Clinical Outcomes of Hepatitis B Virus–Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels

BackgroundWe have demonstrated the ability of Hepatitis-B-virus (HBV)-specific T cell receptor (TCR) bioengineered T cells to recognize and lyse Hepatocellular carcinoma (HCC) cells expressing HBV antigens derived from HBV-DNA integration in patients with liver transplant.1 LioCyx-M is an immunotherapeutic product composing of autologous T cells transiently modified with in-vitro transcribed mRNA encoding HBV-specific TCR. The transient TCR expression makes LioCyx -M amenable to a dose escalating posology.MethodsThe primary endpoint of this phase 1 trial is to assess the safety and tolerability of LioCyx-M in patients with advanced HBV-HCC without curative treatment options. Eligible patients were diagnosed with Barcelona clinic liver cancer stage B or C HCC (Child-Pugh < 7 points), receiving >1 year antiviral treatment prior to enrollment. These patients had matching HLA class I genotypes which present HBV encoded antigen. Peripheral blood was collected from each patient prior to each dose for LioCyx-M manufacturing. Patients received 4 escalating doses of 1×104 cells/kg, 1×105 cells/kg, 1×106 cells/kg, 5×106 cells/kg bodyweight (BW) in the first treatment cycle, each intravenously administered weekly. Patients underwent 1-month safety assessment post the 4th infusion, according to Common Terminology NCI CTCAE Version 4.0.3. If there were no dose associated toxicities, patients were eligible to continue administration of LioCyx-M at dose of 5 × 106 cells/kg BW weekly. Tumor response per RECIST 1.1 criteria and survival time were assessed.ResultsAt data cutoff (30 April 2020), eight patients were enrolled, with a median age of 53 (range: 49 - 67). These patients received a median number of 6 (range: 4 - 12) infusions of LioCyx-M. 1 patient developed Grade 3 elevations in alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and bilirubin after receiving LioCyx-M at dose level of 1×105 cells/kg BW. Another patient had Grade 1 transient fever after receiving LioCyx-M at dose level 5×106 cells/kg BW in the 4th, 5th and 6th infusions. No treatment-related adverse events (trAEs) such as cytokine release syndrome or neurotoxicity were observed. No fatal trAEs were observed. The median time to progression was 1.9 months (range: 0.2 - 9.5 months). The median overall survival was 34 months (range: 3 - 38.2 months).ConclusionsThe encouraging clinical outcome and tolerable safety highlight the good benefit-risk profile of LioCyx-M. Therefore, further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 proof-of-concept clinical study.AcknowledgementsFunding: Lion TCR.Trial RegistrationNCT03899415Ethics ApprovalThe study was approved by Fifth Medical Center of Chinese PLA General Hospital’s Ethics Board, approval number R2016185DI010.ReferenceTan AT, Yang N, Lee Krishnamoorthy T, et al. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy. Gastroenterology 2019;156(6):1862–1876.e9.

Download Full-text

Diagnostic Value of Detection of Pregenomic RNA in Sera of Hepatitis B Virus-Infected Patients with Different Clinical Outcomes

Journal of Clinical Microbiology ◽

10.1128/jcm.01275-19 ◽

2019 ◽

Vol 58 (2) ◽

Cited By ~ 1

Author(s):

Ni Lin ◽

Aizhu Ye ◽

Jinpiao Lin ◽

Can Liu ◽

Jinlan Huang ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Clinical Outcomes ◽

Hepatitis B Surface Antigen ◽

Surrogate Marker ◽

Diagnostic Value ◽

Hbv Dna ◽

Hbv Cccdna ◽

B Virus ◽

Intrahepatic Hbv

ABSTRACT Pregenomic RNA (pgRNA) is a direct transcription product of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), and it plays important roles in viral genome amplification and replication. This study was designed to investigate whether serum pgRNA is a strong alternative marker for reflecting HBV cccDNA levels and to analyze the correlation between serum pgRNA, serum HBV DNA, and hepatitis B surface antigen (HBsAg). A total of 400 HBV-infected patients who received nucleos(t)ide analog (NA) therapy with different clinical outcomes were involved in this research. Case groups included asymptomatic hepatitis B virus carrier (ASC), chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) patients, with 100 patients in each group. The results showed that the levels of HBV pgRNA had significant differences between these 4 groups. Serum pgRNA levels correlated well with serum HBV DNA and HBsAg levels (HBV pgRNA levels versus HBV DNA levels, r = 0.58, P < 0.001; HBV pgRNA levels versus HBsAg levels, r = 0.47, P < 0.001). In addition, we focused on the 108 HBV-infected patients with HBV DNA levels of <500 IU/ml; it was surprising to find that in 17.57% (13/74) of cases, HBV pgRNA could be detected even when the HBV DNA level was below 20 IU/ml. In conclusion, HBV pgRNA levels in serum can be a surrogate marker for intrahepatic HBV cccDNA compared with serum HBV DNA and HBsAg. The detection of serum HBV pgRNA levels may provide a reference for clinical monitoring of cccDNA levels and the selection of appropriate timing for discontinuing antiviral therapy, especially when HBV DNA levels are below the detection limit.

Download Full-text

Intermediate-stage hepatocellular carcinoma patients with a high HBV-DNA load may benefit from postoperative anti-hepatitis B virus therapy

Medicine ◽

10.1097/md.0000000000007608 ◽

2017 ◽

Vol 96 (30) ◽

pp. e7608 ◽

Cited By ~ 2

Author(s):

Shaozhen Rui ◽

Jun Yan ◽

Hui Zhang ◽

Zhengfeng Wang ◽

Wence Zhou

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Intermediate Stage ◽

Hbv Dna ◽

B Virus

Download Full-text

Real-time quantitation of hepatitis B virus (HBV) DNA in tumorous and surrounding tissue from patients with hepatocellular carcinoma

Journal of Medical Virology ◽

10.1002/jmv.10243 ◽

2002 ◽

Vol 68 (4) ◽

pp. 494-499 ◽

Cited By ~ 12

Author(s):

Isabella Zanella ◽

Angelo Rossini ◽

Daniela Domenighini ◽

Alberto Albertini ◽

Elisabetta Cariani

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Real Time ◽

Hbv Dna ◽

Surrounding Tissue ◽

B Virus

Download Full-text

Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels

Gut ◽

10.1136/gut.2007.119859 ◽

2007 ◽

Vol 57 (1) ◽

pp. 98-102 ◽

Cited By ~ 121

Author(s):

M-F Yuen ◽

Y Tanaka ◽

N Shinkai ◽

R T Poon ◽

D Y.-K. But ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Core Promoter ◽

Hbv Dna ◽

B Virus ◽

Virus Genotypes ◽

Enhancer Ii

Download Full-text

Association of Virological Response to Antiviral Therapy With Survival in Intermediate-Stage Hepatitis B Virus-Related Hepatocellular Carcinoma After Chemoembolization

Frontiers in Oncology ◽

10.3389/fonc.2021.751777 ◽

2021 ◽

Vol 11 ◽

Author(s):

Meng Jin ◽

Yong Chen ◽

Shuifang Hu ◽

Meiyan Zhu ◽

Yan Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Antiviral Therapy ◽

Virological Response ◽

Cox Regression ◽

Intermediate Stage ◽

Hbv Dna ◽

Rank Test ◽

B Virus

IntroductionRole of response to antiviral therapies on survival of patients with intermediate-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) undergoing transarterial chemoembolization (TACE) remains unknown. We aimed to determine whether virological response (VR) or prolonged maintained virological response (MVR) to nucelos(t)ide analogues (NA) therapy could result in improved survival in HBV-HCC patients receiving TACE.MethodsBetween January 2012 and October 2018, data of patients with intermediate HBV-HCC who underwent TACE and started NA therapy within one week prior to TACE treatment at our institution were reviewed. Overall survival (OS) was compared using the Kaplan-Meier method with log-rank test between different VR status groups. Univariable and multivariable Cox regression analyses were used to determine the association between achievement of VR or MVR and OS. VR was defined as an undetectable HBV DNA level (<100 IU/ml) on two consecutive measurements during NA treatment. MVR was defined as a persistently undetectable HBV DNA level after achieving a VR.ResultsA total of 1265 patients undergoing TACE with a median follow-up time of 18 months (range, 2-78 months) were included in the analysis. Of 1265 NA-treated patients [1123 (88.8%) male, median (range) age, 56 (18-75) years], 744 patients (58.8%) achieved VR and the remaining patients (41.2%) did not. Patients with achievement of VR showed a significantly longer OS than those without VR (median OS: 21 vs 16 months; HR, 0.707; 95% CI, 0.622-0.804; P<0.001). Among patients with VR, MVR was present in 542 patients (72.8%), while the other 202 patients (27.2%) in the non-MVR group. The OS for the MVR group was significantly higher than the non-MVR group (median OS: 23.2 vs 18 months; HR, 0.736; 95% CI, 0.612-0.885; P=0.001). Additionally, patients with MVR status more than two years showed a better OS than those with just one-year (HR, 0.719; 95% CI, 0.650-0.797; P<0.001) or one-to-two-year MVR (HR, 0.612; 95% CI, 0.471-0.795; P=0.024). On multivariable analyses, splenomegaly and up-to-seven criteria were independent prognostic factors of OS in both VR and MVR cohorts.ConclusionsIn patients with intermediate-stage HBV-HCC, both VR to antiviral therapy and prolonged response are associated with prolonged OS after TACE, especially for those within up-to-seven criteria.

Download Full-text

Role of hepatitis B virus genotypes and quantitative HBV DNA in metastasis and recurrence of hepatocellular carcinoma

Journal of Medical Virology ◽

10.1002/jmv.21117 ◽

2008 ◽

Vol 80 (4) ◽

pp. 591-597 ◽

Cited By ~ 38

Author(s):

Yuehua Huang ◽

Zhanhui Wang ◽

Shengli An ◽

Bin Zhou ◽

Yuanping Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Dna ◽

B Virus ◽

Virus Genotypes

Download Full-text

Clinical outcomes of a cohort series of patients with hepatocellular carcinoma in a hepatitis B virus-endemic area

Journal of Gastroenterology and Hepatology ◽

10.1111/jgh.12470 ◽

2014 ◽

Vol 29 (4) ◽

pp. 820-829 ◽

Cited By ~ 32

Author(s):

Hee-Won Kwak ◽

Joong-Won Park ◽

Byung-Ho Nam ◽

Ami Yu ◽

Sang Myung Woo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Clinical Outcomes ◽

Endemic Area ◽

B Virus

Download Full-text

Two-Year Assessment of Entecavir Resistance in Lamivudine-Refractory Hepatitis B Virus Patients Reveals Different Clinical Outcomes Depending on the Resistance Substitutions Present

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00833-06 ◽

2006 ◽

Vol 51 (3) ◽

pp. 902-911 ◽

Cited By ~ 166

Author(s):

Daniel J. Tenney ◽

Ronald E. Rose ◽

Carl J. Baldick ◽

Steven M. Levine ◽

Kevin A. Pokornowski ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Reverse Transcriptase ◽

Clinical Outcomes ◽

Chronic Infection ◽

Hbv Dna ◽

Wild Type ◽

Pcr Assay ◽

B Virus

ABSTRACT Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.

Download Full-text