The immune system is the protector of our body. In nature, there are many disease-causing factors that can activate our immune system to fight against various pathogens that invade our body, remove aging cells in our body, kill new cancer cells and so on. When our immune system is over-activated, it tends to kill the normal tissue cells, which are the “onlookers”. CTLA4 and PD1, two proteins found on immune cells, are the enforcers of the “brakes”, which we call CTLA4 and PD1, two proteins found on immune cells, are the executors of the “braking mechanism”, which we call “immune checkpoints”. In the course of the struggle between tumor cells and the body’s immune system, they have also evolved the ability to “slam on the brakes” to resist killing by the body’s immune system. Tumor cells express CTLA4 and PD1 ligands on the membrane surface, which activate the immune checkpoint signaling pathway and send “don’t kill me” signals to immune cells, resulting in the inability of immune cells to complete the killing of cancer cells. The immune checkpoint inhibitors we are currently developing in the clinic are all designed to release the “brakes” that are applied by the tumor, so that the immune cells can kill the tumor cells. What is the specific mechanism of the anti-tumor effect of CTLA-4? CTLA-4, also known as CD152, is a transmembrane protein encoded by the CTLA-4 gene and is expressed on activated CD4+ and CD8+ T cells. CD4+ and CD8+ T cells.CTLA-4 was discovered in 1987, and Professor James P. Allison, the discoverer of CTLA-4, and Professor TasukuHonjo, the discoverer of PD-1, were awarded the Nobel Prize in Physiology or Medicine together in 2018. The CTLA-4 monoclonal antibody and PD-L1 monoclonal antibody each have their own role in the various stages of T-cell activation. Among them, CTLA-4 monoclonal antibody is able to maintain the T-cell activation state by disarming the signals that inhibit T-cell activation. In contrast, PD-L1 monoclonal antibody enhances T-cell initiation and activation by blocking the interaction of PD-L1 with B7-1 molecules in lymph nodes. During the effector phase, CTLA-4 monoclonal antibody relieves the immunosuppression of regulatory T cells (Treg cells) in the tumor microenvironment, while PD-L1 monoclonal antibody blocks the interaction between PD-L1 and PD-1 to reactivate the suppressed T cells, allowing the “revived” effector T cells to rapidly kill tumor cells. What is the difference between CTLA-4 antibody and PD-1 antibody? CTLA-4 and PD-1 are two important immune checkpoints that have been identified in humans. Compared to PD-1/PD-L1 antibodies, the unique clinical value of CTLA-4 antibodies is reflected in two aspects – sensitization and longevity. Sensitization refers to the ability of CTLA-4 antibodies to alter the body’s immune response status, thereby improving the effectiveness of other treatments. For example, the CTLA-4 antibody ipilimumab is not as efficient as PD-1 antibody alone, but ipilimumab in combination with PD-1 antibody has high efficiency in the treatment of melanoma, driver gene-wild type non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), renal cell carcinoma, and microsatellite highly unstable (MSI-H) colon cancer. In addition, CTLA-4 antibody can regulate immune memory cells, which means it has the function of inducing long-term immune memory and has a long-lasting effect on the activation of the immune system. What is the efficacy of CTLA-4 in treating liver cancer? The world’s first immune test point inhibitor drug, CTLA-4 antibody Ipilimumab (Ipilimumab, Schweppes), was approved by the FDA in 2011 for the treatment of advanced melanoma. Currently, two antibodies targeting CTLA-4, Ipilimumab (Bristol-Myers Squibb) and Tremelimumab (AstraZeneca), are in the clinic and have been used to treat patients with melanoma, kidney cancer, prostate cancer, and lung cancer. In immunotherapy for hepatocellular carcinoma, the CheckMate040 study evaluated the safety and efficacy of combination therapy with the CTLA-4 antibody Ipilimumab (Ipilimumab) and Navulizumab (Nivolumab) in patients with advanced HCC treated with Sorafenib. The results showed an objective remission rate (probability of tumor shrinkage) of 32% and a median patient survival of 23 months with the combination therapy. Overall population dual immune combination therapy was well tolerated, with 37% of patients having grade 3-4 treatment-related adverse reactions, most commonly pruritus and rash, and 5% of patients discontinuing treatment due to grade 3-4 adverse reactions. The U.S. FDA granted accelerated approval for Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg in March 2020 for the treatment of patients with advanced HCC previously treated with sorafenib, based on the results of the CheckMate040 study. What are the adverse effects of CTLA-4 antibodies for tumor treatment? CTLA-4 antibodies are more likely to produce immune-related adverse reactions due to their powerful and long-lasting ability to activate the immune system. Immune-related adverse reactions may occur in any organ system, with the most common being colitis, hepatitis, dermatitis (including toxic epidermolysis bullosa), neuropathy, and endocrine disorders. Such reactions generally occur during treatment, and in a very small percentage of patients after the end of treatment. If serious immune-related adverse reactions occur, the drug should be permanently discontinued and treated with high-dose glucocorticoids. Patients treated with CTLA-4 immunotherapy need to be carefully evaluated for signs and symptoms associated with colitis, dermatitis, neurological disease, and endocrine disease before each dose is administered, and clinical biochemistry, including liver function, ACTH levels, and thyroid function, should be evaluated to confirm the absence of grade 3 or higher serious adverse reactions before clinical use. Conclusion Currently, the immunotherapeutic efficacy of CTLA-4 antibodies for the treatment of tumors has been validated in several clinical studies. Combination therapy has also been approved as an indication for immunotherapy in advanced hepatocellular carcinoma. Dual immunotherapy may be a new option in the future for patients with advanced hepatocellular carcinoma who have poor efficacy with targeted therapy or targeted immunotherapy. As more phase 3 clinical studies continue to be explored, CTLA-4 antibodies will certainly become an important part of our future systemic therapy for hepatocellular carcinoma, along with PD-1 antibodies.