A Brief Introduction to Immunotherapy v1
Authors: Brown Alex 
Published: April 2019

Immunotherapy is gaining increasing attention, especially in recent decades. The reason of its prevalence lies in the two following facts: Immunotherapy can treat advanced cancer that has been widely metastatic. Advanced cancer patients who failed in some standard therapies still achieved good results after using immunotherapy. Immunotherapy has a "survival period extending effect", that is to say, patients who respond to immunotherapy have a high chance of long-term survival. These late-stage cancer patients who were once sentenced to death are often referred to as “super survivors”! In patients with melanoma, lung cancer, kidney cancer, and children with acute leukemia, immunotherapy has created a number of "super survivors". Many of the patients who received immunotherapy treatment have survived for more than 10 years! The extending of survival period is the biggest difference between immuno-medicine and targeted drugs. Most targeted drugs can rapidly shrink tumors and significantly improve the quality of life of patients in the short term. However, it is difficult for targeted drugs to get rid of drug resistance problems. How does immunotherapy work? Immune cells are the protectors of our bodies. Under normal circumstances, they can eliminate the "cancer cells" at first glance. Two important steps are required for immune cells to clear cancer cells. The first step is identification and the second step is elimination. Identification. Immune cells need to recognize some of the surface features of tumor cells and identify it to be a bad guy. Elimination. After identification, the second task for immune cells is to eradicate those cancer cells. The occurrence of cancer indicates that the regulatory role of immune cells has failed, which is called "immune escape." Something in the two steps of identifying and eliminating must have gone wrong. In some cases, “recognition” can cause problems, because cancer cells are disguised and immune cells just simply cannot recognize them. There are also times when the "destroying" step went wrong. The immune cells clearly recognize the cancer cells, but they do not react at all. Usually, this is because cancer cells are smart enough to send various signals to immune cells to suppress the activity of immune cells. The goal of immunotherapy is to repair these defects, help immune cells recognize cancer cells, or help immune cells eliminate cancer cells. Among the two immunotherapies, CAR-T immune cell therapy mainly helps to identify cancer cells, while immune checkpoint inhibitors mainly help to eliminate cancer cells. What is the mechanism of an immune checkpoint inhibitor? Immune checkpoint inhibitors are currently the most popular immunotherapy because of its wide range of indications and varying degrees of effect in many solid tumors. At present, there are three types of immune checkpoint inhibitors that have been marketed abroad, namely, CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors. Compared with CTLA-4 drugs, PD-1/PD-L1 inhibitors have fewer side effects and are more effective overall. It is now widely believed that they will become the backbone of future cancer treatment. Then how does immune checkpoint inhibitor such as PD-1/PD-L1 work to have a therapeutic effect? In simple terms, immune checkpoint inhibitors work by helping the immune cells that have recognized the cancer cells yet take no action to regain the power of killing cancer cells. The PD-1/PD-L1 inhibitors are usually used to prevent immune cells from injuring normal cells. PD-L1 is expressed on the surface of normal cells, and PD-1 is expressed on the surface of immune cells. But this mechanism has been learned by some clever cancer cells, which provides a way for cancer cells to suppress immune cells. Cancer cells express a large amount of PD-L1 protein that binds to PD-1 on the surface of immune cells. This deceives the immune cells and sends a false signal: the other is a good cell, don't kill it. Either for PD-1 inhibitor or for PD-L1 inhibitor, the MOA is very similar. By inhibiting the binding of the two, the suppression on immune cells is eliminated. Other immune checkpoint proteins (targets) found on T cells or cancer cells include: IDO• TDO• KIR• 4-1BB(also known as CD137)• OX40 (also known as CD134)• LAG3• B7‑H3(also known as CD276)• TIM3• TIGIT• BTLA• VISTA• ICOS• CD39• CD27• CD30(also known as TNFRSF8)• CD28• B7-H4(also known as B7‑S1, B7x and VCTN1)• HHLA2• Galectins• CD155 Do you need to do genetic sequencing before using immunotherapy? Before using targeted drugs, we need to first perform gene sequencing. Only patients with specific gene mutations are recommended to use certain targeted drugs. For example, EGFR gene mutations should be detected before using EGFR-targeted drugs, and ALK gene fusion should be detected before using ALK-targeted drugs. Do you have to do genetic sequencing before using immunotherapy, such as PD-1 inhibitors? The answer is NO. The relationship between the immune system and gene mutations is complex, and it is currently impossible to predict the effects of immunotherapy with simple genetic testing. Before the use of PD-1 inhibitors, some will recommend the detection of the amount of PD-L1 protein in tumor tissues. The study found that patients with high PD-L1 protein expression were more likely to respond to PD-1 inhibitors and would be better. This is actually very easy to understand. Since the role of PD-1 inhibitors is to fight against PD-1 and PD-L1, the higher the PD-L1 expression, the better the effect. Many clinical trials have demonstrated that patients with high expression of PD-L1 are better with PD-1/PD-L1 inhibitors. However, the expression extent of PD-L1 is not the only predicting diameter. On the one hand, some patients with high expression of PD-L1 are not effective. On the other hand, a small number of PD-L1 negative patients still have a certain effect. How to find better "effect predictor markers" (biomarkers) so as to make it possible to screen for appropriate patients using PD-1/PD-L1 inhibitors is currently the hottest research topic in the field of tumor immunotherapy. Recently, preliminary studies have shown that better effects will be achieved using PD-1/PD-L1 inhibitor when the number of tumor gene mutations is larger, and when the tumor size is small. These findings also need to be validated on more patients, but there is reason to believe that cancer immunotherapy and precision medicine will definitely get closer to us.