimensional tumor vaccine strategies are mainly outlined here: (a) Tumor vaccines activate the immune system to kill tumor cells; (b)Tumor vaccines inhibit the tumor growth through overcoming the immunosuppression status; (c) Tumor vaccines activate the immune system to target the endothelial cells or TAMs, thus inhibit tumor angiogenesis.

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