Biomarkers and risk factors for the early prediction of immune-related adverse events: a review

Figures & data

Table 1. Organ-specific biomarker of irAEs

irAEs	Biomarker	Author	Year	Type of study	Cancer type	Patient number	Treatment	Relationship with irAEs
Skin toxicity	HLA-DRB1*11:01 HLA-DRB1*01:01	Hasan et al.^Citation24	2018	Prospective Study	NSCLC MM	102	Anti-PD-1/L1 Anti-CTLA-4	Risk factor Protective factor
	BP180	Hasan et al.^Citation25	2019	Prospective Study	NSCLC	40	Anti-PD-1/L1	Increase is a risk factor
GI toxicity	WBC LYM	Fujisawa et al.^Citation26	2017	Retrospective Study	MM	101	Anti-PD-1	Increase is a risk factor Decrease is a risk factor
	CD177,CEACAM1	Shahabi et al.^Citation27	2013	Prospective Study	MM	162	Anti-CTLA-4	Increase is a risk factor
	HLA-DQB1*03:01	Hasan et al.^Citation24	2018	Prospective Study	NSCLC MM	102	Anti-PD-1/L1 Anti-CTLA-4	Risk factors for colitis
Cardiotoxicity	cTnT	Mahmood et al.^Citation22	2018	Retrospective Study	NA	140	Anti-PD-1/L1 Anti-CTLA-4	≥1.5.ng/ml is a risk factor
Pulmonary toxicity	WBC LYM	Fujisawa et al.^Citation26	2017	Retrospective Study	MM	101	Anti-PD-1	Increase is a risk factor Decrease is a risk factor
	PD-L1 EOS MONO ALB CRP	Isono et al.^Citation28	2020	Retrospective Study	NSCLC	180	Anti-PD-1	High expression is a risk factor Increase is a risk factor Decrease is a risk factor
Thyroid toxicity	Tg, TPO-Ab PLT IL-1β,IL-2,GM-CSF IL-8,G-CSF,MCP-1	Kurimoto et al.^Citation29	2020	Retrospective Study	NA	78	Anti-PD-1 Anti-CTLA-4	Increase is a risk factor Decrease is a risk factor High baseline is a risk factor Decrease is a risk factor
Pituitary Toxicity	HLA-DR15 B52 Cw12	Yano et al.^Citation30	2020	Retrospective Study	NSCLC MM GC	11	Anti-PD-1	Risk factor Risk factor Risk factor
T1D	HLA- DR4 Islet autoantibodies	Stamatouli et al.^Citation31	2018	Retrospective Study	NA	27	Anti-PD-1/L1 Anti-CTLA-4	Risk factor Risk factor
Inflammatory arthritis	HLA B*52: 01 HLA C*12: 02 SE alleles	Cappelli et al.^Citation32	2018	Prospective Study	VC	27	Anti-PD-1/L1 Anti-CTLA-4	Risk factor Risk factor Risk factor

NA: Not available, GC: Gastric carcinoma, VC: Various cancers.

Figure 1. Comparison of the incidence of irAEs between PD-1/L1 inhibitors and CTLA-4 inhibitors in three categories.

Figure 2. The incidence of each organ and organ-specific biomarkers of irAEs.

Table 2. Nonorgan-specific biomarkers of irAEs

Biomarker	Author	Year	Type of study	Cancer type	Patient number	Treatment	Relationship with irAEs
WBC LYM	Isono et al.^Citation28	2020	Retrospective Study	NSCLC	180	Anti-PD-1	Can predict irAEs Can predict irAEs
NLR, PLR	Pavan et al.^Citation51	2019	Retrospective Study	NSCLC	184	Anti-PD-1/L1	NLR<3 and PLR<180 are risk factors
	Khoja et al.^Citation52	2016	Retrospective Study	MM	183	Anti-CTLA-4	No correlation
CRP	Abolhassani et al.^Citation53	2019	Retrospective Study	MM	37	Anti-PD-1 Anti-CTLA-4	Increase is a risk factor
sCD163 CXCL5	Fujimura et al.^Citation54	2018	Retrospective Study	MM	46	Anti-PD-1	Increase is a risk factor Increase is a risk factor
Circulating B cells CD21^lo B cells	Das et al.^Citation55	2017	Prospective Study	MM	39	Anti-PD-1 Anti-CTLA-4	Decrease is a risk factor A twofold increase is a risk factor
Plasmablasts							A twofold increase is a risk factor
IFN-γ	Hirashima et al.^Citation56	2019	Prospective Study	NSCLC	29	Anti-PD-1	On day 22 ± 7 or 43 ± 7 IFN-γ levels <10 IU/ml is a risk factor
CXCL9 CXCL10 CXCL11 CXCL13	Khan et al.^Citation57	2019	Prospective Study	NA	78	Anti-PD-1/L1 Anti-CTLA-4	Increase is a risk factor Increase is a risk factor Increase is a risk factor Increase is a risk factor
LCP1, ADPGK	Jing et al.^Citation58	2020	Retrospective Study	NA	78	Anti-PD-1 Anti-CTLA-4	Positive is a risk factor
PD-L1	Sugisaka et al.^Citation59	2020	Retrospective Study	NSCLC	44	Anti-PD-1	≥50% is a risk factor

Table 3. Population characteristic risk factors for irAEs

Characteristic	Author	Year	Type of study	Cancer type	Patient number	Treatment	Relationship with irAEs
Gender	Takada et al.^Citation63	2020	Retrospective Study	NA	1009	Anti-PD-1 Anti-CTLA-4	Women are a risk factor
	Duma et al.^Citation64	2019	Retrospective Study	MM NSCLC	476	Anti-PD-1	Women are a risk factor
	Kartolo et al.^Citation65	2018	Retrospective Study	MM NSCLC RCC	78	Anti-PD-1 Anti-CTLA-4	Women are a protective factor, men are a risk factor for skin toxicity, GI and endocrine toxicity are not related to gender
Age	Isono et al.^Citation28	2020	Retrospective Study	NSCLC	180	Anti-PD-1	Risk factor
	Kartolo et al.^Citation65	2018	Retrospective Study	MM NSCLC RCC	78	Anti-PD-1 Anti-CTLA-4	No correlation
	Nosaki et al.^Citation66	2019	Retrospective Study	NSCLC	2612	Anti-PD-1	No difference between <75 years old and ≥75 years old
	Marur et al.^Citation67	2018	Retrospective Study	NSCLC	1659	Anti-PD-1/L1	<65 years old are more likely to develop irAEs than ≥75 years old
Smoking	Okada et al.^Citation68	2020	Retrospective Study	Lung cancer	102	Anti-PD-1/L1	≥50 pack-year is the risk factor for ILD irAEs
	Kartolo et al.^Citation65	2018	Retrospective Study	MM NSCLC RCC	78	Anti-PD-1 Anti-CTLA-4	No correlation
Past history	Isono et al.^Citation28	2020	Retrospective Study	NSCLC	180	Anti-PD-1	Idiopathic interstitial pneumonias is the risk factor for ILD irAEs
	Nakanishi et al.^Citation69	2019	Retrospective Study	NSCLC	83	Anti-PD-1	Interstitial lung abnormalities is the risk factor for ILD irAEs
	Kanai et al.^Citation70	2018	Retrospective Study	NSCLC	216	Anti-PD-1	Interstitial lung disease is the risk factor for ILD irAEs
	Cui et al.^Citation71	2018	Retrospective Study	NA	165	Anti-PD-1	pneumothorax, pleural effusion, and pneumonitis, thoracic radiotherapy, combination therapy is the risk factor for ILD irAEs
Body parameters	Okada et al.^Citation68	2020	Retrospective Study	Lung cancer	102	Anti-PD-1/L1	ECOG PS≥2 is a risk factor for grade 3 or higher ILD irAEs
	Cortellini et al.^Citation72	2019	Retrospective Study	NA	1770	Anti-PD-1	BMI≥25 is a risk factor BMI≥30 is a grade 3/4 risk factor
	Kartolo et al.^Citation65	2018	Retrospective Study	MM NSCLC RCC	78	Anti-PD-1 Anti-CTLA-4	No correlation between BMI and irAEs

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