High score review: reviewing the past and learning the new in immunotherapy for primary liver cancer

Introduction Primary liver cancer is currently the fourth most common malignant tumor and the second cause of death in China, which seriously threatens the lives and health of our people
.

Primary liver cancer mainly includes three different pathological types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and HCC-ICC mixed type, of which HCC accounts for 85% to 90%
.

The treatment of liver cancer such as liver resection or liver transplantation is only suitable for early stage patients, and the curative effect of existing systemic treatment programs is also limited
.

This article is a review published by American scholars on Hepatology (impact factor: 14.
679), summarizing some current immunotherapy options, including immune checkpoint inhibitor combined with targeted therapy, immune checkpoint inhibitor combined therapy, immune checkpoint Immunotherapy other than inhibitors and immunotherapy in the early stage of the disease
.

Immune checkpoint inhibitors combined with targeted therapy 1.
CTLA-4 targeted monoclonal antibody A single-group phase II study enrolled 21 patients with advanced HCC, Child-Pugh grade A or B with hepatitis C, and anti-CTLA-4 antibodies Tremelimumab was evaluated
.

The results showed that 45% and 25% of patients had Grade 3 AST and ALT elevations, respectively
.

Among them, the objective response rate (ORR) of 17 patients whose efficacy can be evaluated was 17%
.

The intention-to-treat analysis of all 21 patients showed that the median time to disease progression (TTP) was 6.
48 months (95%CI 3.
95-9.
14), and the median overall survival (OS) was 8.
2 months (95%CI 4.
64-21.
34) )
.

2.
PD-1 targeting monoclonal antibody At present, although PD-1 monoclonal antibody has ORR (14%~20%) and lasting remission in phase I/II studies, the Nivolumab monoclonal antibody (Nivolumab) is used as Both the first-line treatment and the Phase III study using Pembrolizumab as the second-line treatment showed that there was no statistically significant improvement in the patient's OS
.

The development of biomarkers to improve patient treatment options, as well as research on combination therapies, may be able to stimulate the full potential of immune checkpoint inhibitors in the treatment of HCC
.

3.
Exploration of PD-1 monoclonal antibody biomarkers.
In advanced HCC patients receiving anti-PD-1 monoclonal antibody treatment, several potential biomarkers may be related to the improvement of ORR and OS
.

In the CheckMate 040 trial, patients with advanced HCC were treated with Nivolumab monoclonal antibody.
The results showed that patients with increased tumor cell PD-L1 expression had significantly higher ORR [complete remission (CR) + partial remission (PR) vs stable disease (SD) , P = 0.
00009]
.

In addition, CD3 expression was also significantly correlated with ORR (CR + PR vs.
SD, p = 0.
05)
.

In an evaluable subset of 37 tumor patients, some inflammatory markers such as IFN-γ mRNA and T cell depletion were significantly related to the improvement of ORR and OS after anti-PD-1 treatment
.

In contrast, Wnt/β-catenin mutations are associated with poor prognosis in HCC patients receiving anti-PD-1 therapy
.

In short, this is still an area that needs active research, and the combination of multiple biomarkers may help improve patient treatment options
.

Combination therapy with immune checkpoint inhibitors 1.
Anti-PD-1/PD-L1 and anti-VEGF axis targeted drugs combined use Preclinical studies have confirmed that the combined blocking of PD-1 and VEGF axis has a synergistic anti-tumor effect
.

The US FDA has approved Lenvatinib as the first-line treatment for patients with unresectable HCC
.

Regorafenib has been approved as a second-line treatment for patients with advanced HCC who have failed Sorafenib treatment
.

Cabozantinib was approved as a second-line and third-line drug for advanced HCC
.

Although these combination treatments have significant anti-tumor potential, their efficacy may be affected by adverse events (AE).
Clinical trials of advanced HCC are currently underway to determine the efficacy and safety of these combination treatments
.

2.
Anti-PD-1/PD-L1 and anti-CTLA-4 targeted drugs combined use CheckMate 040 cohort study to evaluate patients with advanced HCC treated with sorafenib, the application of anti-CTLA4 antibody Ipilimumab (Ipilimumab) and The safety and efficacy of Nivolumab combination therapy showed that the ORR was 32% and the median OS was 23 months
.

The US FDA accelerated the approval of Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg in March 2020 for the treatment of advanced HCC patients who have previously received sorafenib therapy
.

The incidence of grade 3 to 4 treatment-related AEs of this combination therapy is relatively high, at 53%
.

57.
1% of immune-mediated patients require steroids
.

Immunotherapy other than immune checkpoint inhibitors.
Cell-based immunotherapy, such as TIL or CIK cell adoptive immunotherapy, has a strong anti-tumor effect and is less toxic to normal cells
.

In an enrollment of 230 HCC patients who had undergone surgical resection, radiofrequency ablation (RFA) or percutaneous ethanol infusion, the efficacy and safety of activated CIK cells in adjuvant therapy were evaluated.
The results showed that the CIK treatment group and the control group None of them achieved OS, but the OS in the CIK treatment group was longer (HR 0.
21, 95% CI 0.
06-0.
75, p = 0.
008)
.

Although the overall incidence of AEs in the CIK treatment group was significantly higher (62% vs.
41%, p = 0.
002), the incidence of serious AEs was similar in the two groups (7.
8% vs.
3.
5%, p = 0.
15)
.

Local immunotherapy in the early stage of the disease (such as RFA, transarterial chemoembolization, radioembolization, or external radiation therapy) is an option for treating unresectable HCC confined to the liver
.

The effect of combined therapy with local therapy and immune checkpoint inhibitors remains to be explored.
In theory, immune checkpoint inhibitors can mediate immunogenic cell death and antigen release to promote peripheral immune responses
.

In a cohort study of 32 HCC patients, the anti-CTLA4 antibody Tremelimumab was administered to patients receiving RFA.
The results showed that 5 of the 19 evaluable patients achieved PR and increased CD8+ T cell accumulation in the tumor
.

Literature index: [1] National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of primary liver cancer (2019 edition).
Official website of the National Health Commission of the People's Republic of China.
[2] Rizvi S, Wang J, El-Khoueiry AB.
Liver Cancer Immunity.
Hepatology 2020 Jun 09.
DOI: 10.
1002/hep.
31416