thymalfasin and Liver-Neoplasms

The hepatitis C virus (HCV) is a global public health problem, with chronic infection leading to development of cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Treatment of HCV is suboptimal with overall response rates of slightly greater than 50% when patients are treated with pegylated interferon alfa and ribavirin. Thymosin alpha 1 (Talpha1; TA-1) is an immunomodulatory peptide with intrinsic activities that might improve treatment outcomes for HCV by incorporation of this agent in current treatment paradigms. An extensive body of literature supports a possible role for this agent in difficult to treat populations. However, clinical trials to date have failed to conclusively support the role of TA-1 in combination interferon-based therapies. Therefore, the promise of TA-1 adjunctive therapy for HCV remains, but the proof will require investment in large randomized clinical trials of appropriate patient populations.

Topics: Carcinoma, Hepatocellular; Chronic Disease; Clinical Trials as Topic; Hepacivirus; Humans; Interferons; Liver Cirrhosis; Liver Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Ribavirin; Thymalfasin; Thymosin; Treatment Outcome

Treatment of chronic hepatitis B and C viruses (HBV and HCV) is still disappointing, and both are the major causes of liver cirrhosis and hepatocarcinoma. Interferon and lamivudine are the registered drugs for chronic HBV but are scarcely effective on HBeAg-negative patients, and resistance due to virus mutation is the rule with lamivudine. Interferon and ribavirine represent the standard treatment for chronic HCV but less than the half of the infected population is eligible for this treatment and less of the half of treated patients will experience a sustained response. No single new drug to date has shown the potential to overcome this dismal picture. Combined strategies are thus the currently most available approach to improve the response rate of chronic HBV and HCV infection, with a subsequent decrease in the number of patients developing hepatocellular carcinoma (HCC). Combination of thymosin alpha 1 with interferon or antiviral agents is currently the most promising option, but nontoxic immunomodulants, such as oral MIMP, should be explored. This review focuses on the difficulties with current therapy and the rationale for use of combination therapy with thymosin alpha 1 for both HBV and HCV therapies.

Topics: Adjuvants, Immunologic; Antiviral Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Therapy, Combination; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Viral, Human; Humans; Liver Neoplasms; Thymalfasin; Thymosin

ABSTRACT Background: Thymosin alpha-1 (Ta-1) suppresses HBV viral replication, while the evidence of combination effect with nucleoide is still limited. We aimed to investigate the efficacy and safety of combination therapy of Ta-1 with entecavir (ETV) in patients with compensated liver cirrhosis.. A total of 690 patients were randomized to receive Ta-1 plus ETV (n = 351) or ETV monotherapy (n = 339) for 52 weeks after 26 weeks of ETV treatment, followed by continued entecavir therapy. The primary endpoint was defined as liver decompensation, hepatocellular carcinoma (HCC) or death.. The median followed up was 38.2 months. The cumulative incidence of liver decompensation, HCC, or death were similar between two groups. During the Ta-1 combination treatment, the HCC incidence was 1.7% in combination group and 2.1% in ETV group, without new HCC cases developed during week 39 to week 77 in combination group. The virologic response, serologic response, biochemical response was similar between two groups at week 104. Both therapies were well-tolerated.. There was no significant difference between two groups in endpoint events, while combination therapy with Ta-1 has a tendency to inhibit the development of HCC.

Topics: Adult; Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Guanine; Hepatitis B, Chronic; Humans; Incidence; Liver Cirrhosis; Liver Failure; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Thymalfasin; Treatment Outcome

Topics: Adolescent; Adult; Aged; Autophagy; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Humans; Leukocytes, Mononuclear; Liver Neoplasms; Male; Middle Aged; Thymalfasin; Thymosin; Young Adult

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, is a disease of immune microenvironment. Chronic Hepatitis B virus (HBV) infection, also an immune-related disease, is the major etiological factor for HCC especially in Asia. As an immune regulator, which has pleiotropic activities on T cells, nature killer cells and dendritic cells and so on, the efficacy of thymalfasin on HCC patients has been proven by several pilot studies as an adjuvant therapy. Combination of thymalfasin significantly improved survival and prolonged the time to tumor recurrence in patients who received transcatheter arterial chemoembolization after tumor resection. An improvement in patients' immunity has also been demonstrated. However, there is no large-scale randomized controlled study so far in resectable HCC patients. To confirm the role of thymalfasin adjuvant therapy in patients with HBV-related HCC after curative resection, a large-scale multicenter randomized controlled trial has been planned in China to investigate the effect of thymalfasin (1.6 mg twice a week for 12 months) on 2-year recurrence-free survival rate and tumor immune microenvironment. Here is the first announcement of the study protocol (ClinialTrials.gov Identifier: NCT02281266).

Topics: Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; China; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Neoplasm Recurrence, Local; Research Design; Thymalfasin; Thymosin; Treatment Outcome

To observe the effect of postoperative anti-viral therapy using lamivudine and thymosin alpha1 on recurrence of hepatocellular carcinoma (HCC) coexisting with active hepatitis B.. From Jan. 2000 to Dec. 2002, 33 HCC patients with coexisting with active hepatitis B were randomized into two groups: Group I (n = 17) received hepatectomy only, and Group II (n = 16) received hepatectomy and postoperative therapy using lamivudine plus thymosin alpha1. The suppression of HBV-DNA, HBeAg seroconversion rate, tumor recurrence rate and median survival in the two groups were observed and compared.. In Group II and Group I, the 1-year HBV-DNA suppression rate was 100.0% vs 6.0% (P < 0.01), HBeAg seroconversion rate was 62.5% vs 5.9% (P < 0.05), tumor recurrence rate was 81.3% vs 95.5% (P > 0.05), the recurrence time was 7.0 vs 5.0 months (P < 0.01) and median survival 10.0 vs 7.0 months (P < 0.01).. Anti-viral therapy using lamivudine and thymosin alpha1 postoperatively may suppress the HBV reaction, delay the recurrence and prolong the survival for patients with HCC with coexisting active hepatitis B.

Topics: Adult; Aged; Carcinoma, Hepatocellular; DNA, Viral; Female; Hepatectomy; Hepatitis B; Humans; Lamivudine; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Postoperative Period; Reverse Transcriptase Inhibitors; Survival Rate; Thymalfasin; Thymosin

To observe the effect of postoperative transcatheter hepatic arterial chemoembolization (TACE) and thymosin alpha(1) (T(alpha1)) treatment on recurrence of hepatocellular carcinoma (HCC).. From Jan 2000 to Dec 2002, 57 patients with HCC were randomly divided into three groups: group A (n = 18) received hepatectomy plus postoperative TACE and T(alpha1), group B (n = 23) received hepatectomy plus postoperative TACE and group C (n = 16) received hepatectomy only. The recurrence rate, the time to tumor recurrence and the median survival for the three groups were investigated.. For group A, B and C, the 1 year recurrence rate was 83.3%, 87.0% and 87.5% (P = 0.926), respectively. The time to tumor recurrence was 7.0, 5.0 and 4.0 months (P = 0.039), respectively. The median survival was 10.0, 7.0 and 8.0 months (P = 0.002), respectively.. Postoperative TACE plus Talpha(1) treatment for HCC patients does not decrease the recurrence rate but may delay its occurrence and prolong surviving time.

Topics: Adjuvants, Immunologic; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Carboplatin; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Female; Hepatectomy; Humans; Iodized Oil; Liver Neoplasms; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Postoperative Period; Survival Rate; Thymalfasin; Thymosin

Thymosin alpha-1 (Tα1) is an immunomodulatory and antiviral agent with potential effects on chronic hepatitis B and liver cancer. Its impact on solitary hepatocellular carcinoma (HCC) remains controversial, so we aimed to investigate the efficacy of Tα1 in solitary HBV-related HCC patients after curative resection.Between May 2010 and April 2016, 468 patients with solitary HBV-related HCC after curative resection were analyzed. Propensity score matching (PSM) was used to minimize confounding variables. Risk factors were identified by the Cox proportional hazards model. Recurrence-free survival (RFS) rates, overall survival (OS) rates, immunological, and virologic response were compared.The median follow up was 60.0 months. Immunological response improved in the Tα1 group compared with the control group (P < .001) but the virologic response was similar between 2 groups after 24 months. Patients with Tα1 therapy had better RFS and OS before (P = .018 and P < .001) and after (P = .006 and P < .001) propensity matching. Multivariate analysis revealed that Tα1 therapy was an independent prognostic factor for both OS (P < .001, HR = 0.308, 95% CI: 0.175-0.541) and RFS (P < .001, HR = 0.381, 95% CI: 0.229-0.633).Tα1 as an adjuvant therapy improves the prognosis of solitary HBV-related HCC patients after curative liver resection.

Topics: Adult; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Follow-Up Studies; Hepatectomy; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Propensity Score; Retrospective Studies; Risk Factors; Survival Rate; Thymalfasin

There is limited information available concerning the effect of thymalfasin (Tα1) as an adjuvant therapy in hepatocellular carcinoma (HCC) patient who received liver resection. The present study aimed to evaluate whether Tα1 can improve the prognosis of small HCC patients after liver resection.A total of 206 patients with small HCC who underwent liver resection were analyzed in our retrospective cohort study. Patients were divided into 2 groups: group A (resection + Tα1, n = 44) and group B (resection, n = 162). Clinical data, overall survival (OS), and recurrence-free survival (RFS) were compared. Prognostic factors were identified using multivariate analysis.After a median follow-up of 47.0 months, 134 patients (65%) had recurrence, and 62 patients (30.09%) died. The 1, 3, and 5-year OS rate of patients in group A was 97.7%, 90.6%, and 82.9%, respectively, and 95.1%, 80.5%, and 62.9%, respectively, for patients in group B (P = .014). The 1, 3, and 5-year RFS rate of patients in group A was 70.5%, 56.8%, and 53.3%, respectively, and 65.8%, 41.3%, and 32.1%, respectively, for patients in group B (P = .015). Multivariate analysis indicated that Tα1 was an independent prognostic factor for both OS (P = .015, hazard ratio 0.349, 95% confidence interval 0.149-0.816) and RFS (P = .019, hazard ratio 0.564, 95% confidence interval 0.349-0.910).Tα1 as an adjuvant therapy after liver resection may improve the prognosis of small HCC patients after liver resection.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Comorbidity; Disease-Free Survival; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Retrospective Studies; Sex Factors; Thymalfasin; Thymosin; Young Adult

To explore the impact of triple anti-tumor therapy based on thymosin α1 (Tα1) combined with Huaier granule(HG) and sirolimus on the level of serum alpha-fetoprotein (AFP) in rat models of liver cancer.. Ninety Sprague-Dawley rats were randomly divided into triple anti-tumor therapy group, Tα1 group, HG group, sirolimus group, positive control and blank control groups, with 15 rats in each group. Except the blank control group, the rats in the other groups were induced using diethylnitrosamine (DEN) to establish liver cancer models. After DEN treatment, the triple therapy group underwent 0.8 mg/kg Tα1 subcutaneous injection (from once a day for two weeks to twice a week since the third week), 0.35 g/kg HG gavage (three times a day) and 1 mg/kg sirolimus gavage (once a day). The dose of the rest single drug groups were the same with that of the triple therapy group. The positive control and blank control groups were not treated with the drugs. The treatment lasted 20 weeks. Then, the behavior of the rats were observed at the different time points, and the level of serum AFP in the rats were detected at 6, 16, 18, 20 weeks, respectively.. The typical symptoms of liver cancer were seen in the DEN-induced rats at 16 weeks. Since the tenth week, 6 rats died one after another. Pathological section of rat liver tissue suggested that the rat models were established successfully. According to the incidence rate of liver cancer and the survival rate at 20 weeks, the triple anti-tumor therapy was significantly superior to the single drug treatments. In addition, the triple anti-tumor therapy significantly reduced the level of serum AFP in the rats.. The triple anti-tumor therapy can significantly prolong the survival time of rats with liver cancer, decrease the cancer incidence rate and the level of serum AFP.

Topics: alpha-Fetoproteins; Animals; Antineoplastic Combined Chemotherapy Protocols; Behavior, Animal; Carcinoma, Hepatocellular; Disease Models, Animal; Liver; Liver Neoplasms; Male; Rats; Rats, Sprague-Dawley; Sirolimus; Survival Analysis; Thymalfasin; Thymosin

To investigate the effects of different treatments for hepatocellular carcinoma (HCC) with tumor thrombus in the portal vein (PVTT).. From Jan. 2000 to Jan. 2003, a total of 84 HCC patients with PVTT were divided into five groups based on methed of treatment: Group A (n = 9), HCC resection + PVTT removal + postoperative TACE + thymosin alpha(1); Group B (n = 20), HCC resection + PVTT removal + postoperative TACE; Group C (n = 7), HCC resection + PVTT removal; Group D (n = 38), TACE only; Group E (n = 10), conservative treatment only.. The rate of PVTT shrinkage or disappearance of groups A, B, C, D and E was 66.7%, 70.0%, 57.1%, 7.9% and 0, respectively with respective median survival time of 10.0, 7.0, 8.0, 5.0 and 2.0 months. The one year survival rate was 44.4%, 15.0%, 14.3%, 10.5% and 0.. Resection of HCC and removal of tumor thrombus in the portal vein may have the tumor thrombus cleared in most of the patients and postoperative TACE and thymisin alpha(1) treatment may improve their survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Follow-Up Studies; Hepatectomy; Hepatic Artery; Humans; Liver Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Portal Vein; Survival Analysis; Thymalfasin; Thymosin

The immunomodulatory and antimetastatic/antitumor activity of thymosin alpha(1) (Talpha(1)) was evaluated in BALB/c-mice. Daily subcutaneous application (7 consecutive days, 0.01-10 microg of Talpha(1)/injection per mouse) upregulated the number of thymocytes and peripheral blood cells in tumor bearing mice. To check the influence of Talpha(1) treatment on growth of experimental metastases, RAW H10 lymphosarcoma cells or L-1 sarcoma cells were intravenously injected into BALB/c-mice to establish liver or lung metastases. Local tumor growth was induced by subcutaneous injection of L-1 sarcoma cells. Talpha(1) was subcutaneously administered daily for 7 consecutive days starting 24 h after tumor cell challenge. Organ colonization, as well as local tumor growth, were investigated on day 14 after tumor cell inoculation, and demonstrated a statistically significant (P<0.05) reduction of experimental liver and lung metastases and local tumor growth for Talpha(1) treated mice.

Topics: Adjuvants, Immunologic; Animals; Cell Count; Dose-Response Relationship, Drug; Immunity; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Organ Size; Thymalfasin; Thymosin; Thymus Gland; Tumor Cells, Cultured

Thymosin-alpha 1 is a biological response modifier that has been used clinically, alone and in combination with interferon-alpha for the treatment of chronic hepatitis B viral infection. Both immunomodulatory and immediate intracellular mechanisms have been postulated to explain the effect of these two agents on HBV-infected hepatocytes.. In this study, hepatitis B transfected HepG2 hepatoblastoma cells (HepG2-Nu2), derived from 2.2.15 cells, were used as an in vitro model to determine the efficacy of thymosin-alpha 1 and interferon-alpha, individually and combined, as proliferation inhibitors of HBV-infected cells. For comparison, parental HepG2 cells and an SV40-transfected HepG2 cell line (HepG2P9T2) were also evaluated.. In a clonogenic soft agar assay, thymosin-alpha 1 inhibited the anchorage-independent growth of the HepG2-Nu2 cells by 40% compared with untreated controls, but did not inhibit parental HepG2 or HepG2P9T2 clonal growth. The response was dose dependent over concentrations spanning three log units. In comparison, 10000 units/ml of interferon-alpha inhibited parental HepG2, HepG2-N4Z and HepG2P9T2 by 33%, 41% and 87%, respectively. The combination of thymosin-alpha 1 and interferon-alpha consistently inhibited HepG2-Nu2 clonal growth more effectively than either treatment alone, reaching maximum inhibition levels of 51%.. Thymosin-alpha 1 specifically inhibits the tumorigenic growth of HBV-transfected HepG2 cells in contrast to the general inhibition displayed by interferon-alpha. This panel of cell lines may be an important resource for dissecting the mechanism by which thymosin, alone or in combination with other drugs, influences HBV-infected hepatocytes and/or HBV-associated carcinoma.

Topics: Adjuvants, Immunologic; Antiviral Agents; Cell Division; Cell Transformation, Viral; DNA, Viral; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Hepatitis B virus; Hepatoblastoma; Humans; Interferon-alpha; Liver Neoplasms; Thymalfasin; Thymosin; Transfection; Tumor Cells, Cultured; Virus Replication

We studied the effect of combined chemo-immunotherapy, 5-FU followed by thymosin alpha 1 (T alpha 1) and interleukin-2 (IL-2) at low doses, on liver metastases from colorectal cancer, induced by splenic injection of DHD/K12 cells (1,2-dimethylhydrazine-induced colon adenocarcinoma) in syngeneic BDIX rats. The presence of liver metastases was checked by laparotomy 14 days after tumor-cell injection. Evaluable rats were assigned randomly to 5 experimental groups designated as control, 5-FU, IL-2, 5-FU/IL-2 and 5-FU/T alpha 1/IL-2. 5-FU was administered i.v. as a continuous infusion for 7 days by an osmotic device implanted surgically. T alpha 1 and IL-2 were administered for 4 days and repeated after 11 days. Combined chemo-immunotherapy was shown both to significantly reduce the growth of liver metastases and to prevent extra-hepatic spread. 5-FU/T alpha 1/IL-2 also improved survival rate. Combined immunotherapy after 5-FU restored NK activity of the peripheral-blood-mononuclear-cell (PBMC) in tumor and/or 5-FU immunodepressed rats and enhanced PBMC cytotoxic activity against the DHD/K12 autologous cell line. This model was devised to mimic the clinical situation of unresectable liver metastases.

Topics: Animals; Carcinoma; Colorectal Neoplasms; Combined Modality Therapy; Cytotoxicity, Immunologic; Fluorouracil; Immunotherapy; Interleukin-2; Killer Cells, Natural; Liver Neoplasms; Male; Rats; Rats, Inbred Strains; Survival Analysis; T-Lymphocytes, Cytotoxic; Thymalfasin; Thymosin