Intrahepatic Arterial Infusion Research Articles

Z-domain protein nano-bio interfaced MRI visible anti-program death ligand-1 nanoconjugates for enhanced local immune checkpoint inhibitor immunotherapy

Monoclonal antibody (mAb) based immune checkpoint inhibitors (ICIs) have emerged as an effective and promising therapeutic agent for cancer immunotherapy. In the setting of tumor immune-suppression, an effective delivery of mAbs ICI might be essential to overcome tumor resistance, immune tolerance, and immune-related adverse effects (irAEs). Herein we report engineered MRI visible anti-programmed cell death ligand-1 mAb (aPD-L1) nanoconjugates using nano-bio interface Z-domain (Z) protein adaptors for the local ICI immunotherapy. Z protein adaptors, which are binding with Fc region of IgG mAb, were modified to be attached on the surface of MRI visible ferumoxytol (Fer). Z-protein adaptors on the surface of Fer allowed an oriented conjugation of aPD-L1 exposing active Fab binding sites outward for effective blockage of immune checkpoints. Enhanced affinity and avidity of engineered Z mediated aPD-L1 nanoconjugates (aPD-L1-Z-Fer) to block the PD-1/PD-L1 axis were demonstrated in vitro and in vivo. Transcatheter-directed hepatic intra-arterial (IA) infusion of aPD-L1-Z-Fer showed superior in vivo hepatocellular carcinoma (HCC) tumor suppression, immune conversion, and minimized irAEs compared to the experimental groups treated with systemic aPD-L1, local aPD-L1, or chemically conjugated aPD-L1@Fer. Nano-bio interface Z protein adaptors mediated conjugation of functional nanoparticles and mAbs ICI will provide a new avenue to expand local ICI immunotherapy.

Intra-Arterial Therapy for Unresectable Colorectal Liver Metastases: Which and When? A Commentary on “Intra-Arterial Therapy for Unresectable Colorectal Liver Metastases: A Meta-Analysis”

Systemic chemotherapy is the standard of care for metastatic colorectal cancer (CRC) (1). However, CRC can present with liver-limited or liver-dominant metastatic disease. This has generated many strategies aimed at specifically treating liver metastases, often in combination with systemic therapy. Some trials have shown a survival benefit with strategies incorporating hepatic intra-arterial infusion (HAI) chemotherapy with floxuridine (2). Most studies, however, have not shown a benefit of treatment with intra-arterial hepatic embolic therapy.

Adipose most abundant 2 protein is a predictive marker for cisplatin sensitivity in cancers

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients’ condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).

Multimodal treatment strategies for colorectal liver metastases.

Colorectal cancer is the third most common cancer worldwide. Half of CRC patients develop liver metastases during the course of the disease, with a 5-year survival rate close to zero in the absence of therapy. Surgical resection remains the only possible curative option, and current guidelines recommend adjuvant chemotherapy, resulting in a 5-year survival rate exceeding 50%. Neoadjuvant systemic therapy is not indicated in cases with simple resection but should be offered to all patients with extensive bilobar disease. Personalised systemic treatment is essential to convert upfront non-resectable lesions to resectable ones. Anatomical resections, non-anatomical resections and two-stage hepatectomies can be performed though open or minimally invasive (laparoscopic or robotic) surgery. The extent of a hepatic resection is limited by the risk of postoperative liver failure due to a too small liver remnant, inflow or outflow obstruction or insufficient biliary drainage. About 75% of patients are diagnosed with non-resectable liver metastases not amenable to a standard upfront resection. In recent years, effective therapeutic approaches have revolutionised liver surgery and new strategies have enabled the conversion of primarily non-resectable metastatic disease for resection. These strategies include oncological and surgical therapies, as well as combinations of the two. From an oncological perspective, colorectal liver metastases  may be treated by systemic chemotherapy or immunotherapy, or selective intra-hepatic arterial infusion chemotherapy, depending on the extent of the disease and the mutational status. In surgery, we often apply two-stage strategies using portal vein occlusion, such as portal vein embolisation or ligation, or complex two-stage hepatectomy such as associating liver partition and portal vein ligation for staged hepatectomy. Other additive tools to reach curative resection are tumour ablations (electroporation, microwave or radiofrequency). The role of stereotactic radiation of liver metastases is not yet well defined. Modern radiation techniques, including image guidance, breath hold and gating, were only introduced for a larger patient population in recent years. Therefore, prospective studies with larger patient cohorts are still pending. Over the last decade, liver transplantation has gained increasing attention in selective cases of non-resectable colorectal liver metastases, with promising cohort studies, but definitive recommendations must await the results of ongoing randomised controlled trials. The optimal treatment of patients with colorectal liver metastases requires the timely association of various strategies, and all cases must be discussed at multidisciplinary team conferences. While colorectal liver metastases was a uniformly lethal condition a few decades ago, it has become amenable to curative therapies, with excellent quality of life in many scenarios. This review reports on up-to-date treatment modalities and their combinations in the treatment algorithm of colorectal liver metastases.   &nbsp.

Increased Survival Benefit of Adjuvant Intra-arterial Infusion Chemotherapy in HCC Patients with Portal Vein Infiltration after Hepatectomy.

The role of adjuvant hepatic intra-arterial infusion chemotherapy (HAI) is considered to be a promising option. We examined treatment effects of adjuvant HAI using cisplatin in 37 hepatocellular carcinoma (HCC) patients with portal vein infiltration (PVI) who underwent hepatectomy in comparison with those in 85 patients who did not. PVI in 89 patients. Increased levels of aspartate transaminase, tumor markers, size and microvessel tumor infiltration (MVI) or cirrhosis, poorly differentiation, non-adjuvant HAI was associated with lower overall survival (p = 0.09). Poor differentiation, MVI and HAI were independently risk factors associated with tumor-free and overall survivals by the multivariate analysis (p < 0.05). Adjuvant HAI tended to show longer survivals in comparison with no-HAI (p = 0.08) and the multivariate analysis revealed significant efficacy of HAI for better prognosis. Adjuvant HAI showed effectiveness on prolonging tumor-free and patient survival in HCC with PVI and is a promising option in the daily clinical practice.

Regenerative Therapy for Liver Cirrhosis Based on Intrahepatic Arterial Infusion of Autologous Subcutaneous Adipose Tissue-Derived Regenerative (Stem) Cells: Protocol for a Confirmatory Multicenter Uncontrolled Clinical Trial.

BackgroundLiver cirrhosis results from chronic hepatitis, and is characterized by advanced fibrosis due to long-term hepatic inflammation. Cirrhosis ultimately leads to manifestations of jaundice, ascites, and encephalopathy, and increases the risk of hepatocellular carcinoma. Once cirrhosis is established, resulting in hepatic failure, no effective treatment is available. Therefore, novel therapies to inhibit disease progression of cirrhosis are needed.ObjectiveThe objective of this investigator-initiated clinical trial is to assess the safety and efficacy of autologous adipose tissue-derived regenerative (stem) cell therapy delivered to the liver via the hepatic artery in patients with liver cirrhosis.MethodsThrough consultation with the Japan Pharmaceuticals and Medical Devices Agency, we designed a clinical trial to assess a therapy for liver cirrhosis based on autologous adipose tissue-derived regenerative (stem) cells, which are extracted using an adipose tissue dissociation device. The primary endpoints of the trial are the serum albumin concentration, prothrombin activity, harmful events, and device malfunction.ResultsEnrollment and registration were initiated in November 2017, and the follow-up period ended in November 2019. Data analysis and the clinical study report will be completed by the end of March 2020.ConclusionsCompletion of this clinical trial, including data analysis, will provide data on the safety and efficacy of this novel liver repair therapy based on autologous adipose tissue-derived regenerative (stem) cells using an adipose tissue dissociation device.Trial RegistrationUMIN Clinical Trials Registry UMIN000022601; https://tinyurl.com/w9uqw3qInternational Registered Report Identifier (IRRID)DERR1-10.2196/17904

Study of Intrahepatic Arterial Infusion of TG6002 in Combination With 5-FC in Patients With Metastatic Colorectal Cancer

Study of Intrahepatic Arterial Infusion of TG6002 in Combination With 5-FC in Patients With Metastatic Colorectal Cancer

Safety and efficacy of repeated intra-hepatic artery and intravenous infusion of ET140202, a novel anti-AFP/MHC complex T-cell, in advanced hepatocellular carcinoma.

e14013 Background: Despite the success in hematological malignancies, immunotherapy of solid tumors using redirected T cells such as CAR-T remains challenging due to the lack of a unique tumor antigen, inefficient trafficking of CAR T cells to tumor sites and the presence of immunosuppressive tumor microenvironment. ET140202 is a novel T-cell platform that targets AFP/MHC complex with GPC3-guided co-stimulation aiming to improve the specificity and efficacy. Herein we report a case study of ET140202 for a subject with AFP+ recurrent HCC previous treated with surgery and 2 TACE therapies. Baseline imaging showed multiple nodules on segment 7 of right lobe with enlarged lymph nodes in hepatic hilar region. Methods: From 9/25/18 to 1/29/19 the subject first received 2 intra-hepatic artery infusions (i.a.) of ET140202 T cells at the dose of 3×106 cells/kg followed by 4 i.v. infusions at the dose of 6×106 cells/kg. No lymphodepleting chemotherapy was given prior to T-cell infusion. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 2, 3, 4, 6, 9, 12 and 24. Results: Vital signs are normal after each infusion. No treatment-related Grade 2 or higher AEs observed. Grade 1 events that were possibly attributable to therapy included transient elevation of AST and bilirubin 58 days post the 1st infusion. Both events resolved in 4 days without treatment. The subject did not experience any clinical signs of CRS or neurotoxicity. Month 1, 2, and 3 follow-ups showed that the number and size of the liver nodules slowly increased overtime. Month 4 follow-up showed that the size of liver nodules decreased more than 50% of baseline and resulted in PR based on RECIST criteria. The AFP level elevated in the subject after infusion and reached the peak of 2097 ng/mL 55 days post 1st infusion, gradually dropped to 905 ng/mL on day 67, elevated to the 2nd peak of 2660 ng/mL and gradually decreased to 1235 ng/mL at the last follow-up on day 130. Conclusions: Repeated infusion of ET140202 T cells via i.a. and i.v. routes is safe and shows early sign of efficacy 4 months post initiation of the treatment in AFP+/HLA-A2+ HCC subject.

Clinical Pharmacokinetics and Pharmacodynamics of Transarterial Chemoembolization and Targeted Therapies in Hepatocellular Carcinoma.

The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.

Substantiation of principles of combined stage treatment of patients with colon cancer with unresectable liver metastases

The article presents the results of long-term clinical, molecular-biological and laboratory studies on combined poly-stage treatment of patients with colon cancer with liver metastases. The cytotoxicity of various chemotherapeutic agents for colorectal carcinoma in the lines of HT 29 and NMG 64/84 cells was studied by analysis of human colony-forming tumor (HTCA). In vitro studies on the suspension of tumor cells from remote liver metastases were carried out to determine the most effective chemotherapeutic agents for intra-arterial hepatic infusion (HAI). Individual choice of the scheme of systemic chemotherapy depends on the level of thymidylate synthetase (TS) in the tumor tissue. Long-term own clinical experience and analysis of world literature allow authors to state that stage resection of the liver (STR) in combination with regional (HAI) and systemic chemotherapy is the method of choice in the treatment of patients with colorectal cancer with unresectable liver metastases. In comparison with other treatment methods (ALPPS and TSH), STR has the least negative consequences and is beneficial from the tumor-biological point of view.

Fluorouracil, leucovorin and irinotecan combined with intra-arterial hepatic infusion of drug-eluting beads preloaded with irinotecan in unresectable colorectal liver metastases: side effects and results of a concomitant treatment schedule. Clinical investigation.

Safety evaluation of concomitant systemic chemotherapy and liver chemoembolization in patients with colorectal cancer. Seven patients with metastases confined to the liver were included and stratified into two groups, depending of dosage of systemic chemotherapy. The first group received systemic chemotherapy (FOLFIRI) with 20% dose reduction, and the second group received the full dose of the same chemotherapy. In both groups, chemoembolization of liver metastases with drug-eluting bead irinotecan (DEBIRI) was performed following the application of systemic chemotherapy. The toxicity profiles of the two groups were compared. Of the 7 patients included, 4 received the reduced systemic chemotherapy dose and 3 received the full chemotherapy dose. DEBIRI was performed in all 7 patients. The main toxicities observed in the reduced chemotherapy dose group were leukopenia (25%), anorexia (75%), diarrhea (25%), vomiting (25%), right upper abdominal quadrant pain (100%) and elevated serum amylase level (25%). Main toxicities observed in the full chemotherapy dose group were anorexia (66.6%), vomiting (33.3%), right upper abdominal quadrant pain (100%), and elevated serum amylase level (66.6%). There were no significant differences between the two groups ( P = 0.78541). Patients with isolated liver metastases from a colorectal primary can safely be treated with DEBIRI chemoembolization and a full dose of systemic chemotherapy (FOLFIRI).

Phase I clinical study of liver regenerative therapy for cirrhosis by intrahepatic arterial infusion of freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell.

IntroductionAdipose tissue stromal cells contain a substantial number of mesenchymal stem cells. As such, their application to regeneration of miscellaneous impaired organs has attracted much attention.MethodsWe designed a clinical study to investigate freshly isolated autologous adipose tissue-derived stromal/stem (regenerative) cell (ADRC) therapy for liver cirrhosis and conducted treatment in four cirrhotic patients. ADRCs were isolated from autologous subcutaneous adipose tissue obtained by the liposuction method, followed with use of the Celution system adipose tissue dissociation device. The primary endpoint is assessment of safety one month after treatment. We also characterized the obtained ADRCs.ResultsTwo patients had type C cirrhosis, one had nonalcoholic steatohepatitis-cirrhosis, and one had type B cirrhosis. No serious adverse events were observed during the 1-month study period after freshly isolated ADRC infusion. Serum albumin concentrations were maintained or improved during this period as well as during the succeeding follow-up of approximately 1 year in two patients and 6 months in another patient. Liver regeneration-related factors, namely hepatocyte growth factor and interleukin-6, were elevated 1 day after ADRC treatment in all patients. The obtained freshly isolated ADRCs were expanded in culture and found to express mesenchymal stem cell markers. Gene expression profile analysis of ADRCs was shown to involve inflammatory features, suggesting that characteristics of the obtained ADRCs were related to immunomodulatory biological effects.ConclusionThis clinical study treatment for liver cirrhosis using ADRCs was proven to be safely conductible, and can be further investigated in future for regeneration/repair of liver cirrhosis.

4:21 PMAbstract No. 292 - High hepatopulmonary shunting improves survival in patients undergoing intrahepatic arterial chemotherapy infusion for treatment of liver metastases

4:21 PMAbstract No. 292 - High hepatopulmonary shunting improves survival in patients undergoing intrahepatic arterial chemotherapy infusion for treatment of liver metastases

Use of Hepatic intra-arterial infusion of Yttrium-90 microspheres for downstaging and bridging to liver transplantation in patients with advanced hepatocellular carcinoma

Use of Hepatic intra-arterial infusion of Yttrium-90 microspheres for downstaging and bridging to liver transplantation in patients with advanced hepatocellular carcinoma

Survival analysis of intrahepatic arterial infusion of Endostar combined with transcatheter arterial chemoembolization for treatment of advanced hepatocellular carcinoma

Survival analysis of intrahepatic arterial infusion of Endostar combined with transcatheter arterial chemoembolization for treatment of advanced hepatocellular carcinoma

Intrahepatic arterial infusion of endostatin combined with transcatheter arterial chemoembolization for treatment of advanced hepatocellular carcinoma: A meta-analysis

Intrahepatic arterial infusion of endostatin combined with transcatheter arterial chemoembolization for treatment of advanced hepatocellular carcinoma: A meta-analysis

Fluorouracil, Leucovorin and Irinotecan Combined with Intra-Arterial Hepatic Infusion of Drug-Eluting Beads Preloaded with Irinotecan in Unresectable Colorectal Liver Metastases: Side Effects and Results of a Concomitant Treatment Schedule. Clinical Investigation

Fluorouracil, Leucovorin and Irinotecan Combined with Intra-Arterial Hepatic Infusion of Drug-Eluting Beads Preloaded with Irinotecan in Unresectable Colorectal Liver Metastases: Side Effects and Results of a Concomitant Treatment Schedule. Clinical Investigation

Clinical study on the sensitivity test guided hepato-arterial/portal-vein chemotherapy in patients with unresectable hepatocellar carcinoma

Purpose: Approximately 20 % of tumors have the opportunity to be resected in patients with hepatocellar carcinoma (HCC) and their prognoses were acceptable. For the unrespectable HCC, however, the outcomes were rather poor because the specialty of the tumor blood supply and the tumor was insensitive to the chemotherapy drug. The objective of this study was to find sensitive drugs for individual patients and determine the safety and antitumor activity of hepatic intra-arterial and portal vein infusion chemotherapy. Methods : A total of 120 patients with the mean patient age of 56 years and with unresectable HCC were randomly divided into experimental group and control group. The experiment group was infused through an intra-arterial and portal vein catheter 3 different drugs were chosen by the results of drug sensitive test, whereas the control group was treated for TACE. The changes in tumor-size and AFP, two-step operation rate, survival rate, and complications were observed in these patients. Results: The tumor size reduced in 28(47.6 %) cases, stabilized in 14(23.3 %) cases, and progressed in 18(30 %) cases in experimental group as measured by CT or MRI after six chemotherapy cycles, whereas the corresponding data was 17(28.5 %) cases, 7(11.5 %) cases and 36(60 %) cases in the control group (P &lt; 0.05). The AFP was declined in 51 cases in experimental group and in 30 cases in control group (P &lt; 0.05). In the experimental group, the median follow-up time was 21 months; the overall survival rates (OS) of 6 months, 12 months, and 18 months were 86 %, 72 %, and 65 %, respectively. In the control group, the median follow-up time was 16 months; the OS rates of 6 months and 12 months were 58 % and 40 %, respectively. Six patients in the experimental group and 3 patients in the control group had two-step operation. There was no severe incidence of complications in both groups. In the experimental group, 2 (3 %) patients had wound infection, 8 cases had the chemotherapy relative diarrhea, and 18 (30 %) cases had grade Ⅰ or Ⅱ bone marrow suppression. In the control group, the chemotherapy relative diarrhea were 15 (25 %) cases and grade Ⅰ or Ⅱ bone marrow suppression were 33 (55 %) cases. Conclusion : The artery and portal vein pump transfusion chemotherapy guided by drug sensitive test was efficient for HCC treatment. The patients can get longer OS and lower complication incidence. -------------------------------------------------------- Cite this article as: Wu D, Wei S, Luo C, Wu X, Feng Y, Zhang F, Nie L, Xia X. Clinical study on the sensitivity test guided hepato-arterial/portal -vein chemotherapy in patients with unresectable hepatocellar carci-noma. Int J Cancer Ther Oncol 2014; 2(2):02029. DOI: 10.14319/ijcto.0202.9

8:45 AM; Abstract No. 85 - Phase I clinical trial of intrahepatic arterial infusion of a HSV-1 replication-conditional mutant (rRRp450)

8:45 AM; Abstract No. 85 - Phase I clinical trial of intrahepatic arterial infusion of a HSV-1 replication-conditional mutant (rRRp450)

Effect of Transcatheter Intraarterial Therapies on the Distribution of Doxorubicin in Liver Cancer in a Rabbit Model

Background and AimsTranscatheter intraarterial techniques can effectively deliver chemotherapeutic agents to tumor and improve the efficacy of chemotherapy. The present study is designed to evaluate the effect of transcatheter intraarterial techniques on the distribution of doxorubicin in relation to blood vessels in liver cancer.MethodsVX2 tumors were implanted in the livers of 32 rabbits. The animals were divided into 4 groups of 8 animals each. Group 1 (doxo iv) animals received doxorubicin intravenous injection; group 2 (doxo ia) received doxorubicin hepatic intraarterial infusion; group 3 (doxo ia + E) received doxorubicin hepatic intraarterial infusion followed by embolization; group 4 (doxo + L ia + E) received hepatic intraarterial infusion of doxorubicin mixed with Lipiodol followed by embolization. Ten minutes or 4 hours after treatment, the animals were sacrificed and tumors were sampled. Immunofluorescence techniques were used to evaluate the distribution of doxorubicin in relation to blood vessels.ResultsDoxorubicin fluorescence was distributed around tumor blood vessels and decreased with distance from the blood vessels. Tumor cells in avascular and adjacent regions were not exposed to detectable concentrations of doxorubicin. Tumors in the group 2, 3 and 4 had a significant increase in doxorubicin penetration compared with the group 1 tumors (P<0.05). Among the three groups of transcatheter therapies, doxorubicin penetration distance in group 3 was significantly larger than that in group 2 and 4 (P<0.05), and no significant difference was found between group 2 and 4 tumors (P>0.05) at 10 minutes. In contrast, at 4 hours and in total, both group 3 and 4 tumors had significant increases in drug penetration compared with group 2 (P<0.05), and no significant difference was noted between group 3 and 4 tumors (P>0.05).ConclusionTranscatheter intraarterial therapies improve doxorubicin penetration in liver cancer; nevertheless their effect on drug distribution is somewhat limited.