Immunotherapeutic approaches in biliary tract carcinoma: Current status and emerging strategies

Table 1 Cellular mediators of innate and adaptive immune system in biliary tract carcinoma

Cell type	Frequency of infiltration	Clinical significance	Ref.
Natural killer cells	19.1%-33% overall	No correlation with disease stage, grade, or survival	[12,13]
	20% of ICC, 21% of ECC, 16% of GBC
Mast cells	2% of ICC, 2.5% of ECC, 8.5% of GBC	No correlation with survival	[13]
Macrophages	87% of ICC, 70% of ECC, and 71% of GBC	Associated with more advanced disease	[13]
Dendritic cells	Not determined	Associated with improved survival	[12,14]
CD4+ helper T-lymphocytes	43% of ICC, 30% of ECC, and 34%-51% of GBC	Associated with reduced probability of metastases and improved survival in ECC	[12,13]
CD8+ cytotoxic T-lymphocytes	46% of ICC, 49%-55% of ECC, and 38%-51% of GBC	Associated with reduced probability of metastases and improved survival in ECC	[12,13,15]
B-lymphocytes /plasma cells	4.5% of ICC, 6.7% of ECC, and 10.1% of GBC	Associated with improved survival	[13]

ECC: Extrahepatic cholangiocarcinoma; GBC: Gallbladder carcinoma; ICC: Intrahepatic cholangiocarcinoma.

Table 2 Trials of immunotherapy in biliary tract carcinoma

Immunotherapy	Treatment regimens	Phase	n	Types of BTC	OS (mo)	PFS (mo)	Ref.
Peptide-based vaccine (WT1)	Peptide vaccine + gemcitabine	I	25	Pancreatic, GBC, ICC, ECC	9.3	--	[44]
Peptide-based vaccine (WT1)	Peptide vaccine monotherapy	I	9	Pancreatic, CC	--	--	[45]
Peptide-based vaccine (NUF2, CDH3, KIF20A)	Peptide vaccine triple therapy	I	9	GBC, ICC, ECC	9.7	3.4	[46]
Peptide-based vaccine (LY6K, TTK, IGF2BP3, DEPDC1)	Peptide vaccine quadruple therapy	I	9	GBC, ICC, ECC	12.3	5	[47]
Peptide-based vaccine (Many)	Personalized peptide vaccination	II	25	GBC, ICC, ECC	6.7	--	[48]
	+/- chemotherapy
Dendritic cell-based vaccine (MUC1)	Dendritic cell vaccination	I/II	12	Pancreatic, CC	26	--	[49]
	+/- chemotherapy +/- radiotherapy
Dendritic cell-based vaccine (WT1, MUC1)	Peptide vaccine	--	65	GBC, ICC, ECC	--	--	[50]
	+/- chemotherapy
Dendritic cell-based vaccine, adoptive immunotherapy	Surgery + dendritic cell vaccine + T-cell transfer vs surgery alone	--	36	ICC	31.9	18.3	[51]
Interleukin-2	Induction cisplatin + gemcitabine, consolidation capecitabine + radiation, and maintenance IL-2 + 13-cis-retinoic acid	II	54	Pancreatic, GBC, CC	> 27.5	16.2	[52]

CC: Cholangiocarcinoma; OS: Overall survival; PFS: Progression-free survival; WT1: Wilm’s tumor 1; NUF2: Cell division cycle associated protein 1; CDH3: Cadherin 3; DEPDC1: DEP domain containing 1; ECC: Extrahepatic cholangiocarcinoma; GBC: Gallbladder cancer; ICC: Intrahepatic cholangiocarcinoma; IGF2BP3: Insulin-like growth factor-II mRNA binding protein 3; KIF20A: Kinesin family member 20A; LY6K: Lymphocyte antigen 6 complex locus K; MUC1: Mucin 1.

Table 3 Ongoing clinical trials of immunotherapy in biliary tract carcinoma

Agent	Treatment regimen	Phase	Estimated date of completion	Sponsoring Institution	Identification number
Cytokine induced killer cells	Cytokine induced killer cell monotherapy	I/II	May, 2016	Siriraj Hospital	NCT01868490
Tumor infiltrating lymphocytes	Tumor infiltrating lymphocytes + IL-2 + cyclophosphamide + fludarabine	II	December, 2019	National Cancer Institute	NCT01174121
Poly-ICLC	Cyclophosphamide + radiation therapy + TACE + poly-ICLC	I/II	July, 2014	Rutgers, the State University of New Jersey	NCT00553683

IL-2: Interleukin-2; Poly-ICLC: Polyinosinic-polycytidylic acid polylysine carboxymethylcellulose; TACE: Transcatheter arterial chemoembolization.