Tumor immunotherapy is to stimulate and enhance the body's immune function to achieve the purpose of controlling and killing tumor cells. Tumor immunotherapy is one of the most promising research directions in the field of cancer therapy.
In the past Nobel Prize winners of the Nobel Prize in Medicine, the treatment of cancer has been overwhelming, and everyone is optimistic. Although the final award was won by the Japanese molecular biologist, Otsuka Ryo, in the study of cellular autophagy, tumor immunotherapy still remains. I got quite a lot of attention and affirmation.
PD-1 (programmed death-1) is obtained in apoptotic T cell hybridoma, which is named Programmed Death-1 Receptor because of its association with apoptosis. PD-1 Programmed Death Receptor is An important immunosuppressive molecule that is a member of the CD28 superfamily. PD-1 is mainly expressed in activated T cells and B cells and is a surface receptor of activated T cells. Shanghai Chuangsai Technology provides recombinant human PD-L1, rHu PD-L1-Fc protein, brand: Bofei Metco, commodity number: C22-100-84f-500μg, price 8850 yuan.
PD-1 has two ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). The tumor microenvironment in the body induces high expression of PD-1 molecules in infiltrating T cells, and tumor cells highly express PD-1 ligands PD-L1 and PD-L2, resulting in continuous activation of the PD-1 pathway in the tumor microenvironment. When PD-L1 is linked to PD-1, T cell function is inhibited and a signal to attack the tumor cannot be issued to the immune system. PD-1/PD-L1 inhibitors block the binding of PD-1 to PD-L1, block negative regulatory signals, and restore T cells to activity, thereby enhancing the immune response. Inhibitors of PD-1 and PD-L1 are highly effective in a variety of tumors. This article briefly introduces the current status of PD-1/PD-L1 inhibitors and the research progress on the clinical efficacy of malignant tumors, especially lung cancer.
I. Research status of PD-1/PD-L1 inhibitors
1. Pembrolizumab (Keytruda) pembrolizumab is a high affinity humanized IgG4-kappa antibody that binds to PD-1. The US Food and Drug Administration (FDA) approved pembrolizumab for the treatment of advanced or unresectable melanoma that is unresponsive to other drugs. A phase I clinical trial (KEYNOTE-001) for the treatment of non-small cell lung cancer (NSCLC) alone showed that the toxic side effects of pembrolizumab are often accepted by patients, with a lower rate of grade 3 to 5 adverse events, and patients with advanced NSCLC It is well tolerated, and the effect of patients with high expression of PD-L1 in tumor cells is improved. Currently, the FDA has approved non-small cell lung cancer for the treatment of previous chemotherapy or targeted therapy failure, and is the first immunotherapeutic drug approved for non-small cell lung cancer.
2, nivolumab (Opdivo) nivolumab is a monoclonal drug against PD-1, developed only as a second- or third-line treatment. Nivolumab is now approved by the FDA for second-line treatment of squamous cell lung cancer. Studies have shown that the therapeutic effects of pembrolizumab and nivolumab are similar. The study evaluated the expression of PD-L1. Although the scoring criteria were different, the results were similar. The effect of PD-L1 expression was more obvious. At present, nivolumab has been marketed in Japan, and the indication is melanoma, and its indication for submitting a marketing application in the United States is non-small cell lung cancer. In addition, indications for phase III clinical trials include renal cell carcinoma.
3, other
The PD-L1 inhibitor avelumab (MSB0010718C) is a fully humanized PD-L1 IgG1 antibody that inhibits the binding of PD-1 to PD-L1. Early studies suggest that its anti-tumor mechanism may also be associated with antibody-dependent cell-mediated cytotoxicity and can be used for the treatment of ovarian cancer and gastric cancer. Currently, avelumab is also used to try to treat a variety of solid tumors, especially non-small cell lung cancer and Merkel cell carcinoma.
MP-DL3280A (RG7446) is a monoclonal antibody against PD-L1 and is indicated for PD-L1 positive patients. Studies have shown that the overall response rate in patients with NSCLC reaches 23%, the rate of remission is higher in smokers, and in patients with advanced triple-negative breast cancer. Shanghai Chuangsai Technology provides recombinant human PD-L1, rHu PD-L1-Fc protein, brand: Bofei Metco, commodity number: C22-100-84f-500μg, price 8850 yuan.
Durvalumab (MEDI4736) is a PD-L1 inhibitor for the treatment of non-small cell lung cancer in phase III clinical trials. The treatment of melanoma is in Phase I clinical studies. A phase I clinical trial showed that the response rates of durvalumab to PD-L1 positive and negative patients were 39% and 5%, respectively. Currently durvalumab is also used in the Lung-MAP trial driven by biomarkers of advanced squamous cell carcinoma.
Pidilizumab is a human-derived IgG-1 kappa recombinant monoclonal antibody against PD-1 and is currently in Phase II clinical trials, including large B-cell lymphoma, glioma, and multiple myeloma. Studies have shown that pidilizumab combined with rituximab is effective in the treatment of recurrent follicular lymphoma, and patients are well tolerated. MSB0010718C is a PD-L1 inhibitor currently in Phase I clinical stage, and ongoing indications include breast cancer, colon cancer, and kidney cancer.
Both AMP-514 and AMP-224 are currently in Phase I clinical trials. Clinical indications planned for AMP-514 include advanced malignancies. The clinical indications for AMP-224 are mainly advanced tumors, including melanoma, cutaneous T-cell lymphoma, and uncertain solid tumors.
Second, the clinical efficacy of PD-1/PD-L1 inhibitors on different tumors
1. In the clinical study of non-small cell lung cancer non-small cell lung cancer (NSCLC), nivolumab and pembrolizumab showed higher activity in patients treated with NSCLC and other patients. Nivolumab treatment of NSCLC patients can achieve a total response rate of 17%, the duration of remission can reach more than 18 months. All dose studies showed a median overall survival of 9.2 months in patients with squamous cell carcinoma and a median overall survival of 10.1 months in patients with non-squamous cell carcinoma.
The total remission rate of pembrolizumab (Keytruda) can reach 21%. The overall response rate for PD-L1-positive NSCLC patients was 19% to 23%, and the overall response rate for PD-L1-negative NSCLC patients was 9% to 13%. Therefore, tumors expressing PD-L1 are more sensitive to these drugs, but there is also a remission in patients with PD-L1 negative. The total response rate of the PD-L1 inhibitor MEDI4736 in all NSCLC patients reached 23%. The results of Phase I clinical trials showed that the response rates for PD-L1 positive and negative patients were 39% and 5%, respectively.
Therefore, MEDI4736 has a higher remission rate in PD-L1 positive patients. In addition, in 287 patients with NSCLC, patients with high PD-L1 expression were significantly more effective than docetaxel in receiving MPDL3280A. The ORR and PFS were 38% vs. 13%, 9.7 months vs. 3.9 months, respectively. Comparing PD-L1 positive and PD-L1 negative patients, ORR and PFS were: 18% vs. 8%, 3.3 months vs. 1.9 months, respectively. Therefore, MPDL3280A is more effective in treating PD-L1 positive patients.
2, malignant pleural mesothelioma pleural mesothelioma (pleuralmesothelioma, PM) is a rare, invasive malignant tumor originating in the pleural mesothelial, treatment options are extremely limited. A phase Ib clinical trial showed that in 25 patients with pleural mesothelioma, the overall response rate (ORR) was 28% after receiving keytruda, and 48% of patients were stable and had a disease control rate of 76%. More than 20% of patients had treatment-related adverse events, including fatigue (24%) and nausea (24%). There were no discontinuations in treatment-related adverse events and no treatment-related deaths in the study [30]. Therefore, keytruda has a good effect in the treatment of malignant pleural mesothelioma.
Third, the outlook
With the introduction of the concept of precision medicine, research on the relationship between immunotherapy and tumor gene mutation has received more and more attention. PD-1/PDL1 immunotherapy is currently a high-profile anti-cancer immunotherapy designed to use the body's own immune system to fight tumors and block tumor cells by blocking PD-1/PD-L1 signaling pathway. Many types of tumors. Research institutions have gradually carried out corresponding clinical projects to investigate monotherapy and combination therapy for the treatment of various cancers in order to explore the clinical value of such drugs.
At present, opdivo has been applied to melanoma in Japan, melanoma and non-small cell lung cancer in the United States, melanoma indications in the EU, and opdivo for lung cancer treatment has been supported by EU CHMP. Merck's keytruda has been approved for melanoma indications in the United States and is expected to be approved recently for non-small cell lung cancer indications. At the same time, the keytruda melanoma application has been supported by CHMP. AstraZeneca's MEDI4736 and Roche's RG7446 have not yet received any indications. EvaluatePharma, a world-renowned pharmaceutical market research organization, predicts that opdivo will be one of the most successful PD-1 immunotherapy.
The research and development of new targets is the trend of current antibody research. At present, research on PD-1/PD-L1 is concentrated, and the development of new targets is lacking. At the same time, with the combination of tumor treatment, the "immunotherapy +" model is becoming more and more clear, and it will become the direction of future cancer treatment. The current survival period of 2.5 to 6 months can only be considered clinically meaningful, and it is yet to be studied which combination of drugs can reach this new standard. A variety of clinical trials should be conducted in depth to discover the optimal drug regimen for immunotherapeutic drugs, providing a basis for safe, effective, and rational drug use.
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