Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons

Table 1 Characteristics of hepatocellular carcinoma patients receiving immunotherapy as a downstaging or bridging approach to liver transplantation

No.	Ref.	Age	Sex	Underlying liver disease	MTD (cm)	Pathology milan in/out	Cycles/duration	Immunotherapy	Days before LT	Post-LT follow-up (mo)	Initial immunosuppression	Rejection
1	Tabrizian et al[6]	69	M	None	10	Milan out within UCSF	21 cycles	Nivolumab	18	23	Tapering steroids + tacrolimus + MMF	No
2	Tabrizian et al[6]	56	F	HCV	5.4	Milan out within UCSF	8 cycles	Nivolumab	22	22	Tapering steroids + tacrolimus + MMF	No
3	Tabrizian et al[6]	58	M	HBV	21	Milan in	32 cycles	Nivolumab	1	22	Tapering steroids + tacrolimus + MMF	No
4	Tabrizian et al[6]	63	M	HCV, HIV	4.4	Milan in	4 cycles	Nivolumab	2	21	Tapering steroids + tacrolimus + MMF	No
5	Tabrizian et al[6]	30	M	HBV	3.2	Milan in	25 cycles	Nivolumab	22	16	Tapering steroids + tacrolimus + MMF	Mild
6	Tabrizian et al[6]	63	M	HBV	2	Milan in	4 cycles	Nivolumab	13	14	Tapering steroids + tacrolimus + MMF	No
7	Tabrizian et al[6]	66	M	HBV	2.5	Milan in	9 cycles	Nivolumab	253	14	Tapering steroids + tacrolimus + MMF	No
8	Tabrizian et al[6]	55	F	HBV	2.8	Milan in	12 cycles	Nivolumab	7	8	Tapering steroids + tacrolimus + MMF	No
9	Tabrizian et al[6]	53	F	NASH	8.7	Milan out within UCSF	2 cycles	Nivolumab	30	8	Tapering steroids + tacrolimus + MMF	No
10	Schwacha-Eipper et al[7]	66	M	Alcohol-associated liver cirrhosis	6.4	Milan out	34 cycles	Nivolumab	105	12	NA	No
11	Nordness et al[8]	65	M	HCV	5.5	Milan in	2 yr	Nivolumab	8	Death at day 10	Tacrolimus + MMF + steroids	Yes

M: Male; F: Female; MTD: Max tumor diameter; HBV: Hepatitis B virus; HCV: Hepatitis B virus; UCSF: The University of California San Francisco criteria; LT: Liver transplantation; NASH: Nonalcoholic steatohepatitis; MMF: Mycophenolate mofetil; NA: Not available.

Table 2 Characteristics and reported outcomes of published cases with hepatocellular carcinoma recurrence receiving immunotherapy after liver transplantation

No.	Ref.	Age	Sex	HCC recurrence	Immunosuppression protocol before immunotherapy	Compound	Duration of IMT (wk)	Interval from LT to IMT (yr)	Graft rejection	Tumor respon-se	Follow-up (mo)	Cause of death
1	De Toni and Gerbes[27]	41	M	IR and ER	Low-dose tacrolimus	Nivolumab	30	1	No	PD	10	-
2	Friend et al[59]	20	M	ER	Sirolimus	Nivolumab	4	4	Yes, lethal (17 d)	NA	1	OF (4 wk after ICI initiation)
3	Friend et al[59]	14	M	ER	Tacrolimus	Nivolumab	2	3	Yes, lethal (7 d)	NA	1	OF (5 wk after ICI initiation)
4	Varkaris et al[25]	70	M	ER	Low-dose tacrolimus	Pembrolizumab	11.3	8	No	PD	3	PD
5	DeLeon et al[60]	57	M	HCC recurrence	Tacrolimus	Nivolumab	5.1	2.7	No	PD	1.2	Probably PD
6	DeLeon et al[60]	56	M	HCC recurrence	Sirolimus + MMF	Nivolumab	4.7	7.8	No	PD	1.1	Probably PD
7	DeLeon et al[60]	35	F	HCC recurrence	Tacrolimus	Nivolumab	5.6	3.7	No	PD	1.3	Probably PD
8	DeLeon et al[60]	64	M	HCC recurrence	Tacrolimus	Nivolumab	1.3	1.2	No	NA	0.3	MOF
9	DeLeon et al[60]	68	M	HCC recurrence	Sirolimus	Nivolumab	3.9	1.1	Yes (27 d)	NA	0.9	PD
10	Gassmann et al[58]	53	F	ER	Everolimus + MMF + steroids	Nivolumab	2	3	Yes, lethal (7 d)	NA	0.8	OF (2 wk after ICI initiation)
11	Rammohan et al[32]	57	M	ER	Tacrolimus + MMF + steroid + mTOR inhibitor	Pembrolizumab	42.9	4.3	No	CR	10	Alive
12	Zhuang et al[90]	54	M	ER	Tacrolimus	Nivolumab	62	2.7	No	PD	20	PD
13	Al Jarroudi et al[91]	70	M	IR	Tacrolimus	Nivolumab	8	> 3.0	Yes (45 d)	NA	4	PD
14	Al Jarroudi et al[91]	62	F	ER	Tacrolimus	Nivolumab	10	2.5	No	PD	2.5	Alive
15	Al Jarroudi et al[91]	66	M	IR and ER	Tacrolimus	Nivolumab	12	> 4.75	No	PD	3	Alive
16	Amjad et al[24]	62	F	IR and ER	-	Nivolumab	82.7	1.3	No	CR	20	Alive
17	Wang et al[92]	48	M	ER	Sirolimus + tacrolimus	Pembrolizumab	3	1	Yes (5 d)	NA	8	Alive
18	Qiu et al[93]	54	M	IR and ER	Sirolimus	Camrelizumab	39	4.3	No	PD	11	PD
19	Tan et al[21]	56	M	ER	Tacrolimus + MMF	HBV-TCR T cells	52	1.1	No	PR	12	Alive
20	Tan et al[21]	45	M	IR and ER	Sirolimus	HBV-TCR T cells	16	4.4	No	PD	3.7	Alive
21	Qasim et al[20]	70	M	ER	Tacrolimus	HBV-TCR T cells	8.6	11	No	PD	2	PD
22	Hafezi et al[19]	-	-	HCC recurrence	Tacrolimus + sirolimus	HBV-TCR T cells	10	1.5	-	-	-	-
23	Hafezi et al[19]	-	-	HCC recurrence	Tacrolimus + sirolimus + MMF	HBV-TCR T cells	4	1	-	-	-	-
24	Hafezi et al[19]	-	-	HCC recurrence	Tacrolimus + sirolimus	HBV-TCR T cells	9	1.8	-	-	-	-
25	Hafezi et al[19]	-	-	HCC recurrence	Tacrolimus + MMF	HBV-TCR T cells	4	0.4	-	-	-	-
26	Hafezi et al[19]	-	-	HCC recurrence	Sirolimus	HBV-TCR T cells	4	0.5	-	-	-	-
27	Hafezi et al[19]	-	-	HCC recurrence	Tacrolimus + sirolimus	HBV-TCR T cells	8	0.7	-	-	-	-
28	Xie et al[22]	29	M	IR	-	NK cells	12.9	1.5	No	PR	18	Alive
29	Pandey and Cohen[49]	54	F	IR and ER	Tacrolimus	Ipilimumab	55.7	7.5	No	CR	27	Alive

M: Male; F: Female; IMT: Immunotherapy; IR: Intrahepatic recurrence; ER: Extrahepatic recurrence; MMF: Mycophenolate mofetil; CR: Complete response/remission; PR: Partial response/remission; PD: Disease progression/progressive disease; NA: Not available; OF: Organ failure; MOF: Multiple organ failure.