Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens

Table 1 Clinical vaccination trials focused on colorectal cancer patients

Target type	Target molecule	Vaccination strategy	Therapy	No. of CRC Patients	Clinical response	Ref.
TAA	CEA	Altered peptide loaded on DC		10/12	2 CR, 2 SD, 1 MR, 7 PD	[8]
TAA	CEA	CEA peptides pulsed DC		10	2 SD, 8 PD	[9]
TAA	CEA	CEA peptides pulsed DC		10	7 had CTL increase	[10]
TAA	MAGE	MAGE-A-pulsed DC		21	21 PD	[15]
TAA	MAGE	synthesized helper/killer-hybrid epitope long peptide (H/K-HELP) of MAGE-A4		1	SD	[14]
TAA	MUC1	MUC1-mannan fusion protein	Chemo- therapy	18	2 SD, 16 PD	[17]
TAA	MUC1	100-amino acid synthetic MUC1 peptide with Poly-ICLC		39	20 responders (IgG), 19 non-responders	[18]
TAA	MUC1	irradiated allogeneic colorectal carcinoma cell lines with GM-CSF-producing bystander cell line (K562)		9	4 CR, 5 PD	[19]
TAA	Survivin	survivin-2B peptide		15	1 MR, 3 SD, 11 PD	[21]
TAA	WT1	HLA-A or HLA-DR restricted peptides on DCs	Chemo- therapy	3	3 SD	[22]
TAA	RNF43, TOMM34	peptides,with Montanide ISA 51	Chemo- therapy	21	16 SD	[29]
TAA	RNF43, TOMM34	HLA-A*2402-restricted peptides	Chemo- therapy	22	13 CTL induction	[31]
TAA	RNF43, TOMM34	Peptides with Montanide ISA 51		24	6 SD, 18 PD	[30]
TAA + VEGFR	RNF43, TOMM34, FOXM1, MELK, HJURP, VEGFR-1, VEGFR-2	HLA-A2402- restricted peptides with Montanide ISA 51	Chemo- therapy	30	3 PR, 15 SD, 12 PD	[32]
TAA + VEGFR	RNF43, TOMM34, KOC1, VEGFR-1, VEGFR-2	HLA-A*2402-restricted peptides with Montanide ISA 51		19	1 CR, 6 SD, 12 PD	[33]
PPV TAA	cypB, Ick, SART 1-3, ART4	2-4 HLA-A24-restricted Peptides matching to patient’s pre-vaccination immune response with Montanide ISA 51		10	1 PR, 1 SD, 8 PD	[34]
PPV TAA	SART3, Lck, WHS, HNR, MRP3, PAP, EZH2, CEA, PSCA, UBE, Her2/neu, PSA, CypB	2-4 HLA-A24- or HLA-A2 restricted Peptides matching to patient’s pre-vaccination immune response with Montanide ISA 51	Chemo- therapy	7	1 SD, 6 PD	[35]
PPV TAA	SART2-3, Lck, MRP3, EIF4EBP, WHSC2, CypB, CEA, UBE, Her2/neu,	2-4 HLA-A24- or HLA-A2 restricted Peptides matching to patient’s pre-vaccination immune response with Montanide ISA 51	Chemo- therapy	14	3 MR, 3 SD, 8 PD	[36]
Neoantigen	AIM2(-1), HT001(-1), TAF1B(-1)	Frameshift peptides with Montanide ISA 51		22	16 immune response (CTL/IgG induction)	[52]
Neoantigen	KRAS	13-mer ras peptide with Detox adjuvant		10	1 SD, 2 cytotoxic activity	[62]
Neoantigen	KRAS	13-mer ras peptide with Detox adjuvant		7	4 remained with no evidence of disease	[64]
Neoantigen	KRAS	13-mer ras peptide with Il-2 or GM-CSF or both		38	4 SD, 34 PD	[66]

CRC: Colorectal cancer; CR: Complete response; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; GM-CSF: Granulocyte macrophage colony-stimulating factor; HLA: Human leukocyte antigen; MR: Minor response; PD: Progressive disease; PR: Partial response; SD: Stable disease; CEA: Carcinoembryonic antigen; TAA: Tumor-associated antigen.

Table 2 Current clinical vaccination studies including colorectal cancer patients

Target type	Target molecule	Vaccination strategy	Therapy	Number of patients	Trial identifier
TAA	CEA	alphavirus replicon (VRP) encoding CEA		12	NCT01890213
TAA	CEA	ETBX-011 ad-CEA, ALT-803 (IL-15)		3	NCT03127098
TAA	CEA	anti-CEA CAR-T cells		18	NCT03682744
TAA	CEA	anti-CEA CAR-T cells		5	NCT02850536
TAA	CEA	anti-CEA CAR-T cells, SIR-Sphere		8	NCT02416466
TAA	Her2	2 Her2 peptides in Montanide ISA 720		36	NCT01376505
TAA	Her2/neu	B-Cell and monocytes with HER2/neu antigen		9	NCT03425773
TAA	Brachyury, CEA, MUC1	ETBX-051; adenoviral brachyury vaccine, ETBX-061; adenoviral MUC1 vaccine, ETBX-011; adenoviral CEA vaccine		32	NCT03384316
TAA	7 cancer testis antigens	6 synthetic peptides in Montanide	Standard-of care maintenance	15	NCT03391232
Immune stimulation, TAA	MUC1	activated CIK and CD3-MUC1 bispecific antibody	cryotherapy	90	NCT03524274
TAA	HPV	DPX-E7		44	NCT02865135
TAA	hTERT	INO-1400 or INO-1401 alone or in combination with INO-9012		93	NCT02960594
TAA	MUC1	anti-MUC1 CAR-pNK cells		10	NCT02839954
TAA	MUC1	MUC1 peptide-poly-ICLC		110	NCT02134925
TAA	EpCAM	CAR T Cells targeting EpCAM		60	NCT03013712
Immune checkpoint, TAA	PD-1, p53	Pembrolizumab, modified vaccinia virus Ankara vaccine expressing p53		19	NCT02432963
Neoantigen		frameshift-derived neoantigen-loaded DC		25	NCT01885702
Neoantigen		personalized neoepitope yeast-based vaccine, YE-NEO-001		16	NCT03552718
Neoantigen		mRNA-based vaccine targeting neoantigens		64	NCT03480152
Neoantigen		ADXS-NEO (Advaxis NEO expressing personalized tumor antigens)		48	NCT03265080
Neoantigen	ras	anti-KRAS G12 V mTCR	Cyclophosphamide, Fludarabine, Aldesleukin	110	NCT03190941
Immune checkpoint	PD-L1	Avelumab, autologous dendritic cells		33	NCT03152565
Immune checkpoint	PD-1	Pembrolizumab, GVAX (allogeneic colon cancer GM-CSF secreting cells)	Cyclophosphamide	17	NCT02981524
Immune checkpoint	PD-L1	Atezolizumab, Imprime PGG (PAMP recognized by innate immune effector cells)	Regorafenib/ Isatuximab/ Bevacizumab	120	NCT03555149
Immune checkpoint	A2aR, A2bR	AB928 (A2aR and A2bR antagonist)	FOLFOX	98	NCT03720678
Immune checkpoint, TAA	PD-1, CEA, MUC-1	Nivolumab, MVA-BN-CV301 (modified vaccinia Ankara-Bavarian Nordic encoding CEA, MUC1, B7-1, ICAM-1 and LFA-3)	FOLFOX	78	NCT03547999
Immune checkpoint, TAA	PD-L1	Atezolizumab, RO7198457 (mRNA-based individualized, TAAs vaccine)		567	NCT03289962
Immune checkpoint, TAA	PD-L1, CEA	Avelumab + Ad-CEA	FOLFOX, Bevacizumab, Capecitabine	81	NCT03050814
Immune checkpoint, TAA, Immune stimulation	CEA, Her2/neu, Brachyury, MUC1, RAS, NK cells ICI	Aldoxorubicin, ETBX-011, ETBX-021, ETBX-051, ETBX-061, GI-4000, GI-6207, GI-6301, haNK, avelumab, HCI, ALT-803	Capecitabine, Cetuximab, Cyclophosphamide, Fluorouracil, Leucovorin, Nab-paclitaxel, Oxaliplatin, Regorafenib, SBRT, Trastuzumab	332	NCT03563157
Immune checkpoint, Mutated proteins	PD-1	Personalized peptides, Pembrolizumab		60	NCT02600949
Immune stimulation		GVAX (allogeneic colon cancer GM-CSF secreting cells)	Cyclophosphamide, SGI-110 (DNA Methyltransferase Inhibitor)	18	NCT01966289
Immune stimulation		GVAX (allogeneic colon cancer GM-CSF secreting cells)		15	NCT01952730
Immune stimulation		OncoVAX (non-dividing tumor cells)	Surgery	550	NCT02448173
Immune stimulation		Autologous or allogeneic immune stimulatory tumor cells		50	NCT00722228
Immune stimulation		autologous dendritic cells loaded with autologous tumour homogenate + IL-2		19	NCT02919644
Immune stimulation		autologous dendritic cells loaded with tumor antigens		58	NCT01348256
Immune stimulation		autologous dendritic cells loaded with tumor lysate antigens		30	NCT03214939
Oncolytic virus		GL-ONC1 oncolytic vaccinia virus, which disrupts nonessential genes and expression of the foreign gene expression		36	NCT02714374
Oncolytic virus, Immune checkpoint	PD-L1	Talimogene Laherparepvec, Atezolizumab		36	NCT03256344

CEA: Carcinoembryonic antigen; GM-CSF: Granulocyte macrophage colony-stimulating factor; TAA: Tumor-associated antigen.