Immunotherapy is now a hot spot for cancer treatment, and immune checkpoint inhibitors against PD1/PD-L1 have been widely used clinically. At present, there are eight PD-1/PD-L1 inhibitors on the market in China. Imported PD1 inhibitors include Pembrolizumab (Drug K), Nivolumab (Drug O), and the domestically produced one is Terip Lizumab, carrelizumab, tislelizumab. The imported PD-L1 is Duvalizumab (I drug) and Atelizumab (T drug). It can be seen from the above eight immunotherapy drugs that have been on the market that there is still no domestically produced PD-L1 inhibitor on the market. It is worth celebrating that this situation is about to be broken, and the domestic PD-L1 inhibitor CS1001 will be launched soon. CS1001 is the country’s first natural full-length, fully human-derived anti-PD-L1 innovative monoclonal antibody that is independently developed by a domestic pharmaceutical company and has completely independent intellectual property rights. In July 2017, CS1001 received the clinical trial approval issued by the State Food and Drug Administration. In more than two years, CS1001 has shown good anti-tumor activity and tolerance in phase I clinical trials of multiple cancer types. CS1001-302 is a phase III clinical study for non-small cell lung cancer. The study included nearly 500 patients with non-small cell lung cancer with histological subtypes of squamous cell carcinoma and non-squamous cell carcinoma, all of which were not first-line Treatment of advanced non-small cell lung cancer. PD-L1 expression is ≥1% or <1%. The test method is CS1001+ chemotherapy group versus placebo+ chemotherapy group. The results of the study showed that among all patients with squamous and non-squamous NSCLC, the median progression-free survival of the CS1001+ chemotherapy group was 7.8 months, and the median progression-free survival of the placebo+ chemotherapy group was 4.9 months. Progression-free survival was significantly prolonged and the risk of disease progression and death was reduced by 50%; subgroup analysis showed that patients with squamous and non-squamous NSCLC, PD-L1 expression ≥1% and PD-L1 expression <1% were both Shows clinical benefit. (Progress-free survival refers to the time period during which the tumor does not increase or shrink during the treatment process. This is the most valuable and valuable observation indicator for the patient’s quality of life.) In terms of adverse reactions, CS1001 combined with chemotherapy is safe. No new safety signals were found. At present, there is no domestically produced PD-L1 monoclonal antibody on the market, and there is no PD-L1 monoclonal antibody approved for the first-line treatment of advanced (stage IV) non-small cell lung cancer. If CS1001 is launched, it will become the world’s first PD-L1 monoclonal antibody. Anti-combination chemotherapy first-line treatment for domestic immune drugs for squamous and non-squamous non-small cell lung cancer. Based on the Phase III clinical study of CS1001-302, R&D pharmaceutical companies are about to submit an application for CS1001 to the National Medical Products Administration for the first-line treatment of advanced non-small cell lung cancer. It is believed that it will benefit patients with advanced lung cancer soon. For patients, the best medicine is used. The team of immunotherapy drugs for lung cancer continues to grow. The more intense the competition, the more room for price reduction.
Is PD-L1 expression level a reliable biomarker for immunotherapy? Immunotherapy has developed rapidly in recent years, including PD-1/PD-L1 immune checkpoint inhibitors, CTLA-4 inhibitors, CAR-T and so on. Among them, PD-1/PD-L1 immune checkpoint inhibitors are the main ones. The overall effective rate of immunotherapy for patients with advanced tumors is 15%-65% (related to tumor types), most of which are 20-30%. Although immunotherapy shows the characteristics of long effective time, but the effective rate is low. Strictly speaking, the curative effect is far from everyone’s expectations. A few days ago, a patient with advanced lung cancer was resistant to targeted drugs. The family members consulted about the efficacy of immunotherapy and objectively told him about the possible effectiveness. This family member who was not in a good family condition decisively gave up immunotherapy. Now that anti-tumor therapy has entered the era of precision therapy, how to screen out potential immunotherapy effective populations is very important. What are the reliable biomarkers for immunotherapy? Is the PD-L1 expression level necessarily a reliable biomarker? As an important tumor immune escape mechanism, the expression of PD-L1, especially the expression of PD-L1 in tumor cells, reflects to a certain extent the presence of neoantigens and tumor immune surveillance in the tumor itself. Therefore, in theory, the evaluation of PD-L1 expression level has a high predictive effect in PD-1/PD-L1 blocker immunotherapy. A number of studies have also shown that whether it is immunization single drug or immunization combined with first-line chemotherapy, the efficacy of PD-1/PD-L1 inhibitors is closely related to the expression level of PD-L1. However, in actual clinical applications, this expression level only exerts its due value in predicting the efficacy of some tumors, such as non-small cell lung cancer. The reasons include two aspects: 1. Due to the heterogeneity of tumors, the expression of PD-L1 in different locations of the same lesion and between different lesions is different; in different stages of treatment, different treatment methods will also affect PD -L1 expression. Therefore, in clinical use, we will find that PD-L1 positive is not necessarily effective. Conversely, negative is not necessarily ineffective. 2. The detection of PD-L1 is quite different and there is no “gold standard” for reference. The reliability of the results detected by some companies is questionable. PDL1 can only guarantee accuracy through daco22c3 platform testing, and testing must be organized. In short, PD-L1 is not a perfect biomarker for predicting immunotherapy, but it can be used as a reference. At present, other biomarkers are usually combined to make comprehensive judgments in clinical practice, including tumor mutation burden (TMB), mismatch repair defect/high microsatellite instability (dMMR/MSI-H) and T cell inflammatory gene expression profile GEP. Studies have shown that CTC (circulating tumor cells) can be used to achieve dynamic monitoring of PD-L1 expression levels. A study published in “Oncoimmunology” recruited 36 patients with advanced gastrointestinal tumors treated with PD-1 monoclonal antibody. The “tumor catcher” technology was used to test the CTC before and after the treatment of the patients. The results found that the peripheral blood Patients with PD-L1 highly expressing CTCs are more likely to benefit from PD-1 drugs, and the higher the proportion of such cells, the higher the response rate. The researchers said that the proportion of CTCs with PD-L1 high expression (PD-L1high) can be used to predict the effect of PD-1 monotherapy.
In 2018 ASCO, the results of M7824 second-line treatment of advanced NSCLC were announced, and the overall response rate ORR of PD-L1 positive patient population (PD-L1>1%) reached 40.7% (n=11/27). The ORR of patients with high PD-L1 expression (PD-L1>80%) is as high as 71.4% (n=5/7)! In the 2018 financial report disclosed by GSK, the ORR of M7824 in the treatment of NSCLC in the second-line therapy reached 86%, setting a new high in the history of immune single-drug efficacy! And this year, the results of the Phase I open and ongoing clinical trial (NCT02517398) released by JTO have reached a new high. M7824500mg/1200mg is used to treat advanced NSCLC (non-small cell lung cancer) patients (78.8% of patients who have previously received platinum-based chemotherapy). First-line treatment, the rest have received second-line and above treatment options). The results showed (1) In patients with high PDL1 expression, the ORR can reach 61.5%, and the ORR in the 1200 mg group even soared to 85.7%! The efficacy of M7824 is based on the increased expression of PDL1, and the benefits are becoming more and more obvious. (2) The overall survival (OS) trend is also the same, the OS of all patients was 13.6 months, the median OS of the 500 mg and 1200 mg groups were 10.9 months and 15.6 months, respectively, and the 12-month survival rate was 44.6 % And 65.5%. In the 1200 mg group, the OS of patients with positive and high expression of PDL1 was not achieved.  . .
Understand PD1/PD-L1 in three minutes. 1: T lymphocytes in the human body are immune cells that can recognize and kill tumor cells; PD-1 is a regulatory protein of T lymphocytes, but inhibits the immune killing of lymphocytes. Benefits It is to prevent T lymphocytes from killing normal human cells. The disadvantage is that it reduces the killing effect of T lymphocytes on tumors, which leads to tumors; 2: PD-L1 is a ligand protein produced by tumor cells, which can interact with T lymphocytes. The combination of PD-1 cells suppresses the immune recognition function of T lymphocytes, so that T lymphocytes will not kill tumor cells with PD-L1, so that tumors can grow smoothly; 3: based on the above In principle, the PD-1 antibody can specifically bind to PD-1, thus eliminating the immunosuppressive regulation of T lymphocytes, so that T lymphocytes can kill tumor cells; 4: The PD-L1 antibody is Can be combined with tumor cell PD-L1, so that tumor cell PD-L1 can not be combined with lymphocyte PD-1, the immune function of lymphocytes can be restored normally, killing tumor cells. 5: There are currently two commonly used PD1 inhibitors, one is the O drug: Nivolumab. The other is the K drug: Keytruda. It is currently available in China. Generally, before using O and K drugs, it is recommended to conduct genetic testing to evaluate the efficacy of PD1/PD-L1.  .
Acute leukemia can be divided into two major categories: acute lymphocytic leukemia (emergency, ALL) and acute nonlymphocytic leukemia (emergency, non-lymphatic, ANLL). According to the FAB classification standard revised in 1985, ANLL is divided into 7 types such as M1-M7, which are: M1: undifferentiated myelocytic leukemia. M2: partially differentiated myelocytic leukemia. M3: acute promyelocytic Cell leukemia. M4: acute myelocytic and monocyte leukemia. M5: acute monocyte leukemia. M6: acute red blood disease or erythroleukemia. M7: acute megakaryocytic leukemia. According to FAB morphological characteristics, ALL is divided into three types: L1, L2, and L3. Type L1: primitive lymphocytes have uniform round nuclei and less cytoplasm. Type L2: primitive lymphocytes vary greatly, the nucleus may be irregular, and the cytoplasm is more than L1. Type L3: primitive lymphocytes have smaller nuclear staining The cytoplasm is blue to dark blue with vacuoles formed. In addition, according to immunological characteristics, AI can be divided into two categories of T cells and B cells, and then divided into multiple subtypes. Except that the L1 type emergency shower is necessarily a B-cell type acute shower, there is no obvious correlation between the morphological classification of acute shower and immunological classification.