What is a reliable immunotherapy? There is no doubt that “immunotherapy” is the hottest concept in the anti-cancer field nowadays, which has changed the fate of many patients. However, once any concept is hot, it will definitely be exploited and over-promoted. It is urgent to standardize and standardize immunotherapy in China. To prevent being fooled, both patients and families should understand some basics of immunotherapy. These 5 points below are important. I. Why is immunotherapy worthy of attention? Immunotherapy is exciting because of two main points: 1. Immunotherapy can treat advanced cancer that has metastasized extensively. Some patients with advanced cancer who have failed all standard therapies still have good results after using immunotherapy. 2. Immunotherapy has a “survival trailing effect”. Patients who respond to immunotherapy have a high chance of high quality long-term survival, and this group of advanced cancer patients who were once sentenced to death are often referred to as “super survivors”! In patients with melanoma, lung cancer, kidney cancer, pediatric acute leukemia, etc., immunotherapy has created a cohort of “super survivors” who have survived for more than 10 years from the initial cohort of patients treated! This “tail-dragging effect” is the biggest difference between immunotherapies and targeted drugs. Most targeted drugs can rapidly shrink tumors and significantly improve patients’ quality of life in the short term. However, except for individual drugs, most targeted drugs are difficult to get rid of the resistance problem, so there are few “super survivors”. Which immunotherapies are worthy of patients’ attention? For researchers and investors, this is a complex question, because technology is evolving rapidly, and new data are available every minute, and new effective immunotherapies may emerge at any time. But for the vast majority of Chinese patients, not only do they need the therapy to be effective, they should also be concerned about whether it has been approved in China or abroad. This makes the answer much simpler. For most patients with solid tumors, the focus now is on “immune checkpoint inhibitors”. Immune checkpoint inhibitors are a class of drugs, of which three are currently available abroad: PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors. These drugs are effective in some solid tumors (such as lung cancer, melanoma, kidney cancer, bladder cancer, head and neck cancer) and Hodgkin’s lymphoma. Immune checkpoint inhibitors, especially PD-1 inhibitors, have been marketed abroad, clinically used for several years, and approved for many indications, so many times, when people say immunotherapy, they actually mean immune checkpoint inhibitors. For example, the recent conference on immunotherapy for lung cancer in China specifically pointed out that the current clinical talk about immunotherapy for lung cancer is equivalent to immune checkpoint inhibitors. Another immunotherapy that is more niche, still in the trial stage, but worthy of attention for blood cancer patients is CAR-T cell therapy. However, it is not yet available and there have been no major breakthroughs in treating solid tumors, so it is not appropriate for most patients. It is worth mentioning that lymphoma is unique in that it has some characteristics of both hematologic cancers and solid tumors, and depending on the subtype, both immune checkpoint inhibitors and CAR-T therapies may be effective. III. How does immunotherapy actually work? Immune cells are the protectors of our body and can normally remove the “cancer cells” that are not good at all. There are two important steps for immune cells to remove cancer cells, the first step is to identify and the second step is to destroy. First is recognition. Immune cells need to recognize some superficial characteristics of tumor cells and find out that they are bad guys. This is like a patrolman who determines if a person on the street is a gangster from comprehensive appearance information such as hair style, clothing, and tattoos. Then comes the elimination. It is not useful for the police to just know that a person is a gangster, they also need to be able to eradicate them. By the same token, immune cells cannot just find cancer cells, they also need to remove it. The occurrence of cancer means that the regulatory role of immune cells has failed, which is called “immune escape”. At least one of these two steps, recognition and elimination, has gone awry. In some cases, “recognition” can be a problem because cancer cells are disguised to look like good people and immune cells cannot recognize them. Other times, there is a problem with the “elimination” step. The immune cells clearly recognize the cancer cells, but they do not react to them and become the “onlookers and eaters”. Usually, this is because cancer cells are smart enough to send various signals to immune cells to inhibit their activity. It’s like a bad guy giving a gift to the police to get them to “get off on the wrong foot”. Immunotherapy is to repair these defects and help immune cells to recognize cancer cells or help immune cells to destroy cancer cells. The previously mentioned CAR-T immunotherapy is mainly to help identify cancer cells, while the immune checkpoint inhibitors are mainly to help destroy cancer cells. IV. What is the principle of immune checkpoint inhibitors? Immune checkpoint inhibitors are currently the most popular immunotherapy because they have a wide range of indications and are effective to varying degrees in many solid tumors. There are three types of immune checkpoint inhibitors that have been marketed abroad, which are CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors, according to the time of marketing. Compared to CTLA-4 drugs, PD-1/PD-L1 inhibitors have fewer side effects and better overall efficacy. It is now widely believed that they will become the backbone of cancer treatment in the future. So how exactly do immune checkpoint inhibitors like PD-1/PD-L1 work? Simply put, they help immune cells that have already recognized cancer cells but are in a state of “eating the crowd” to regain their fighting power. PD-1/PD-L1 are two proteins whose normal function is to prevent immune cells from accidentally injuring normal cells. Normal cells express PD-L1 on the surface and immune cells express PD-1 on the surface, they are a pair of lovebirds, once combined, immune cells know that the other is a good cell. But this mechanism is learned by some smart cancer cells and becomes a key set up for cancer cells to suppress immune cells. Cancer cells bind PD-1 on the surface of immune cells by expressing large amounts of PD-L1 protein, thus tricking immune cells into sending a wrong signal: the other side is a good cell, don’t kill it. PD-1 inhibitor or PD-L1 inhibitor, the principle of action is very similar, that is, to break the inhibition by forcibly separating the two. After the inhibition is removed, the immune cells will attack the cancer cells like a chicken blood. V. Do I need to do gene sequencing to use immunotherapy? Before using targeted drugs, we need to do genetic sequencing, and only patients who carry specific genetic mutations are recommended to use certain targeted drugs. For example, EGFR mutations should be tested before using EGFR-targeted drugs, and ALK fusions should be tested before using ALK-targeted drugs. Is genetic sequencing also necessary before using immunotherapies, such as PD-1 inhibitors? Not really. The relationship between the immune system and gene mutations is complex and it is not possible to predict the effect of immunotherapy with a simple genetic test. Some would recommend testing the amount of PD-L1 protein in tumor tissue prior to the current use of PD-1 inhibitors. It has been found that patients with high PD-L1 protein expression have a higher chance of responding to PD-1 inhibitors and have better outcomes. This is actually quite understandable, since the role of PD-1 inhibitors is to beat the PD-1 and PD-L1 pair of lovebirds, theoretically the more lovebirds (the higher PD-L1 expression), the better the effect of the fight. Many clinical trials have demonstrated that patients with high PD-L1 expression have better outcomes with PD-1/PD-L1 inhibitors. However, the prediction of efficacy with PD-L1 alone is not perfect. On the one hand, some patients with high PD-L1 expression do not have significant efficacy, while on the other hand, a few PD-L1 negative patients still have some efficacy. How to find better “efficacy predictive markers” (biomarkers) to screen appropriate patients for PD-1/PD-L1 inhibitors is currently the hottest research topic in the whole field of tumor immunotherapy. Preliminary studies have recently shown that patients with a high number of tumor gene mutations, small individual tumors, and the more immune cells are activated after drug use have better efficacy with PD-1/PD-L1 inhibitors. These findings still need to be verified in larger scale patients, but there is reason to believe that cancer immune precision medicine will definitely come closer and closer to us.