Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma
Cancer Center of the First Hospital of JilinUniversity, Changchun, 130021, China. International Journal of Cancer
(Impact Factor: 5.09).
01/2014; 134(2). DOI: 10.1002/ijc.28372
Hepatocellular carcinoma (HCC) recurs frequently after minimally invasive therapy. This study was to observe the efficiency and safety of the combined treatment of radiofrequency ablation (RFA) with cellular immunotherapy (CIT) for HCC patients. In this study, sixty-two patients with HCC who were treated with radical RFA were divided into two groups: RFA alone (32 patients) and RFA/CIT (30 patients). Autologous mononuclear cells were collected from the peripheral blood and separated by apheresis, and then induced into natural killer (NK) cells, γδT cells and cytokine-induced killer (CIK) cells. These cells were identified by flow cytometry with their specific antibodies and then were infused intravenously to RFA/CIT patients for 3 or 6 courses. The tumor recurrent status of these patients was evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) every 3 months after RFA. Progression-free survival (PFS), liver function, viral load, and adverse effects were examined. The results implied that PFS was higher in RFA/CIT group than that in RFA group. In RFA/CIT group, six courses had better survival prognosis than three courses. Viral load of hepatitis C was decreased in two of three patients without antiviral therapy in RFA/CIT group, but was increased in RFA group. No significant adverse reaction was found in the patients with CIT. In summary, these preliminary results suggest that combination of sequential CIT with RFA for HCC patients was efficient and safe, and may be helpful in the prevention of the recurrence for the patients with HCC after RFA. © 2013 Wiley Periodicals, Inc.
Available from: Elena L Chernolovskaya
- "Moreover, HCC patients with tumors containing infiltrated tumor-specific effector T cells have a reduced risk of tumor recurrence following liver transplantation . The following methods of adjuvant therapy were proposed for the treatment of HCC patients: cellular immunotherapy , interferon (IFN) therapy , and therapy using endogenous IFN inducers . It should be noted that in many cases, HCC develops on a background of chronic inflammatory liver disease such as hepatitis B and C or cirrhosis. "
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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Since HCC has been shown to be immunogenic, immunotherapy is considered a promising therapeutic approach. Small interfering RNAs (siRNAs), depending on their structure and sequence, can trigger the innate immune system, which can potentially enhance the adaptive anticancer immune response in the tumor-bearing subjects. Immunostimulatory properties of nucleic acids can be applied to develop adjuvants for HCC treatment.
The transplantable HCC G-29 tumor in male CBA/LacSto (CBA) mice was used to study the effects of immunostimulatory RNA on tumor growth. Tumor size, metastases area in different organs of mice and mouse survival rate were analyzed. Furthermore the mouse serum IFN-α levels were measured using ELISA.
In the present study, we found that a 19-bp RNA duplex (ImmunoStimulattory RNA or isRNA) with 3-nt overhangs at the 3′-ends of specific sequence displays immunostimulatory, antitumor, and antimetastatic activities in mice bearing HCC G-29. Our results demonstrate that isRNA strongly increases the level of interferon-α (IFN-α) by up to 25-fold relative to the level in mice injected with Lipofectamine alone (Mock), and to a lesser extent increases the level of proinflammatory cytokine interleukin-6 (IL-6) (by up to 5.5-fold relative to the Mock level), in mice blood serum. We showed that isRNA reliably (P < 0.05) inhibits primary tumor growth in mice compared to the mock group. Furthermore, injections of isRNA significantly enhanced necrotic processes in the center of the primary tumor, and decreased by twofold the width of the undifferentiated peripheral zone and the number of mitotic cells in this zone. The results showed that isRNA efficiently reduces the area of metastases in the liver, kidneys, and heart of CBA/LacSto mice with HCC.
The obtained results clearly demonstrate immunostimulatory and antimetastatic properties of the isRNAs in mice with HCC. Consequently, this short double-stranded RNA can be considered as a potential adjuvant for the therapy of HCC.
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ABSTRACT: Tumor-initiating cells(TICs) are a subpopulation of chemoresistant tumor cells that have been shown to cause tumor recurrence. Targeting and eliminating of TICs are therefore priorities for the development of new therapeutic paradigms. Much promise lies in adoptive immunotherapy. Cytokine-induced killer (CIK) cells are heterogeneous ex vivo-expanded T lymphocytes, with a mixed T-NK phenotype. It represents a realistic new option in the field of Hepatocellular carcinoma(HCC) immunotherapy. In the very recent years, Large clinical trials demonstrated that CIK cells could improve the Progression Free Survival (PFS) and Overall Survival(OS) in patients with HCC. By the same time, several studies reported that CIK cells were capable of clearing cells with stemness features in Lymphoma, Melanoma, Bone and Soft-Tissue Sarcomas. Based on the findings above mentioned, we hypothesized that CIK cells could eliminate the tumor-initiating cells, improving the PFS and OS of patients with HCC when combined with radiofrequency ablation(RFA) or transcatheter arterial chemoembolization(TACE).
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ABSTRACT: Objective : To evaluate the clinical efficacy of combined therapy using autologous dendritic cells-cytokine induced killer cells (DC-CIK) and percutaneous microwave coagulation (PMCT) in the treatment of hepatocellular carcinoma. Methods: Forty four patients with hepatocellular carcinoma treated with PMCT and DC-CIK (combination group) and 44 patients treated with PMCT alone (control group) were enrolled in the Department of Biotherapy of Eastern Hepatobiliary Surgical Hospital from January 2012 to February 2014. For patients in the combination group, peripheral blood mononuclear cells (PBMCs) were isolated on day 1 and PMCT were performed on the second day. After a ten day-culture, the DC-CIK cells were generated and transfused back to patients together with intradermal injection of DC vaccine. The second and third course of DC-CIK therapy were given one month and two months later respectively. The AFP level, immune function, progression-free survival, overall survival, and adverse effects were assessed for all the patients. Results: Although the level of AFP and regulatory T cells in peripheral blood decreased in the patients of both groups, their decline in the combination group was significantly more than that of the control group (P<0.05). Compared with that of pre-treatment, the lymphocyte number and subpopulations didn’t change significantly in the control group (P>0.05), but they did increase markedly in the combination group (P<0.05). The median progression-free survival and median overall survival were both increased in the combination group compared with that of the control group (7.1 m vs 4.9 m, 215 m vs 14.0 m, P<0.05). Conclusion: Adoptive transfer of autologous DC-CIK in combination with PMCT is an effective treatment for patients with hepatocellular carcinoma. It improves the immune function, postpones the recurrence of tumor, and prolongs the overall survival with acceptable toxicities. © 2015, Editorial office of Chinese Journal of Cancer Biotherapy. All rights reserved.
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