Effect And Significent Of CAR-T Celltherapy On TH1/TH2 Related Cytokines In Patients With Blymphocytes Malignent Tumor

Research backgroundB-lymphocyte malignant tumor mainly includes acute lymphoblastic leukemia(ALL),chronic lymphoblastic leukemia(CLL)and B-cell lymphoma.Chemotherapy,as a traditional treatment mode,is easy to lead to drug resistance and recurrence,while hematopoietic stem cell transplantation(HSCT)is restricted by the low coincidence rate of gene matching and the high incidence of graft-versus-host reaction(GVRs).In 2017,the United States approved two chimeric antigen receptor T-cell(chimeric antigen receptor t cells,CAR-Tproducts: Novartis’ kymriah and kite’s yescarta,bringing new hope to cancer patients.Prior to this,CAR-T cell technology was certified by the US fda " Breakthrough Therapy" and was hailed as the "fourth Revolution in Cancer Therapy".The CAR-T cells of hematologic b-lymphocyte malignant tumor have aroused great concern in the world at present.In many countries and regions,medical treatment,scientific research institutions have carried out a large number of clinical trials and obtained a lot of achievements.Successful cases mainly focus on CD19-CAR-T cell therapy for B-cell malignant tumor(CD19),including relapsing refractory b-acute lymphoblastic leukemia(b-acute lymphoblastic leukemia,b-all),).At the same time,researchers have applied CAR-T in the treatment of solid tumors such as neuroblastoma,gliomas,and chronic lymphoblastic leukocytosis(chronic lymphocytic leukemia,CLL)and B-cell lymphoma(B-cell lymphomas),).Pancreatic cancer,cervical cancer,osteosarcoma,and so on,also achieved initial results.Despite the many "achievements" of CAR-T therapy,CAR-T therapy also faces many challenges.With the deepening of the study and the increase of clinical samples,more and more studies have found that there are adverse reactions and high recurrence rate of CAR-T.Major side effects include cytokine storms,neurotoxicity and B-cell dysplasia.Although some progress has been made in the prevention and treatment of side effects,it is still the basis of developing new CAR-T cells to explore the mechanism of reducing the side effects and improving the therapeutic effect.In the course of clinical use,due to the short application time of CAR-T cell therapy,a large sample clinical trial should be carried out on its curative effect and prognosis,so that the statistical data can be obtained to guide the determination of clinical treatment plan.The determination of th1/th2 cell-related factors here can be used to evaluate the immune balance of patients and evaluate the efficacy of treatment.AimBy detecting the levels of th1/th2 cytokines in peripheral blood of patients with relapsed or refractory b-lymphocyte tumor treated with CAR-T cells.The determination of Th1/Th2 cytokines can be used to evaluate the immune balance of patients and to guide the treatment of CAR-T.MethodsTen cases of B-lymphocyte malignant tumors were selected,including 6 cases of diffuse large B-cell lymphoma(DLBCL),2 cases of acute lymphoblastic leukemia(ALL).The average age of DLBCL patients was 46.5 years(15-66 years).Among them,5 were males and 1 were females.The average age of ALL patients was 32.5years(17-48 years),including 1 male and 1 female,Peripheral blood was taken on an empty stomach in all patients before and after CAR-T cell IFNusion and day 1,3,7,9,11,14,18,21,25,30,60 days after re-IFNusion,as well as from the early morning of 3 months after IFNusion of car t cells in the patients.Flow cytometry was used to monitor the expression of tregs in peripheral blood and the levels of cytokines Il-2,Il-4,IL-6 Il-10,IFN-γ,TNF in plasma by enzyme-linked immunosorbent assay(elisa).The changes of the patient’s condition and the occurrence of CRS were recorded.Spearman rank correlation analysis was carried out on the data obtained by using the software of matlab.ResultsAfter transfusion of CAR-T cells in 8 patients,7 cases were effective,5 cases got CR and 2 cases got PR.The duration of maintenance was 2-6 months.Two cases had recurrence of CR(1 case survived SD and 1 case had PD1).The median time of CRS reaction was 13 days(10-16 days)after IFNusion of CAR-T cells in 8 patients and 7patients.There are 5 cases were grade 1 CRS,2 cases were grade 3 CRS,with high fever,low blood pressure,abnormal blood coagulation and high expression of IFNlammatory factors.After treatment with IL-6 antibody and glucocorticoid,the fever was improved.CRS duration ranged from 32 to 90 days in all cases.IL-2,IL-6,IL-10,IFN-γ,TNF and other cytokines were significantly increased before CRS occurred,and the more severe CRS,the more obvious the increase of IFNlammatory cytokines,especially IL-6;IL-4,TNF had no significant correlation.IL-2,IL-6,IL-10,IFN-γ,TNF and other cytokines increased significantly in about 7-9 days.CRS,especially severe CRS,occurred more than2 weeks.CRS duration ranged from 32 to 90 days in all cases.IL-6,IL-10,IFN-γ was strongly correlated with CRS grading(rs value was 0.701068,0.783547,0.673575),TNF,IL-2 was moderately correlated with CRS grading(rs value was 0.481125,0.439886),and IL-4 was weakly correlated with CRS grading(r value was 0.288675).ConclusionThe occurrence of cytokine release syndrome(CRS)is related to the elevation of plasma levels of cytokines IL-2,IL-4,IL-6,IL-10,IFN-γ and TNF,especially the elevation of IFN-γ,IL-6 and IL-10,and the severity of CRS is positively correlated with the level of relevant cytokines.Detection of cytokine levels may be an effective monitoring indicator for predicting the occurrence of severe CRS.