4 results on '"Krishnamoorthy, Thinesh Lee"'
Search Results
2. Immunosuppressive Drug-Resistant Armored T-Cell Receptor T Cells for Immune Therapy of HCC in Liver Transplant Patients.
- Author
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Hafezi M, Lin M, Chia A, Chua A, Ho ZZ, Fam R, Tan D, Aw J, Pavesi A, Krishnamoorthy TL, Chow WC, Chen W, Zhang Q, Wai LE, Koh S, Tan AT, and Bertoletti A
- Subjects
- Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular virology, Coculture Techniques, Drug Resistance genetics, Graft Rejection immunology, Graft Rejection pathology, Hep G2 Cells, Hepatitis B pathology, Hepatitis B surgery, Hepatitis B virology, Hepatitis B virus immunology, Hepatitis B virus metabolism, Humans, Immunotherapy, Adoptive methods, Liver drug effects, Liver immunology, Liver pathology, Liver virology, Liver Neoplasms pathology, Liver Neoplasms virology, Liver Transplantation adverse effects, Mycophenolic Acid pharmacology, Mycophenolic Acid therapeutic use, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Protein Engineering, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Tacrolimus pharmacology, Tacrolimus therapeutic use, Carcinoma, Hepatocellular surgery, Graft Rejection prevention & control, Liver Neoplasms surgery, Neoplasm Recurrence, Local therapy, T-Lymphocytes transplantation
- Abstract
Background and Aims: HBV-specific T-cell receptor (HBV-TCR) engineered T cells have the potential for treating HCC relapses after liver transplantation, but their efficacy can be hampered by the concomitant immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR-T cells that could retain their polyfunctionality in such patients while minimizing the associated risk of organ rejection., Approach and Results: We first analyzed how immunosuppressive drugs can interfere with the in vivo function of TCR-T cells in liver transplanted patients with HBV-HCC recurrence receiving HBV-TCR T cells and in vitro in the presence of clinically relevant concentrations of immunosuppressive tacrolimus (TAC) and mycophenolate mofetil (MMF). Immunosuppressive Drug Resistant Armored TCR-T cells of desired specificity (HBV or Epstein-Barr virus) were then engineered by concomitantly electroporating mRNA encoding specific TCRs and mutated variants of calcineurin B (CnB) and inosine-5'-monophosphate dehydrogenase (IMPDH), and their function was assessed through intracellular cytokine staining and cytotoxicity assays in the presence of TAC and MMF. Liver transplanted HBV-HCC patients receiving different immunosuppressant drugs exhibited varying levels of activated (CD39
+ Ki67+ ) peripheral blood mononuclear cells after HBV-TCR T-cell infusions that positively correlate with clinical efficacy. In vitro experiments with TAC and MMF showed a potent inhibition of TCR-T cell polyfunctionality. This inhibition can be effectively negated by the transient overexpression of mutated variants of CnB and IMPDH. Importantly, the resistance only lasted for 3-5 days, after which sensitivity was restored., Conclusions: We engineered TCR-T cells of desired specificities that transiently escape the immunosuppressive effects of TAC and MMF. This finding has important clinical applications for the treatment of HBV-HCC relapses and other pathologies occurring in organ transplanted patients., (© 2020 by the American Association for the Study of Liver Diseases.) more...- Published
- 2021
- Full Text
- View/download PDF
Catalog
3. Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.
- Author
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Jin Y, Wong YS, Goh BKP, Chan CY, Cheow PC, Chow PKH, Lim TKH, Goh GBB, Krishnamoorthy TL, Kumar R, Ng TP, Chong SS, Tan HH, Chung AYF, Ooi LLPJ, Chang JPE, Tan CK, and Lee CGL
- Subjects
- Biomarkers, Tumor blood, Carcinoma, Hepatocellular blood, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular virology, Case-Control Studies, Disease Progression, Female, Follow-Up Studies, Gene Expression Profiling, Hepatitis B virus isolation & purification, Hepatitis B, Chronic virology, Humans, Liver Cirrhosis blood, Liver Cirrhosis genetics, Liver Cirrhosis virology, Liver Neoplasms blood, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms virology, Male, MicroRNAs blood, Middle Aged, Prognosis, Survival Rate, Biomarkers, Tumor genetics, Carcinoma, Hepatocellular pathology, Early Detection of Cancer methods, Gene Expression Regulation, Neoplastic, Hepatitis B, Chronic complications, Liver Cirrhosis pathology, MicroRNAs genetics
- Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3
rd cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival. more...- Published
- 2019
- Full Text
- View/download PDF
4. Hepatitis B: encouraging the use of interferon.
- Author
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Krishnamoorthy TL and Mutimer D
- Subjects
- Adjuvants, Immunologic therapeutic use, Contraindications, Drug Administration Schedule, Drug Therapy, Combination, Guanine analogs & derivatives, Guanine therapeutic use, Hepatitis B e Antigens blood, Hepatitis B, Chronic blood, Hepatitis B, Chronic physiopathology, Humans, Interferon-alpha therapeutic use, Telbivudine, Thymidine analogs & derivatives, Antiviral Agents therapeutic use, Carcinoma, Hepatocellular prevention & control, Hepatitis B e Antigens drug effects, Hepatitis B virus drug effects, Hepatitis B, Chronic drug therapy, Liver Cirrhosis prevention & control, Liver Neoplasms prevention & control
- Abstract
Purpose of Review: Hepatitis B is a major cause of hepatocellular carcinoma and liver cirrhosis. Interferon (IFN)-based therapies provide the highest likelihood of achieving off-treatment virological and serological control although their use is often avoided because of the side-effect profile. We review recent developments regarding the use of IFN in the treatment of chronic hepatitis B, including proposed strategies to enhance efficacy while limiting treatment exposure for patients who are unlikely to achieve acceptable treatment endpoints., Recent Findings: The utility of host genetics (human leukocyte antigen associations and interleukin 28B) is yet to be defined. In hepatitis B e antigen (HBeAg)-positive disease, add-on IFN therapy to patients on entecavir may allow curtailment of nucleos(t)ide analogue treatment. In HBeAg-negative disease, an on-treatment stopping rule that measures decline of hepatitis B surface antigen and hepatitis B virus DNA at 12 and 24 weeks may identify up to two-thirds of poor responders. Prolonging IFN therapy to 96 weeks in patients with HBeAg-negative disease may improve virological and serological response rates. The combination of telbivudine and IFN therapy is contraindicated because of high rates of peripheral neuropathy., Summary: These findings need to be confirmed in larger trials before they can be instituted into routine clinical practice. more...
- Published
- 2015
- Full Text
- View/download PDF
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