orabase and Carcinoma--Hepatocellular

The efficacy of treatment for advanced hepatocellular carcinoma (HCC) has remained limited. Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded RNA that serves as a viral mimic and induces an immune response. Intratumoral (IT) poly-ICLC injections can induce an autovaccination effect and prime the immune system, whereas intramuscular (IM) injection of poly-ICLC can attract and maintain tumor-specific cytotoxic T lymphocytes in tumors. We found that IT injection of poly-ICLC upregulated the expression of CD83 and CD86 on conventional type 1 dendritic cells in tumors. Combination therapy with IT followed by IM injections of poly-ICLC significantly inhibited tumor growth and increased the tumor-infiltrating CD8

Topics: Animals; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Liver Neoplasms; Mice; Poly I-C; Polylysine; Vaccination

To evaluate the therapeutic efficacy of irreversible electroporation (IRE) combined with the intratumoral injection of the immunogenic adjuvant poly-ICLC (polyinosinic-polycytidylic acid and poly-L-lysine, a dsRNA analog mimicking viral RNA) inmediately before IRE.. Mice and rabbits bearing hepatocellular carcinoma tumors (Hepa.129 and VX2 tumor models, respectively) were treated with IRE (2 pulses of 2500V), with poly-ICLC, or with IRE + poly-ICLC combination therapy. Tumor growth in mice was monitored using a digital caliper and by computed tomography in rabbits.. Intratumoral administration of poly-ICLC immediately before IRE elicited shrinkage of Hepa.129 cell-derived tumors in 70% of mice, compared to 30% and 26% by poly-ICLC or IRE alone, respectively (P = .0004). This combined therapy induced the shrinkage of VX-2-based hepatocellular carcinoma tumors in 40% of rabbits, whereas no response was achieved by either individual treatment (P = .045). The combined therapy activated a systemic antitumor response able to inhibit the growth of other untreated tumors.. IRE treatment, immediately preceded by the intratumoral administration of an immunogenic adjuvant such as poly-ICLC, might enhance the antitumor effect of the IRE procedure. This combination might facilitate the induction of a long-term systemic response to prevent tumor relapses and the appearance of metastases.

Topics: Adjuvants, Immunologic; Animals; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Cell Line, Tumor; Electroporation; Injections, Intralesional; Liver Neoplasms, Experimental; Mice, Inbred C3H; Poly I-C; Polylysine; Rabbits; Tumor Burden

Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro, in association with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon. Tumor cell apoptosis and host immune responses in the tumor microenvironment were enhanced. Particularly, the activation of local NK cells, T cells, macrophages and dendritic cells was enhanced. Decreased expression of the inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating CD8+ T cells and tumor cells, respectively. Tumor infiltration by monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating the reversion of the immunosuppressive tumor microenvironment. Our data demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances tumor control and local immune response hence providing a rationale for future clinical studies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Humans; Immune System; Immunosuppressive Agents; Liver Neoplasms; Male; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Niacinamide; Phenylurea Compounds; Phosphorylation; Poly I-C; Polylysine; Proto-Oncogene Proteins c-akt; Signal Transduction; Sorafenib; Toll-Like Receptor 3

We report herein the development of a smart magnetic nanoparticle-aptamer probe, or theranostic nanoprobe, which can be used for targeted imaging and as a drug carrier for hepatocellular carcinoma treatment. The theranostic nanoprobe combines the delivery potential of a non-toxic cellulose derivative polymer, specific capability of cancer-specific molecule (DNA-based EpCAM aptamer) and the imaging capability of magnetic iron oxide nanoparticles. Our proof-of-concept design demonstrates efficient in vitro MR imaging of the cancer cells, and enhanced delivery of an anticancer drug into the cancer cells with comparable treatment efficacy.

Topics: Antigens, Neoplasm; Antimetabolites, Antineoplastic; Aptamers, Nucleotide; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Cell Adhesion Molecules; Cell Survival; Doxorubicin; Epithelial Cell Adhesion Molecule; Ferric Compounds; Hep G2 Cells; Humans; Liver Neoplasms; Magnetic Phenomena; Magnetic Resonance Imaging; Metal Nanoparticles

To quantify tumor blood flow by using contrast material-enhanced destruction-replenishment ultrasonography (US) to evaluate tumor response to different doses of an agent for antiangiogenic treatment in hepatoma-bearing mice, with histologic measurements of microvascular density (MVD) as the reference standard.. Experiments were approved by the regional animal care committee. Mice bearing subcutaneous H22 hepatoma were treated with different doses of thalidomide, 100 mg/kg in group B and 200 mg/kg in group C. Group A (control group) was treated with 0.5% carboxylmethylcellulose. Treatment groups and the control group included 10 mice each. Contrast-enhanced US was used to evaluate the percentage of nonenhanced area, and contrast-enhanced destruction-replenishment US was used to evaluate tumor blood flow. Tumor blood flow was compared with measurements of MVD. Comparisons were made by using one-way analysis of variance and the post hoc least significant difference test for multiple comparisons.. Contrast-enhanced gray-scale US showed significant increases in the percentage of nonenhanced area in group C (mean, 10.56% ± 7.25 [standard deviation]), as compared with groups A (mean, 2.40% ± 3.12; P = .004) and B (mean, 3.75% ± 5.55; P = .012). Contrast-enhanced destruction-replenishment US showed significant decreases of tumor blood flow in groups B and C, as compared with group A (P = .003 and P < .001, respectively), and the blood flow in group C was significantly lower than that of group B (P = .01). Immunohistochemical analysis revealed significant decreases of MVD in groups B and C, as compared with MVD in group A (P = .002 and P < .001, respectively); however, there was no significant difference in MVD between groups B and C (P = .21).. Quantification of tumor blood flow by using contrast-enhanced destruction-replenishment US shows the potential to guide drug dosage during antiangiogenic therapy.

Topics: Analysis of Variance; Angiogenesis Inhibitors; Animals; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Cell Line, Tumor; Contrast Media; Liver Neoplasms, Experimental; Mice; Neovascularization, Pathologic; Random Allocation; Statistics, Nonparametric; Sulfur Hexafluoride; Thalidomide; Ultrasonography

Topics: Adult; Aged; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Dextrans; Drug Combinations; Embolization, Therapeutic; Female; Gelatin Sponge, Absorbable; Humans; Iodamide; Iodized Oil; Iron; Liver; Liver Neoplasms; Male; Middle Aged

Topics: Analysis of Variance; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Dextrans; Drug Combinations; Embolization, Therapeutic; Gelatin Sponge, Absorbable; Humans; Iodamide; Iodobenzoates; Iron; Liver Neoplasms; Methylcellulose; Prognosis

Topics: Animals; Biological Products; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Catheterization; Dextrans; Drug Combinations; Embolization, Therapeutic; Gelatin Sponge, Absorbable; Hepatic Artery; Humans; Iodamide; Iodized Oil; Iron; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Middle Aged; Picibanil; Rabbits

Ferromagnetic microembolization (FME) was applied to patients with hepatoma, using iron microspheres (30-50 mu), suspended in aqueous polysaccharide solution; dextran 40 (12%), sodium carboxymethyl-cellulose (2%) in saline solution. Hepatic arterial infusion of this agent was performed under external magnetic control to confine iron microspheres within the target organs. The therapeutic effect of this procedure on 44 patients with hepatoma was evaluated in relation to the stages of the disease, showing excellent, improved survival terms; survival rates calculated by Kaplan-Meier's method for patients with stage I to III hepatomas were 80% (1 year), 50% (2 years) and 30% (3 years). In order to extend the therapeutic effect of this procedure further, polysaccharide solution was also utilized as a carrier of anti-cancer agents. Serologic and histologic data in experimental animals showed evidence of prolonged release of Mitomycin from polysaccharide solution admixed, indicating its potential use as a method of chemo-embolization. In addition to this, we have also been developing the induction heating of the magnetic microspheres, introduced into the lesion by means of FME, to heat the lesion selectively. The procedure is still in the experimental phase. However, recent results strongly suggest the possibility of its clinical use. In conclusion, we consider FME to be one of the most reliable and potentially valuable methods for extending the capability of multidisciplinary treatment of hepatoma.

Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Dextrans; Drug Combinations; Embolization, Therapeutic; Humans; Hyperthermia, Induced; Iodamide; Iron; Liver Neoplasms; Liver Neoplasms, Experimental; Magnetics; Microspheres; Rabbits

Topics: Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Dextrans; Drug Combinations; Embolization, Therapeutic; Humans; Iodamide; Iron; Liver Neoplasms; Microspheres