Antibiotics and immunotherapy in gastrointestinal tumors: Friend or foe?

Table 1 Microbes that may cause gastrointestinal tumors

Tumor	Microbes involved
Esophageal cancer	H. pylori, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Fusobacteria phyla.
Gastric cancer	H. pylori, Porphyromonas, Neisseria, Prevotella pallens, Streptococcus sinensis, Lactobacillus coleohominis, Klebsiella pneumoniae, and Acinetobacter baumannii
Colorectal cancer	Faecalibacterium prausnitzii, Eubacterium rectale, Proteobacteria, Bacteroidetes, Fusobacterium
Hepatocellular carcinoma	H. pylori, Escherichia coli
Biliary tract cancer	Pseudomonadaceae, Oxalobacteraceae, Clonorchis sinensis, and Opisthorchis viverrini
Pancreatic cancer	H. pylori

H. pylori: Helicobacter pylori.

Table 2 Completed clinical trials of immune checkpoint inhibitors on gastrointestinal tumors

Trial	Phase	Treatment	ORR% (95%CI)	DCR% (95%CI)	Median PFS months (95%CI)	Median OS months (95%CI)	Adverse events
Esophageal and gastric cancers
	II	Nivolumab (n = 64)	11 (10-28)	27 (31-54)	1.5 (1.4-2.8)	11 (7.3-13)	G3/4 25%; All-grade 73%
ATTRACTION 02	II	Nivolumab (n = 330)	11 (8-16)	40 (34-46)	1.6 (1.5-2.3)	5.3 (4.6-6.4)	G3/4 27%; All-grade 43%
		Placebo (n = 163)	0(0-3.0)	25 (18-34)	1.5 (1.5-1.5)	4.1 (3.4-4.9)	G3/4 4%; All-grade 27%
CHECKMATE32	I/II	Nivolumab 3 (mg/kg)	12 (5-23)	NR	1.4 (1.2-1.5)	6.2 (3.4-12)	G3/4 17%
		Nivolumab 1 + Iplilimumab 3	24 (13-39)	NR	1.4 (1.2-3.8)	6.9 (3.7-12)	G3/4 47%
		Nivolumab 3 + Iplilimumab 1	8.0 (2.0-19)	NR	1.6 (1.4-2.6)	4.8 (3.0-8.4)	G3/4 27%
KEYNOTE59	II	Pembrolizumab (n = 259)	12 (8-16)	27(21.7-32.9)	2.0 (2.0-2.1)	5.5 (4.2-6.5)	G3/4 18%; All-grade 60%
JAVELIN Gastric 300	III	Avelumab (n = 185)	2.2 (0.6-5.4)	22 (16-29)	1.4 (1.5-2.0)	4.6 (3.6-5.7)	G3/4 9.2%
		Chemotherapy (n = 186)	4.3 (1.9-8.3)	44 (37-52)	2.7 (1.8-2.8)	5.0 (4.5-6.3)	G3/4 32%
KEYNOTE61 PDL CPS ≥ 1	III	Pembrolizumab (n = 196)	16 (11-22)	NR	1.5 (1.4-2.0)	9.1 (6.2-11)	G3/4 25%
		Paclitaxel (n = 199)	14 (9.0-19)	NR	4.1 (3.1-4.2)	8.3 (7.6-9.0)	G3/4 35%
Hepatocellular carcinoma
CHECKMATE40	I/II	Nivolumab (dose-escalation)	15 (6.0-28)	58 (43-72)	NR	15 (9.6-20)	G3/4 25%
		Nivolumab (dose-expansion)	20 (15-26)	64	5.4 (3.9-8.5)	NR	G3/4 63%
KEYNOTE224	II	Pembrolizumab (n = 169)	18 (11-26)	62 (52-71)	4.9 (3.4-7.2)	13 (10-16)	G3/4 25%; All-grade 73%
Biliary tract cancer
KEYNOTE28	I	Pembrolizumab (n = 24)	17 (5.0-39)	34	NR	NR	G3/4 17%; All-grade 63%
Pancreatic cancer
	II	Iplilimumab (n = 27)	0	0	NR	NR	NR
	I	Tremelimumab + gemicitabine (n = 34)	NR	NR	NR	7.4 (5.8-9.4)	All-grade 94%
	Ib/II	Pembrolizumab + gemcitabine + nab-paclitaxel (n = 17)	18	76	9.1 (4.9-15.3)	15 (6.8-23)	G3/4 71%; All-grade 100%
Colorectal cancer (dMMR)
	II	Pembrolizumab (n = 10)	40 (12-74)	90 (55-100)	NR	NR	G3/4 41%; All-grade 98%
KHECKMATE 142	II	Nivolumab (n = 74)	31 (21-43)	69 (57-79)	NR	NR	G3/4 20%; All-grade 70%

DCR: Disease control rate; ORR: Objective response rate; OS: Overall survival; PFS: Progression free survival; G: Grade; NR: Not reported; dMMR: Mismatch repair deficiency.

Table 3 Studies about antibiotics and immunotherapy

	Research subjects	Tumor type	Patients No.	Research conclusion	Ref.
1	Patients	NSCLC/RCC/urothelial carcinoma	249	ATB use presents a predictor of resistance to ICI	Routy et al[44], 2018
	Mice	Sarcoma/melanoma
2	Patients	NSCLC	74	ATB use does not affect the efficacy of nivolumab	Kaderbhai et al[43], 2017
3	Patients	RCC/NSCLC	360	ATB use reduces clinical benefit from ICI	Derosa et al[45], 2018
4	Mice	Lymphoma/colon cancer/melanoma		ATB treated mice respond poorly to CpG-oligonucleotide	Lida et al[42], 2013
5	Mice			ATB mice are resistant to cyclophosphamide	Viaud et al[41], 2013

ATB: Antibiotics; ICI: Immune checkpoint inhibitor.