免疫检查点抗体 z-bo 2020-09-23 373

　　The successful listing of immune checkpoint inhibitor drugs has changed the pattern of solid tumor treatment and has shown great prospects. As everyone knows, the side effects of immune checkpoint inhibitor drugs can cause a series of problems. The following will sort out the intricate relationship between the toxic effects of immune checkpoint antibody therapy and tumor treatment.

　　Since the anti-CTLA-4 monoclonal antibody ipilimumab for the treatment of metastatic melanoma was approved for marketing, a series of other drugs, especially targeting the PD-1/PD-L1 pathway, have shown good results in the treatment of different types of tumors The clinical effect. Such drugs can reactivate the immune system, but at the same time they can cause new immunotoxic effects, namely immune-related side effects (irAEs). irAEs involve many organs and tissues, and the treatment method is completely different from other cytotoxic drugs. irAEs require treatment with immunosuppressive agents such as adrenocorticoid or tumor necrosis factor TNFα antibody.

　　The appearance of these side effects also triggered the thinking of several key issues.

　　The correlation between drug dose and irAEs: There are currently three trials studying the relationship between irAEs and ipilimumab dose. At 3-10mg/kg, the risk rate of irAEs is not significantly related to the dose; there is currently only one study of antibody drugs against PD-1/PD-L1. When different doses of pembrolizumab are used to treat non-small cell lung cancer, There is no obvious correlation with the occurrence of irAEs.

　　The correlation between irAEs and efficacy: The current clinical efficacy of ipilimumab is inconsistent in the treatment of melanoma. One of the results of the study found that: patients with a relatively high overall treatment response rate all had high-grade irAEs; but when the standard dose of ipilimumab was used, 85% of the patients had irAEs, while there were no irAEs and different grades. There was no significant difference in the efficacy of irAEs in patients with no clinical effect or overall survival. Skin irAEs have a certain relationship with the results of PD-1 treatment of melanoma. Patients with better treatment progress have different types of skin irAEs.

　　The safety of immune checkpoint inhibitors in patients treated for autoimmune diseases: The use of immune checkpoint inhibitors for treatment may cause serious autoimmune diseases. A large number of reports have pointed out that when ipilimumab is used to treat metastatic melanoma, different types of autoimmune diseases, such as rheumatoid arthritis and psoriasis, can be produced. There are not enough data reports on whether treatment with pembrolizumab will produce autoimmune diseases.

　　Steroids control the effect of irAEs on tumor growth: Although there is currently no data to support the possible immunosuppressive effects of steroids, they will have an impact on the anti-tumor effect. A series of studies have shown that when CTLA-4 blockers are used for the treatment of metastatic melanoma, the use of steroids to control irAEs will not have an impact on overall survival. There are not enough data reports on PD-1/PD-L1 or CSF-1R inhibitors.

　　The use of immune checkpoint inhibitors is usually accompanied by short-term immune-related side effects. Most irAEs can be alleviated within a few weeks. The problems caused by these side effects have changed the development of traditional anti-tumor drugs. Treatment with immune checkpoint inhibitors is mainly a switch effect, not a dose effect. At the same time, the maximum tolerated dose has not been determined. More importantly, the challenge of these immunotherapies is to determine the minimum activating dose to better control tumor growth while minimizing related side effects.