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Immunotherapy: liver transplantation for liver cancer
Immunotherapy: liver transplantation for liver cancer. Due to the breakthrough of immunotherapy in the treatment of liver cancer, the mode of liver cancer treatment is also changing.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer death in the world. New liver cancer patients in some countries account for more than half of the world’s liver cancer patients each year. Most liver cancer patients in some countries develop on the basis of hepatitis B cirrhosis. Nearly half of liver cancer patients are in the middle and advanced stages at the time of diagnosis and lose the opportunity for surgical treatment.
The main treatment methods for liver cancer include liver resection, liver transplantation, ablation, transhepatic arterial chemoembolization, targeted therapy and immunotherapy, etc. However, due to the strong heterogeneity of HCC, the treatment effect is not good. Multidisciplinary comprehensive treatment is An effective way to prolong the survival time of patients with liver cancer.
Liver transplantation has the triple advantages of complete tumor removal, liver cirrhosis, and HBV removal. Nearly half of liver transplant patients in some countries are liver cancer patients. Since the Milan criteria were introduced in 1996, the academic community has proposed many selection criteria for liver transplantation for liver cancer, and the long-term effects after transplantation are also improving. The 5-year survival rate of liver cancer liver transplant patients who meet the Milan criteria can exceed 85. %.
However, the severe shortage of organs caused liver cancer patients on the transplant waiting list to fall off the waiting list due to long waiting time and tumor progression. Liver transplant patients with liver cancer who exceed Milan’s standards can be downgraded by interventional therapy, ablation therapy and other downgrading methods, so that some patients will be re-entered into the waiting list for liver transplantation.
For some patients who exceed the liver transplantation standards for liver cancer, if they meet the relevant transplantation standards after down-stage treatment and then receive liver transplantation, they can achieve tumor-free survival and overall survival similar to those of eligible recipients.
In the field of liver cancer system therapy in recent years, with the emergence of new targeted therapies and immunotherapy, the treatment mode of advanced liver cancer has undergone major changes, among which immunotherapy represented by immune checkpoint inhibitors (ICIs) is the most significant , The patient’s survival period has been significantly prolonged, and some patients can even be transformed from unresectable to resectable, and even transplant successfully.
A recent study of ICIs combined with anti-angiogenesis inhibitors (IMbrave150) shows that the combined treatment of the two can effectively overcome drug resistance and improve the efficacy , and has become a new first-line treatment for advanced HCC, for immunotherapy of different stages of liver cancer Related clinical research is also in progress. Therefore, the era of immunotherapy for liver cancer has come, and it will definitely have a certain impact on the field of liver transplantation for liver cancer.
This article will sort out and prospect from this perspective. At the same time, this issue also invites many domestic experts in the field of liver transplantation for the down-stage treatment of liver cancer liver transplantation, the treatment of tumor recurrence after transplantation, and the immunosuppressant treatment after tumor recurrence In-depth discussion on applications and other aspects.
1 The relationship between liver transplantation and immunity
The liver has a very close relationship with immunity. Normal human liver contains very abundant immune cells, such as Kupffer cells, hepatic sinusoidal endothelial cells, dendritic cells, hepatic stellate cells, lymphocytes and so on.
Normal human liver contains about 1010 lymphocytes, which are widely distributed in liver parenchyma and portal area, most of which are T lymphocytes (63%), followed by natural killer cells (31%) and B lymphocytes (6%). Cells build the liver’s powerful immune function, and it is the environment where multiple immune-related cells coexist in the liver that makes the liver an “immune-exempt” organ.
HCC is a tumor highly related to inflammation. It gradually develops into liver cancer on the basis of chronic hepatitis. The proportion of immune cells in the liver tumor microenvironment (TME) is seriously unbalanced, immune cell function and antigen presentation function are impaired, and multiple inhibitory properties The activation of the receptor-ligand pathway leads to immune tolerance and immune escape.
Immune checkpoints are inhibitory molecules expressed on immune cells, such as anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 and anti-programmed death receptor (PD-1), which prevent excessive activation of T lymphocytes. It plays a protective role in inflammation damage and maintaining autoimmunity.
PD-1/PD-L1 is the key pathway for immune escape in TME. The combination of PD-L1 expressed by tumor cells and PD-1 expressed by lymphocytes will inhibit the killing of tumor cells by lymphocytes, and at the same time, the growth of tumors will be accelerated. Angiogenesis, which in turn leads to the activation of multiple immunosuppressive pathways in TME .
Tumor immunotherapy is to correct the imbalance of the immune microenvironment and kill tumor cells by enhancing or restoring the body’s immune system’s surveillance and killing capabilities .
At present, tumor immunotherapy mainly includes three aspects: tumor vaccine, immune checkpoint suppression and immune cell adoptive therapy. Immune checkpoint suppression therapy is mainly monoclonal antibodies against key targets of immune tolerance, such as PD-1/PD-L1 It is precisely by blocking the combination of PD-L1 and PD-1, that the anti-tumor cells can increase the killing ability of T lymphocytes. Combined with anti-angiogenesis inhibitors can induce the normalization of tumor blood vessels by inhibiting vascular endothelial growth factor and reshape liver cancer. TME .
For organ transplantation, the combination of multiple immunosuppressive regulatory pathways and targeted blocking of the pathways that activate the immune response can induce transplant immune tolerance. Among them, CTLA-4 and PD-1 costimulatory signal pathways can induce transplant immunity Tolerance, the former plays a leading role in inducing and maintaining immune tolerance, while the latter mainly plays a role in the maintenance of immune tolerance.
Immunosuppressive pathways have different roles in tumor immunity and transplantation immunity, which is reflected in how to achieve a balance between immune tolerance and anti-tumor immunity in liver transplantation for liver cancer.
2 Application of immunotherapy in liver cancer
Since 2013, cancer immunotherapy represented by ICIs has made substantial progress. Compared with tyrosine kinase inhibitors (TKIs), ICIs have a higher objective response rate and lower adverse reactions, which makes it It is more effective for liver cancer.
Both Nivolumab and Pembrolizumab are PD-1 specific antibodies. Early clinical studies have shown that Nivolumab has a response rate of 14.3% to advanced HCC, while Pembrolizumab is 17%. In a clinical study involving 262 patients with advanced HCC , through the use of Nivolumab treatment, more than 58% of patients got disease control, and more than 20% of patients showed a significant decrease in tumor burden.
Based on good clinical trial research results, both have been approved by the U.S. Food and Drug Administration (FDA) as second-line treatment options for unresectable liver cancer in advanced stages.
In March 2020, the National Medical Products Administration of China approved the first second-line immunotherapy drug for liver cancer-Camrelizumab, which is a clinical study based on the characteristics of HBV-related liver cancer patients in China, with objective clinical relief The rate reached 14.7%, and the median survival time reached 13.8 months , which made it approved for advanced HCC patients who have received sorafenib treatment or oxaliplatin-containing system chemotherapy, becoming the first in China PD-1 monoclonal antibody approved to treat patients with advanced HCC. The 2020 Liver Cancer Guidelines of the Chinese Society of Clinical Oncology listed the above three PD-1 monoclonal antibodies as second-line treatment options for liver cancer (level 2A evidence, level I recommendation).
Anti-angiogenesis therapy and immunotherapy have a synergistic effect , and the combination of ICIs and TKIs has caused widespread concern in the treatment of HCC. A phase I study reported by the American Society of Clinical Oncology in 2018  showed that the combination of lenvatinib and Pembrolizumab can achieve a response rate of 42.3%.
The results of the IMbrave150 study showed that atezolizumab combined with bevacizumab (Atezolizumab + Bevacizumab, A+T regimen) compared with sorafenib in the treatment of 501 patients with metastatic or unresectable advanced HCC, the combined treatment regimen makes the risk of death of the patients relatively The 12-month survival rate was reduced by 42%, and the 12-month survival rate was increased to 67.2%, which significantly prolonged the overall survival time of patients. This program was immediately approved by the US FDA for the treatment of unresectable HCC patients who had not received systemic treatment before, becoming the first Approved first-line immunotherapy for liver cancer.
At present, the National Comprehensive Cancer Network of the United States, the European Society of Medical Oncology, and the liver cancer guidelines of the Chinese Society of Clinical Oncology have recommended the A+T regimen as the first-line treatment for advanced liver cancer (Class 1A evidence, level I recommendation). In March 2020, the US FDA accelerated the approval of Nivolumab combined with Ipilimumab (CTLA-4 monoclonal antibody) as a second-line treatment for patients with advanced liver cancer. This is the first approved “dual immunity” therapy.
At present, there are more clinical studies of immunotherapy combined with anti-angiogenesis targeted therapies in extensive development, such as the phase I clinical trial of lenvatinib combined with Nivolumab (NCT03418922), and the phase III clinical trial of lenvatinib combined with Pembrolizumab ( NCT03713593) and the ORIENT-32 study of Sintilizumab (PD-1 monoclonal antibody) combined with IBI30 (bevacizumab biosimilar), and even the clinical study of combined cabozantinib on the basis of dual immunotherapy ( NCT01658878) is also in progress. The preliminary results show that the objective response rate, disease control rate, and median progression-free survival in the three-drug combination treatment group are better than those in the control group (26% vs 17%, 83% vs 81%, 6.8 Months vs 5.5 months).
The treatment options for advanced liver cancer have completely changed due to the advent of the immunotherapy era, and it is expected that more exciting data will be presented. In this context, the combination of immunotherapy and transhepatic arterial chemoembolization, ablation therapy, radiotherapy, targeted therapy, etc., has also shown a strong potential trend in the down-stage conversion therapy of advanced liver cancer.
In a randomized clinical study of preoperative neoadjuvant immunotherapy for resectable liver cancer , 33.3% of patients who underwent surgical resection after treatment with Nivolumab and/or Ipilimumab showed complete remission after surgery. , Which significantly improves the safety of surgery and reduces the recurrence rate after surgery. There have also been reports of successful translational surgical resection using immunotherapy combined with targeted therapy. The Weidong team  used lenvatinib combined with Nivolumab to shrink the right lobe tumor of a 69-year-old female liver cancer patient and finally implemented the right hepatic liver. resection.
Massachusetts General Hospital also reported the application of Nivolumab combined with Y-90 radiotherapy embolization to successfully perform conversion surgery on a 34-year-old male liver cancer patient with portal vein and hepatic vein tumor thrombi . The domestic Sun Huichuan team reported on the study of TKIs combined with PD-1 antibody to transform unresectable liver cancer into resectable liver cancer at the 2020 American Society of Clinical Oncology Annual Meeting. Among the 60 patients included in the study, 11 patients have met the resection criteria, 9 One patient has undergone surgery, and seven patients survived without tumors.
It is believed that in the future, more patients will obtain radical surgery and achieve long-term survival through this combined treatment model based on immunotherapy.
3 Application of immunotherapy in liver transplantation for liver cancer
In these cases of resection after transformation by immunotherapy, only 10% of cases can achieve complete remission under pathology, so complete surgical resection after transformation is still very necessary, in addition to the successful implementation of immunotherapy for unresectable liver cancer In addition to transformational surgical resection, there are also reports of successful down-stage liver transplantation.
Schwacha-Eipper et al.  reported that a 66-year-old patient with liver cancer developed multiple intrahepatic metastases after hepatectomy. The tumor was successfully downgraded through the application of Nivolumab combined with targeted drugs, and then liver transplantation was successfully implemented. Currently, the patient has 1 For more than a year, the follow-up is good, which provides a successful example of the use of immunotherapy in the down-stage treatment of liver transplantation for liver cancer.
However, the application of ICIs in the perioperative period of liver transplantation has the risk of inducing fatal acute rejection. Therefore, for this type of down-stage treatment based on immunotherapy, the transplant timing is recommended to be at least 6 weeks after the end of immunotherapy (the half-life of Nivolumab is about 4 weeks) If transplantation is carried out again, there is a risk of rejection after transplantation. However, whether this time extension will affect the effect of transplantation and cause tumor recurrence again needs to be further summarized.
The literature  reported that the incidence of rejection in all solid organ transplants using ICIs is very high, with a fatality rate as high as 40.4%. The incidence of acute rejection in patients with tumor recurrence after liver cancer liver transplantation using immunotherapy is about It is 35% . Therefore, most studies believe that ICIs should be used with caution in patients with tumor recurrence after liver transplantation.
However, there have been many successful application cases in the real world. In 2017, Gastroenterology magazine reported a case of liver cancer after liver transplantation. After tumor recurrence, the dosage of immunosuppressive agents was adjusted, and then Nivolumab immunotherapy was performed. The patient has survived. Over 10 months, no rejection has been observed .
In 2018, Hepatology also reported a case of liver cancer in a living-donor liver transplantation patient with tumor recurrence and lung metastasis, the application of sorafenib targeted therapy was not effective, and then combined with Pembrolizumab treatment, after 15 cycles of treatment of upper lung metastasis The focus disappeared completely, and the tumor-free survival was 10 months without rejection .
These case reports all show the possibility of successful immunotherapy for patients with liver cancer and liver transplantation tumor recurrence. Munker et al.  summarized 14 cases of immunotherapy after liver transplantation for liver cancer, and considered whether acute rejection occurred after application and the choice of immunotherapy drugs, the concentration and dose of anti-rejection drugs, and PD- in liver transplants. The expression level of L1 is related to the start time of immunotherapy. The key to achieving a balance between graft rejection and anti-tumor effects lies in the accurate assessment of the immune microenvironment. With the emergence of more and more successful treatment cases, the characteristics of the population of such benefited patients will be summarized.
In summary, due to the breakthroughs made in immunotherapy in the treatment of liver cancer, the mode of liver cancer treatment is also changing. It is indeed a gratifying thing for some patients with advanced liver cancer to achieve transformational surgical resection or liver transplantation through immune-based combination therapy.
However, in the application of immunotherapy in patients with liver cancer and liver transplantation, it is necessary to precisely adjust the transplant immune tolerance state and maintain tumor-specific immunity, in-depth study of the immune microenvironment in both liver cancer and transplantation states, and individual patients based on the specific conditions of the patients.
Comprehensive treatment. How to screen the potential beneficiaries and formulate appropriate application specifications is a brand new topic, which requires multidisciplinary team collaboration and further clinical research are verified.
As the concept of transplantation oncology continues to deepen, I believe that immunotherapy will play a greater role in the field of liver transplantation for liver cancer in the future.
(source:internet, reference only)