Immunotherapy of tumors has a long history, dating back as far as the late nineteenth century. After a silent period of about half a century, immunotherapy of tumors has developed rapidly since the 1960s, with a variety of tumor-specific monoclonal antibodies as well as immune system modulators all achieving good results in the treatment of tumors.
Types of tumor immunotherapy
In the disease state, the body’s normal immune function is “bribed” by the tumor cells, allowing them to escape the body’s immune surveillance. Tumor immunotherapy is a treatment that restores the body’s normal anti-tumor immune response by restarting and maintaining the immune system’s ability to recognize and kill tumor cells, relying on its own immune function to kill cancer cells.
Unlike traditional classical surgery, chemotherapy, radiation and targeted therapy, immunotherapy targets not tumor cells and tissues, but the body’s own immune system.
Cellular therapy
Tumors are treated with either CAR-T therapy, which primarily uses cytokine stimulation to activate T cells and restore their ability to kill tumor cells, such as tumor-infiltrating lymphocytes, CIK cells, and CTL cells, or by genetically engineering T cells to increase their specificity in recognizing tumor receptors.
Tumor vaccines
The Sipuleucel-T vaccine, the first tumor vaccine, was approved for marketing by the FDA on April 29, 2010 for the treatment of prostate cancer by injecting tumor antigens into the body to activate the body’s immune system.
Immune system agonists
The body’s immune function is enhanced by giving the body a certain amount of the cytokine IL-2 or the immune adjuvant BCG.
Immune checkpoint inhibitors
Usually, the body’s immune system can recognize and kill tumor cells, but tumor cells can avoid surveillance by the body’s immune system by reducing the immunogenicity of their own antigens or by inducing immunosuppression.
The most studied PD-1 and CTLA-4 are typical examples of immune checkpoint inhibitors.
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Clinical applications of immunotherapy for liver cancer
Blockers targeting immune checkpoints such as PD-1/PD-L1 and CTLA-4 have all been clinically studied in hepatocellular carcinoma.
Nabumab
On September 23, 2017, immunotherapy finally came as a surprise to liver cancer patients and doctors. the PD-1 inhibitor nabumab was approved by the FDA for hepatocellular carcinoma previously treated with sorafenib, making it the first FDA-approved immunotherapy drug for liver cancer treatment.
The approval was based on a phase I/II CheckMate-040 clinical study of nabumab in advanced or metastatic hepatocellular carcinoma, which showed that patients on nabumab had better tumor response rates and duration of response. More than 50% of patients with hepatocellular carcinoma in the treatment group survived more than 15 months, with a disease control rate of 65% and an objective remission rate of 20%.
In analyzing the population of benefit for nabumab, stratification based on PD-L1 expression did not have a significant impact on objective remission rates, and given the still low overall efficiency, it is important to find the true population of benefit. dMMR/MSI-H, tumor mutation burden (TMB), and other predictors of efficacy still need to be explored, so The value of efficacy predictors such as dMMR/MSI-H and tumor mutation burden (TMB) remains to be explored, and therefore the efficacy predictive biomarkers for immunosuppressive drugs in hepatocellular carcinoma are unclear and awaiting answers from phase III clinical studies.
Pimozumab
On May 23, 2017, the FDA approved the PD-1 antibody pembrolizumab for the treatment of 15 solid tumors with defective mismatch repair (dMMR)/microsatellite instability high (MSI-H). This means that patients with solid tumors with these specific mutations can benefit from the use of pairomumab regardless of cancer classification. This is a milestone as it differentiates anti-tumor therapies not by tumor source but by biomarker.
But the rate of occurrence of dMMR/MSI-H varies by tumor type, with relatively high numbers in colorectal, endometrial, and gastric cancer types, about 13% to 22%, and in hepatocellular carcinoma, about 16%.
These tumors, if they progress to advanced stages, are usually insensitive to chemotherapy and have a poor prognosis because they are prone to drug resistance due to many DNA mutations. However, with the advent of PD-1/PD-L1 inhibitors, these tumors have responded exceptionally well to immunotherapy, far outpacing the majority of tumor types.
Tumor mutational buren (TMB) is also one of the more popular biomarkers, and liver cancer has a higher average tumor mutational load compared to other solid tumors, so TMB could also be a biomarker for precision immunotherapy in liver cancer.
Outlook for immunotherapy in liver cancer
The approval of nabumab opens a new era of immunotherapy for liver cancer. In addition, the use of pembrolizumab in hepatocellular carcinoma has been granted priority review status by the FDA, with approval expected by November 9, 2018.
This is a non-randomized, open-label, multicenter phase II clinical trial (KEYNOTE-224). In this clinical trial, 104 patients with hepatocellular carcinoma who were treated with sorafenib received pembrolumab.
Results showed an objective remission rate of 17%, complete remission in 1%, partial remission in 16%, and stable disease in 44% of patients in the pembrolizumab group. Following the KEYNOTE-224 clinical trial, the KEYNOTE-240 and KEYNOTE-394 clinical phase III trials will explore the efficacy of pembrolumab as a second-line therapy alone for advanced hepatocellular carcinoma.
In summary, because of the low efficacy of immunotherapy, combination therapy may be the future direction in the field of liver cancer treatment, such as PD-1/PD-L1 monoclonal antibody in combination with chemotherapy, PD-1/PD-L1 monoclonal antibody in combination with targeted drugs, and the combination between different immunotherapy drugs, of which PD-1/PD-L1 in combination with CTLA-4 has been applied in malignant melanoma and other The combination of PD-1/PD-L1 and CTLA-4 has been applied in the treatment of malignant melanoma, etc. and has achieved certain efficacy. We look forward to the combination therapy to bring new hope to liver cancer patients!