Immunotherapy after liver transplantation: Where are we now?

Table 1 Patients with prior liver transplantation and subsequent immunotherapy

Ref.	Drug	No. of cycles	Sex	Age	Indication	Year from transplant	Line of therapy	Rejection	Early mortality	PD-L1 status		Immunosuppression	Best response	PFS (mo)	OS (mo)
										Graft	Tumor
De Toni and Gerbes[10]	Nivolumab	15	M	41	HCC	NA	1	No	No	NA	0%	Tacrolimus	PD	3.5	7
Friend et al[11]	Nivolumab	2	M	20	HCC	4	2	Yes	Yes	Pos	Pos	Sirolimus	NA	1	1
Friend et al[11]	Nivolumab	1	M	14	HCC	3	3	Yes	Yes	Pos	Pos	Tacrolimus	NA	1	1
Varkaris et al[12]	Pembrolizumab	NA	M	70	HCC	8	NA	No	No	NA	NA	Tacrolimus	PD	NA	NA
Munker and De Toni[13]	Nivolumab	NA	M	57	HCC	2.7	3	No	No	NA	10%	Tacrolimus	PD	2.2	1.2 (surviving)
Munker and De Toni[13]	Nivolumab	NA	M	56	HCC	7.8	4	No	No	5%	NA	Sirolimus/MMF	PD	0.7	1.1 (surviving)
Munker and De Toni[13]	Nivolumab	NA	F	35	HCC	3.7	5	No	No	0%	0%	Tacrolimus	PD	1.3	1.3 (surviving)
Munker and De Toni[13]	Nivolumab	NA	M	64	HCC	1.2	2	No	Yes	NA	0%	Tacrolimus	NA	0.3	0.3
Munker and De Toni[13]	Nivolumab	NA	M	68	HCC	1.1	2	Yes	Yes	30%	0%	Sirolimus	NA	0.9	0.9
Al Jarroudi et al[14]	Nivolumab	4	M	70	HCC	2.75	3	Yes	No	NA	NA	Tacrolimus	NA	4	4
Al Jarroudi et al[14]	Nivolumab	5	F	62	HCC	1	4	No	No	NA	NA	Tacrolimus	PD	2.5	NA
Al Jarroudi et al[14]	Nivolumab	6	M	66	HCC	5	4	No	No	NA	NA	Tacrolimus	SD	3	NA
Rammohan et al[15]	Pembrolizumab	14	M	57	HCC	4.3	2	No	No	NA	NA	Tacrolimus/mTOR inhibitor	CR	10 (no progression)	10 (surviving)
Gassmann et al[16]	Nivolumab	1	F	53	HCC	3	2	Yes	Yes	NA	NA	Everolimus	NA	0.8	0.8
Nasr et al[17]	Pembrolizumab	35	M	63	HCC	4.6	2	No	No	NA	NA	Tacrolimus/MMF	CR	25 (no progression)	25 (surviving)
Wang et al[18]	Pembrolizumab	1	M	48	HCC	1	1	Yes	No	NA	NA	Tacrolimus/Everolimus	NA	NA	8 (surviving)
Au (current research)	Nivolumab	4	M	62	HCC	2.2	3	No	No	NA	NA	Tacrolimus/Everolimus	PD	4.0	7.3
Au (current research)	Nivolumab	6	M	53	HCC	6.0	2	No	No	NA	NA	Sirolimus	PD	2.8	10.6
Au (current research)	Pembrolizumab	16	M	77	HCC	32	1	No	No	NA	NA	Tacrolimus/Everolimus	SD	12.4	19.2
Ranganath and Panella[19]	Ipilimumab	4	F	59	Melanoma	8	NA	No	No	NA	NA	Sirolimus	PR	5	9 (surviving)
Morales et al[20]	Ipilimumab	4	M	67	Melanoma	8	2	No	No	NA	NA	Sirolimus/MMF	PR	4 (no progression)	14 (surviving)
Munker and De Toni[13]	Pembrolizumab	NA	M	55	Melanoma	5.5	2	No	No	0%	5%	Everolimus/MMF	CR	21.1 (no progression)	21.1 (surviving)
Munker and De Toni[13]	Pembrolizumab	NA	M	64	Melanoma	3.1	2	Yes	No	25%	NA	MMF/Prednisolone	NA	NA	0.7 (surviving)
Kuo et al[21]	Ipilimumab/Pembrolizumab	4/25	M	62	Melanoma	6	NA	No	No	NA	NA	Sirolimus	PR	24 (no progression)	24 (surviving)
Dueland et al[22]	Ipilimumab	1	F	67	Melanoma	1.5	1	Yes	No	NA	NA	Prednisolone	PD	3 (no progression)	4
Schvartsman et al[23]	Pembrolizumab	2	M	35	Melanoma	20	1	No	No	NA	NA	Tacrolimus	CR	6	6 (surviving)
Tio et al[24]	Pembrolizumab	1	F	63	Melanoma	NA	NA	Yes	Yes	NA	NA	Ciclosporin	NA	NA	NA
Biondani et al[25]	Nivolumab	3	M	54	SCC lung	13	1	No	No	NA	NA	Tacrolimus/Everolimus	PD	2.25	15

CR: Complete response; F: Female; HCC: Hepatocellular carcinoma; M: Male; NA: Not available; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; PR: Partial response; SCC: Squamous-cell carcinoma; SD: Stable disease.

Table 2 Descriptive characteristics of all patients with prior liver transplantation and subsequent immunotherapy

	All	Rejection	No rejection	P value
Total (%)	28	9 (32)	19(68)
Gender (M/F; %M)	22/6 (79)	6/3 (67)	16/3 (84)	0.29
Age	61 (53-66)	63 (34-67.5)	59 (54-64)	1.00
Year after transplant	3.9 (2.5-6.5)	2.9 (1.2-3.1)	5.3 (2.7-8.0)	0.02
Indication (%)				0.93
HCC	19 (68)	6 (67)	13 (68)
Melanoma	8 (29)	3 (33)	5 (26)
SCC of lung	1 (4)	0 (0)	1 (5)
Line of systemic therapy	2 (1-3)	2 (1-3)	2 (1-4)	0.52
Immunotherapy by drug (%)				0.92
Nivolumab	15 (54)	5 (56)	10 (53)
Pembrolizumab	10 (36)	3 (33)	7 (37)
Ipilimumab	4 (14)	1 (11)	3 (16)
Immunotherapy by class (%)				1.00
PD1/PD-L1	24 (86)	8 (89)	16 (84)
CTLA-4	3 (11)	1 (11)	2 (11)
Both	1 (4)	0 (0)	1 (5)
PD-L1 positivity (%)
Graft	5/7 (71)	4/4 (100)	1/3 (33)	0.053
Tumor	4/8 (50)	2/3 (67)	2/5 (40)	0.47
Immunosuppression (%)
Single agent tacrolimus	10 (36)	2 (22)	8 (42)	0.31
Single agent mTOR-inhibitor	6 (21)	3 (33)	3 (16)	0.29
Tacrolimus with mTOR-inhibitor	5 (18)	1 (11)	4 (21)	0.52
Others	7 (25)	3 (33)	4 (21)	0.48
Acute rejection (%)	9 (32)
Mortality in 30 d (%)	6 (21)	5 (56)	1 (5)	0.002
Progression-free survival	3 ± 0.6	1.0 ± 0.1	3.5 ± 1.1	0.02
Overall survival	10.6 ± 5.3	1.0 ± 0.1	19.2 ± 5.5	0.001

CTLA-4: Cytotoxic T-Lymphocyte antigen-4; F: Female; HCC: Hepatocellular carcinoma; M: Male; mTOR: Mammalian target of rapamycin; PD-1: Programmed cell death protein-1; PD-L1: Programmed death ligand-1; SCC: Squamous-cell carcinoma.

Table 3 Descriptive characteristics of patients with immunotherapy for post-transplant hepatocellular carcinoma recurrence

	All	Nivolumab	Pembrolizumab	P value
Total (%)	19	14 (74)	5 (26)
Rejection (%)	6 (32)	5 (36)	1 (20)	0.52
Early mortality (%)	5 (26)	5 (36)	0 (0)	0.12
Line of systemic therapy	2 (1-3)	3 (2-4)	2 (1-2)	0.03
Tumour PD-L1 positivity (%)	3/7 (43)	3/7 (43)	0/0 (-)
Best treatment response (%)
Complete response	2 (11)	0 (0)	2 (40)	0.03
Partial response	0 (0)	0 (0)	0 (0)	0.64
Stable disease	2 (11)	1 (7)	1 (20)	0.58
Progressive disease	8 (42)	7 (50)	1 (20)	0.03
Progression-free survival	2.5 ± 1.0	1.3 ± 1.1	12.4	0.004
Overall survival	7.3 ± 2.7	4.0 ± 3.4	19.2	0.006

PD-L1: Programmed death ligand-1.