Administration of anti-CD19 chimeric antigen receptor (CAR)-modified T cells for B-cell malignancies has been remarkably effective in recent clinical trials. To investigate the critical parameters affecting efficacy and evaluated the safety of using CAR T cells targeting CD19 in B-lineage malignancies. We performed a systematic review of reported phase I clinical trials using CAR T cells targeting CD19 in B-lineage malignancies.We searched Medline and Embase for studies on anti-CD19 CAR-modified T cells in patients with B-cell malignancies in October 2014. Univariate analyses were performed using the Kaplan-Meier method, and a Cox regression model was used to determine the independent prognostic factors of progression-free survival (PFS).Six trials involving 50 patients were included in this review. After CAR T-cell infusion, the overall response rate was 48% (complete responses in 24%). The 6-month PFS and 1-year PFS were 43% and 27%, respectively. Statistically significant factors favorably influencing PFS were conditioning chemotherapy (P < 0.001), B-cell aplasia (P = 0.040), and durable persistence of CAR T cells (P = 0.013) in univariate analyses. After multivariate analysis, conditioning chemotherapy remained as an independent prognostic factor for PFS. The most common adverse events were fever, hypotension, rigor, fatigue, bacteremia, chill, dyspnea, and headache, but all were temporary and resolved.Anti-CD19 CAR-modified T cells have shown therapeutic efficacy in patients with B-lineage malignancies and were well tolerated in most patients. Conditioning chemotherapy is a prerequisite to improve the clinical outcome.
This paper introduces a new technique for assessing the diversity of approximation of exact set. The diversity is assessed by the exposure degree of the exact set against the approximation set in the new technique where the projection of the approximation set on the exact set, not the approximation set, is used to cover the exact set. Therefore, the new technique still works well for the problems with 3 and more objectives, significantly improving the existing techniques. Computational results show that it assesses the diversity well. Rigorous analysis
To study the impact of the nursing model based on the interactive model of health behavior (IMCHB) on the self-efficacy and negative emotions of prostate cancer patients.
Gastrointestinal (GI) perforation is a serious adverse event associated with aflibercept, a novel vascular endothelial growth factor (VEGF)-targeted agent currently approved as second-line treatment for previously treated metastatic colorectal cancer, but the incidence and risk of GI perforation associated with aflibercept has not been well determined. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing GI perforation associated with aflibercept. Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meeting up to January, 2014 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating aflibercept in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio, and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. A total of 4,101 patients with a variety of solid tumors from eight clinical trials were included in our analysis. The incidence of GI perforation associated with aflibercept was 1.9% (95%CI, 1.0-3.8%), with a mortality of 10.8% (95%CI, 4.1-25.5%). In addition, patients treated with aflibercept had a significantly increased risk of developing all-grade (OR 3.76; 95%CI, 1.94-7.25; p < 0.001) and high-grade GI (OR 4.14; 95%CI; 2.12-8.06; p < 0.001) perforation compared with patients treated with control medication. No evidence of publication bias was observed. The use of aflibercept is associated with a significantly increased risk of GI perforation compared to controls.
Objective
To explore the safety and efficacy of chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory acute B-cell lymphoblastic leukemia (B-ALL) with T315I mutation.
Methods
The clinical data of a patient with relapsed/refractory B-ALL with T315I mutation who underwent CAR-T therapy in the Second Affiliated Hospital of Anhui Medical University was analyzed, and the related literature was reviewed.
Results
The patient was a 34-year-old man. He was diagnosed with chronic myelogenous leukemia (CML) in January 2017 and started to take imatinib orally. However, the primary affection transformed to B-ALL 4 months later. Because of the E355G gene mutation, the treatment drug was adjusted to dasatinib, and induction chemotherapy was given at the same time. The sequential consolidation chemotherapy was given for 3 times after complete remission (CR). After half a year of remission, T315I mutation was detected and re-induced chemotherapy was given, but ineffective. The patient was treated with CAR-T 3 days after FC regimen (fludarabine 30 mg/m2 per day, day 1 to day 3; cyclophosphamide 200 mg/m2, day 1 to day 3). The number of CD19 CAR-T was 1.0×109, 98% activity degree. Grade 1 cytokine-releasing syndrome appeared after infusion, and was resolved after symptomatic treatment. No serious adverse reactions were observed. CR was achieved half-month after CAR-T treatment, and umbilical cord blood transplantation was successfully performed 1 month later. At the last follow-up, the relapse-free survival time of the patient was 396 days.
Conclusion
CAR-T therapy may be a new, safe and effective therapy for patients with relapsed/refractory B-ALL with T315I mutation.
Key words:
Leukemia, B lymphocyte, acute; T315I mutation; Chimeric antigen receptor T-cell
Objective To investigate the relationship between polymorphism at C3435T of ABCB1 and serum and cerebrospinal fluid(CSF) P-gp expression in Han people with epilepsy.Methods 118 cases of Han people with epilepsy were collected in the study,which included 57 cases of antiepileptic drugs(AEDs) sensitive patients and 61 cases of AEDs resistant patients.CC genotype in epilepsy patients was 39,and non-CC genotype patients was 79.ELISA method was used to detect the P-gp in serum and cerebrospinal fluid,and ABCB1_C3435T genotypes were detected by polymerase chain reaction_restriction fragment length polymorphism(PCR-RFLP) method.Results There was no statistical difference in P-gp in serum or CSF or the ratio of serum P-gp and CSF P-gp between epilepsy patients with non-CC genotype and patients with CC genotype,CC genotype or non-CC genotype AEDs sensitive and resistant patients(all P0.05).Conclusion There is no relationship between ABCB1_C3435T polymorphism and P-gp expression and AEDs tolerance in Han people with epilepsy.
Aurora kinase B (AURKB) is a type of functional kinase with primary functions of participating in cell mitosis, which has been identified to be involved in the occurrence and development of malignant tumors strongly. However, it still remains a controversial with respect to the relationship between the phosphorylation level of AURKB and its function. In our initial research, there was no significant difference in the relative content of AURKB protein between drug-resistant breast cancer cells and wild-type cells; however, its phosphorylation level in drug-resistant cells was significantly higher than that in wild-type cells. Subsequent cell and animal experiments both confirmed the positive correlation between AURKB phosphorylation and drug resistance. Furthermore, PRKCE in the upstream was identified to regulate the phosphorylation of AURKB, which promoted the change of spatial localization of AURKB from nucleus to cytoplasm. Accordingly, phosphorylated AURKB reduced the negative regulation of downstream RAB27B transcription physically, and interacted with RAB27B in cytoplasm to maintain its protein stability. Eventually, it promoted exosome secretion of drug-resistant cells and drug efflux. Using shRNA to knockdown AURKB expression, using hesperadin to inhibit AURKB activity, mutating the AURKB phosphorylation site, or using siRNA as well as BIM to inhibit the activity of the upstream AURKB phosphorylation regulatory protein PRKCE, all of which directly or indirectly reduce AURKB phosphorylation, are effective in reversing PTX resistance in cells. Collectively, this study provides experimental evidence for PRKCE/AURKB/RAB27B axis in regulating the resistance to paclitaxel (PTX) in breast cancer cells, offering a potential intervention target for reversing drug resistance.
Acute GVHD is the primary limitation of allogeneic HSCT. We have previously reported that plasma concentrations of suppressor of tumorigenicity 2 (ST2) at the onset of GVHD therapy predicted response at day (D) 28 and non-relapse mortality (NRM) at D180 after therapy initiation. We hypothesized that ST2 measured early in HSCT would predict GVHD occurrence by D100 and D180 NRM after HSCT. We measured ST2 in plasma taken at D0, D14 and D21 after HSCT in a pilot set. ST2 concentrations at D14 were most different between patients who developed GVHD and those without GVHD, and were twice higher in patients receiving full intensity conditioning (FIC) compared to those receiving reduced intensity conditioning (RIC). We then measured ST2 concentrations at D14 in two independent sets: 1) 598 patients from the University of Michigan (UM), 69% receiving FIC (15% receiving TBI) and 31% receiving RIC HSCT, 2) 75 patients receiving unrelated, FIC (92% receiving TBI) HSCT from the Dana Farber Cancer Institute (DFCI). UM patients who developed GVHD were older and more likely to receive mismatched or unrelated donor HSCT. Median day of GVHD onset was D35 in FIC and D42 in RIC (p=0.08). DFCI patients who received sirolimus as GVHD prophylaxis were over-represented in the no-GVHD group. As ST2 concentrations differed between conditioning intensities, we used 3 models for prediction using the median ST2 concentrations for UM FIC, UM RIC, and DFCI FIC as cutpoints. In multivariate analysis including the age, disease status, donor source, and HLA match, high ST2 predicted the development of GVHD in UM FIC, and trended toward significance in the DFCI set (Table 1 Top). Patients with high ST2 at D14 were at increased risk of D180 NRM for all conditioning intensities, independent of the clinical characteristics (Table 1 Bottom). High ST2 was not associated with increased risk of relapse mortality 1 year after HSCT. In conclusion, high ST2 early in HSCT identifies patients at high risk for acute GVHD and NRM following HSCT. This has therapeutic consequences including increased monitoring and potential preemptive interventions. Table 1ST2 concentrations at D14 predict GVHD development by D100 and predict D180 NRMUM FIC (n = 414)UM RIC (n = 184)DFCI (n = 75)Hazard Ratio (HR)P-valueHRP-valueHRP-valueAge (55 and Over vs. Under 55)1.50.010.80.40.10.02Disease Status (High vs. Low risk)1.00.991.80.02n/aDonor (Unrelated vs. Related)1.9<0.0010.90.7n/aHLA match (Mismatched vs. Matched)2.1<0.0011.00.92.70.09ST2 Concentration (High vs. Low)∗Effect of ST2 calculated with regression models adjusting for age, disease status, donor, and HLA match.†High defined as ST2 concentration >600 pg/mL for UM FIC, >300 pg/mL for UM RIC, >1660 pg/mL for DFCI.1.50.0041.30.32.00.08Age3.1<0.0010.70.40.70.5Disease Status1.10.62.70.02n/aDonor1.50.11.10.8n/aHLA match1.70.060.50.31.90.2ST2 Concentration2.8<0.0014.80.0052.60.04* Effect of ST2 calculated with regression models adjusting for age, disease status, donor, and HLA match.† High defined as ST2 concentration >600 pg/mL for UM FIC, >300 pg/mL for UM RIC, >1660 pg/mL for DFCI. Open table in a new tab
Despite high remission rates following chimeric antigen receptor T cell (CAR-T) cell therapy in B-cell acute lymphoblastic leukemia (B-ALL), relapse due to loss of the targeted antigen is increasingly recognized as a mechanism of immune escape. We hypothesized that simultaneous targeting of CD19 and CD22 may improve the CAR-T effect. The in vitro and in vivo leukemia model was established, and the anti-tumor effects of BiCAR-T, CD19 CAR-T, CD22 CAR-T, and LoopCAR6 cells were observed. We found that the BiCAR-T cells showed significant cytotoxicity in vitro and in vivo. The CD19/CD22 bivalent CAR provides an opportunity to test whether simultaneous targeting may reduce the risk of antigen loss.
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