ABSTRACT
Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.
Subject(s)
B-Cell Maturation Antigen/immunology , Chemokine CCL19/biosynthesis , Immunotherapy, Adoptive , Interleukin-7/biosynthesis , Multiple Myeloma/immunology , Multiple Myeloma/therapy , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Aged , Animals , B-Cell Maturation Antigen/antagonists & inhibitors , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm , Female , Gene Order , Genetic Vectors/genetics , Humans , Immunologic Memory , Immunophenotyping , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Male , Mice , Middle Aged , Multiple Myeloma/diagnosis , Multiple Myeloma/genetics , Recurrence , Retreatment , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
This study aimed to investigate the therapeutic effect of berberine on renal ischemia-reperfusion injury in rats and its effect on Bax and Bcl-2. Sixty adult SD rats were randomly divided into four groups: control group A, renal ischemia-reperfusion group B, berberine group C and berberine + exendin-(9-39) treatment group D. In group A, right kidney was resected and left renal pedicle was separated, but left renal artery was not blocked. Renal ischemia-reperfusion model was established in other groups. Rats in group C were not subjected to any treatment after model construction. Rats in group C and D were subjected to intraperitoneal injection of berberine 7 days before the experiment. Besides that, intraperitoneal injection of exendin-(9-39) was performed at day 1 and 4 after model construction. Automatic biochemical analyzer was used to measure serum creatinine (SCr) and blood urea nitrogen (BUN). Malondialdehyde (MDA) in renal cortex was measured by enzyme-linked immunosorbent assay and contents of Bax and Bcl-2 in renal tissue were measured by western blot analysis. Apoptosis of rat renal cells was detected by TUNEL assay. The results showed that levels of SCr, BUN, MDA and Bax were significantly higher in group B than in other groups (P<0.05). Levels of Bcl-2 in group B were significantly higher than those in group A but significantly lower than those in group C and D. Compared with group A, apoptosis of renal cells was more severe in group B. Compared with group B, apoptosis of renal cells was significantly improved in group C and D, but was still more severe than that in group A. In conclusion, berberine can effectively improve renal function in rats with renal ischemia-reperfusion injury by inhibiting Bax expression and promoting Bcl-2 expression.
ABSTRACT
BACKGROUND AND OBJECTIVES: Human papillomaviruses have been linked causally to some human cancers such as cervical carcinoma, but there is very little research addressing the effect of HPV infection on human liver cells. We chose the human hepatoma derived cell line Hep G2 to investigate whether HPV gene integration took place in liver cells as well. METHODS: We applied PCR to detect the possible integration of HPV genes in Hep G2 cells. We also investigated the expression of the integrated E6 and E7 genes by using RT-PCR and Western blotting. Then, we silenced E6 and E7 expression and checked the cell proliferation and apoptosis in Hep G2 cells. Furthermore, we analyzed the potential genes involved in cell cycle and apoptosis regulatory pathways. Finally, we used in situ hybridization to detect HPV 16/18 in hepatocellular carcinoma samples. RESULTS: Hep G2 cell line contains integrated HPV 18 DNA, leading to the expression of the E6 and E7 oncogenic proteins. Knockdown of the E7 and E6 genes expression reduced cell proliferation, caused the cell cycle arrest at the S phase, and increased apoptosis. The human cell cycle and apoptosis real-time PCR arrays analysis demonstrated E6 and E7-mediated regulation of some genes such as Cyclin H, UBA1, E2F4, p53, p107, FASLG, NOL3 and CASP14. HPV16/18 was found in only 9% (9/100) of patients with hepatocellular carcinoma. CONCLUSION: Our investigations showed that HPV 18 E6 and E7 genes can be integrated into the Hep G2, and we observed a low prevalence of HPV 16/18 in hepatocellular carcinoma samples. However, the precise risk of HPV as causative agent of hepatocellular carcinoma needs further study.
