Table 2.

Summary of in vivo APC targeting studies in the framework of antitumor vaccination.

Targeting moiety	Injection	Content	Effect	References
CLR
DEC205  α-GalCer NP	fp	OVA	↑iNKT, ↓growth in B16F10, and EG7-OVA (P + T)	[147]
Selected nucleic acid aptamer	i.v.	OVA	↑CD8, ↓growth OVA-B16 tumor (T if OT-I transfer)	[95]
Anti-CD11c and DEC205 scFv coupled to NP	i.v.	OVA + ADJ	↑CD8, ↓growth OVA-B16 tumor (P)	[83]
mAb fused protein	s.c.	OVA + ADJ	↑CD8, ↓growth OVA-B16 (P + T)	[131]
mAb fused protein	i.p.	HER2 + ADJ	↑CD8, ↑CD4, ↑humoral, and ↓growth neu-expressing mammary tumor (P)	[148, 149]
mAb fused protein	i.p.	Mesothelin + ADJ	↑cross-presentation, ↑CD4, ↑humoral, and ↓growth neu-expressing mammary tumor (P)	[150]
scFV modified adenoviral vector	fp	OVA	↑T cell, ↑humoral (at low doses), ↓growth OVA-B16 (P) BUT better for untargeted vectors	[127]
mAb fused protein	fp	OVA + ADJ	↑CD8, ↓growth B16 pseudo-metastasis model (P + T)	[120]
Bacteriophage displaying scFV	fp	OVA	↓growth B16F10 (Pro + Ther)	[151]
mAb fused protein	s.c.	Trp2 and gp100 + ADJ	↑CD8, ↑CD4, and ↓growth B16 melanoma (P + T)	[152]
scFV fused to DNA vaccine	i.m.	Her2/neu + CPM	↑CD8, ↑humoral, long lasting memory ↓growth HER2/neu + D2F2/E2 breast tumor + spontaneous mammary carcinomas (P + T)	[153]
Phase I clinical trial with CDX-1401 = human mAb fused protein	i.d.	NY-ESO-1 + ADJ	Patients with advanced malignancies: ↑cellular, ↑humoral (T)	[154]
DEC206  Mannosylated NP	s.c.	OVA + ADJ	↑TH1 cell, ↑humoral, and ↓growth B16F10 (P + T)	[155]
mAb fused to protein	s.c.	OVA + ADJ	↑T cell, ↑humoral, and ↓growth B11-OVA (P)	[156]
Mannan coupled protein	i.p.	MUC-1	↑CD8, ↓growth P815 mastocytoma (T)	[157]
Mannose coupled dendrimer	i.d.	OVA	↑CD8, ↑CD4, ↑humoral, ↓growth B16-OVA (P)	[158]
Mannosylated NP	s.c.	ErbB2/HER3 + ADJ	↓growth huErbB2+ renal carcinoma cells (T)	[125]
Mannan coated liposome-protamine-DNA	U	HPV16 E7	↓growth E7+ TC-1 (P + T)	[159]
Mannosylated and/or histidylated NP loaded with mRNA	i.v.	MART-1	↑CD8, ↓growth B16F10 (P)	[160, 161]
Mannan or pullulan NP complexed with protein	U	HER2	↑CD8, ↓growth HER2+ tumors (P + T)	[162]
D-mannose conjugated lipid-core peptide system	s.c.	HPV16 E7	↓growth TC-1 HPV-16 tumor (P)	[163]
Clinical trial with mannan coupled protein	s.c.	MUC-1	↑humoral, less ↑CD8, protection against recurrence in breast cancer patients	[106]
Two phase I studies with CDX-1307 = hCG-β fused to mAb	i.d. or i.v.	hCG-β + ADJ	↑humoral and T cell with clinical benefit in patients with advanced epithelial malignancies	[164]
DC-SIGN  LV pseudotyped with point-mutated Sindbis virus glycoprotein	i.d.	OVA or PSCA	↑CD8, ↑CD4, and ↓growth transgenic adenocarcinoma, E.G7-OVA and PSCA-expressing B16-F10 (P + T)	[5, 103, 165]
mAb coupled protein	U	KLH	↓growth human Burkitt's lymphoma cell line in humanized mice (P)	[166]
IDLV pseudotyped with engineered Sindbis virus glycoprotein + currently tested in Phase I clinical trial ID-VP02	s.c.	NY-ESO + Vpx	↑CD8, ↓growth CT26 colon carcinoma cells (P + T)	[167, 168]
LOX-1  HSP70 fused to protein	s.c.	OVA	↑CD8 and cross-priming, ↓growth E.G7 cells (P)	[169]
CLEC9A  mAb coupled to peptide	s.c.	MUC-1 + ADJ	↑TH1, ↓growth MUC-1-A2K/b+ MC38 (P + T)	[170]
mAb coupled to peptide	s.c.	OVA + ADJ	↑CD8, ↓growth B16 lung pseudo metastases (P + T)	[138]
DCIR2  Anti-DCIR2 or anti-DEC205 mAb coupled protein	i.p.	OVA + ADJ	↑CD8, ↑CD4 (mixed TH1/TH2), ↑humoral, and ↓growth B16F10-OVA (P + T)	[171]
Integrin
CD11c  Targeted lipopeptide	i.d.	OVA, WT1, tumor lysate + ADJ	↓growth for OVA: E.G7-OVA, for mWT1: mWT1–1498 cells and for tumor lysate: MHC-I− B16D8 melanoma (T)	[172]
Tumor-derived plasma membrane vesicles engrafted with two CD11c binding peptides	i.v.	OVA	↑CD8, ↑humoral, and ↓growth of metastatic B16-OVA (T)	[173]
CD11b  Adenylate cyclase- (CyaA-) based vector	i.p. vs. i.v. or i.d.	OVA vs. HPV E7	↓growth OVA-B16 or E.G7-OVA versus TC-1 (P + T)	[113, 174]
Phase II study with ProCervix = CyaA-based vector	s.c.	HPV16 and 18 E7 + ADJ	Clinical phase I trial indicated good safety and local tolerance at the highest dose, ↑T + ↑viral clearance + controlled HPV recurrence	NCT01957878
Fcγ receptor
IgG1-Fc tumor cells	s.c.	TAAs	↓growth E.G7 (P + T)	[175]
HER2-Fc cDNA	i.m. + EP	HER2	Mu: ↑T, ↓growth HER2+ D2F2/E2 cells (P)  Hu: in vitro cross-processing and ↑CD8 + T cells from breast cancer patients	[176]
MHC-II molecule
DNA loaded dendrimer with targeting peptide	s.c.	Trp2 or gp70 vs. OVA	↑CD8, ↑humoral, ↓growth, strong for B16OVA, and weak for gp70 BUT better with EP (P) ↔ B16 with Trp2 (T)	[177]
LV pseudotyped with scFv coupled to H protein of measles virus envelope	i.v.	OVA or male HY gene	↑CD4, ↑cytotoxic, and memory CD8 BUT not to the same extent as broad tropism LVs	[112, 178]
LV pseudotyped with scFV coupled to murine leukemia virus envelope	s.c.	OVA	↑CD8 mediated IFNγ secretion	[179]
DNA encoding anti-MHC II and anti-CD40 scFv or chemokines (MIP-1α, RANTES) with scFV of idiotype	i.m. or i.d. + EP	Idiotypes	↑CD8, ↑humoral, and ↓growth Id+ tumors (P)	[180, 181]
Non-CLR surface marker
BST2  Protein fused anti-BST2 Ab	i.p.	OVA or pHEL + ADJ	↑CD4, ↑CD8, ↑humoral + ↓growth B16-OVA (P)	[182]
Undefined
NP with cholesteryl pullulan towards medullary macrophages	s.c.	MAGE-A4 or mERK2 + ADJ	↑cross-presentation, ↓growth MAGE-A4+ CMS5+ CT26, and mERK2+ sarcoma cell line (P + T)	[183]
Listeria monocytogenes expressing TAAs	i.p.	VEGFR2 + ADJ	↑CD8 with epitope spreading, ↓growth breast tumors (P + T)	[114, 184]
Coronavirus vector	i.v.	MelanA or Gp33 + ADJ	↑CD8, expanded epitope repertoire, growth MelanA+ or gp33+ B16F10 (P + T)	[185, 186]
APC specific nanobody displaying LV	i.n.	OVA	↑CD4, ↑CD8, ↓growth (T) BUT not to the same extent as broad tropism LVs	[45]
ISCOM vaccine	s.c.	OVA	↑CD8, ↓growth EG-7-, B16-, or Panc-OVA (P)	[187]
Costimulatory molecule
CD40  PLGA-NP coated with mAb	s.c.	OVA and E7 + ADJ	↑CD8, ↑CD4 + ↓growth B16-OVA (P + T)	[188]
CD40 targeted adenoviral vector	i.p.	PSMA + ADJ	↑CD8, ↓growth RM-1-PSMA model (T)	[189]
CD40L extracellular domain to adenoviral vector in mice +  Clinical trial	i.d.	Mice: Trp2 or gp100  Human: MART-1	Mice: ↑CD8, ↓growth B16F10 (T)  ↑CD8 in melanoma-draining sentinel lymph nodes	[190, 191]
B7  Syngeneic epithelial cells continuously secreting CTLA-4-ErbB2 fusion vaccine	s.c.	HuErbB2 + IL-15	↑CD8, ↑humoral, ↓growth ErbB2+ renal cell carcinoma (T)	[192]
Treml4, Ig superfamily member  mAb against Treml4	i.p.	OVA or HER2 + ADJ	↑CD8, ↑CD4, ↓growth neu+ mammary tumor cell line NT2.5 (P)	[193]
TLRs  TLR9 targeting protein (via DNA sequence)	i.d.	OVA + CpG	TH - independent ↑CD8 + ↓growth E.G7-OVA (P + T)	[194]
TLR2 targeting lipid moiety + epitopes	s.c.	OVA	↑CD8, ↑humoral + ↓growth B16-OVA, and Lewis lung-OVA (P + T)	[195]
TLR5 targeted peptides (via flagellin) engrafted onto liposomes	i.v.	OVA	↑maturation of DCs, ↑CD8, ↑humoral, ↓growth B16, and P815 (P + T)	[173, 196]
TLR4 targeting protein (via fibronectin)	i.t. or i.v.	HPV E7 w or w/o ADJ or CPM	↑CD8 with cure of established TC-1 tumors i.t.: in the absence of additional ADJ i.v.: when + ADJ or CPM + ADJ	[197]
TLR4 targeting protein (via fibronectin) + anti-CD40, TLR3 and TLR7 ligands	s.c.	OVA + ADJ	↑CD8, ↓growth B16-OVA or B16.F10 (T)	[198]
Chemokine related  Fusion of chemokine MCP3 or IP10 to lymphoma-derived scFv as protein or DNA plasmid	s.c. or i.d.	scFV	↑humoral, ↓growth 38C-13 and A20 (P)	[199]
OVA with mAb or chemokine ligand XCL1 against XCR1	i.v.	OVA + ADJ	↑CD8, ↓growth E.G7 (P)	[200]

P: prophylactic, T: therapeutic, fp: footpad, i.v.: intravenous, s.c.: subcutaneous, i.p.: intraperitoneal, i.m.: intramuscular, EP: electroporated, i.d.: intradermal, i.n.: intranodal, i.t.: intratumoral, U: unknown, ADJ: adjuvant, CPM: cyclophosphamide iNKT: induced natural killer T cell, and in bold: all studies with human APCs.