Therapy For Hepatocellular Carcinoma Patients Research Articles

High number of PD-1 positive intratumoural lymphocytes predicts survival benefit of cytokine-induced killer cells for hepatocellular carcinoma patients.

Background & AimsAdjuvant cytokine‐induced killer (CIK) cells treatment has shown potential in reducing the recurrence rate and prolonging the survival of patients with hepatocellular carcinoma (HCC). We aimed to identify the best predictive biomarker for adjuvant CIK cells treatment in patients with HCC after curative resection.MethodsThis study retrospectively included 145 pairs of HCC patients by one‐to‐one propensity score matching. One group received CIK cells transfusion after surgery (surgery‐CIK group); the other one group underwent surgery only (surgery‐only group). Immunohistochemistry (IHC) was used to measure PD‐1, PD‐L1, CD4, CD8 and Foxp3 expression in tumour tissues of surgery‐CIK group; IHC of PD‐1 and PD‐L1 was conducted in the surgery‐only group.ResultsThe surgery‐CIK group had a significantly higher disease‐free survival (DFS) and overall survival (OS) rates compared to the surgery‐only group. Of all the intratumoural biomarkers, in the surgery‐CIK group, multivariate analysis showed that a high number of PD‐1+ tumour infiltrative lymphocytes (TILs) was the only factor that independently predicted favourable OS and DFS. By contrast, in the surgery‐only group, no significant correlations between PD‐1/PD‐L1 expression and survival of patients were identified. Further correlation analysis showed a high number of PD‐1+ TILs associated with a high number of both CD4+ and CD8+ TILs in surgery‐CIK group.ConclusionsA high number of PD‐1+ TILs can serve as a potent biomarker for adopting CIK cells therapy in HCC patients after curative resection.

Efficacy of Transarterial Chemoembolisation with or without Antiviral Therapy for Patients with Hepatocellular Carcinoma after Radical Hepatectomy.

Objective This study aimed at assessing the effects of transcatheter arterial chemoembolisation (TACE) and antiviral therapy on improving the prognosis of patients with hepatocellular carcinoma (HCC) after radical hepatectomy. Methods This study reviewed the data of 120 patients with HCC who received either radical hepatectomy alone (control group), radical hepatectomy with postoperative TACE (TACE group) or radical hepatectomy with combined postoperative TACE, and antiviral therapy (combined group) from January 2000 to May 2015. To reduce the impact of the possible biases on the conclusion of this study to the minimum, the cases with similar demographic and clinicopathological characteristics were collected and 40 cases were assigned into each group. Recurrence, disease-free survival (DFS), and overall survival (OS) rates were compared. Results Median follow-up period was 54.26 ± 22.65 months with a range of 17–110 months. Recurrence after radical surgery was observed for 39 (97.5%) patients in the TACE group, 32 (80%) in the combined group, and 40 (100%) in the control group with median recurrence duration of 33, 43, and 16.5 months, respectively. Postoperative TACE with or without antiviral therapy significantly prolonged the DFS rate compared with radical hepatectomy alone (P = 0.000). TACE combined with antiviral therapy significantly extended the DFS rate compared with TACE alone (P = 0.008). Postoperative TACE with or without antiviral therapy also significantly prolonged the OS rate compared with radical hepatectomy alone (P = 0.000). In addition, antiviral therapy combined with TACE significantly extended the 5-year OS rate of patients compared with individual TACE and radical hepatectomy (67.5% versus 55% and 2.5%; P = 0.032). Conclusion TACE is an appropriate therapy for HCC patients after radical hepatectomy. When combined with antiviral therapy, this treatment may further prolong the recurrence time and thus lead to high DFS and OS rates.

Cumulative dose of radiation therapy of hepatocellular carcinoma patients and its deterministic relation to radiation-induced liver disease

This study aimed to investigate the relationship between dose and radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) receiving 3-dimensional conformal radiotherapy (3DCRT). Twenty-three patients with HCC who received conventional fractionated 3DCRT, including 7 who were diagnosed with classic RILD, were enrolled in this retrospective investigation. Cone-beam computed tomography (CBCT) scans were acquired at the time of treatment for each patient. The beams from each patient's treatment plan were applied to each pretreatment CBCT (the modified CBCT or mCBCT) to construct the delivered dose distribution of the day considering inter-treatment anatomy changes. The daily doses were summed together with the help of deformable image registration (DIR) to obtain the adjusted cumulative dose (Dadjusted). The dose changes to the normal liver between the original planned dose (Dplan) and Dadjusted were evaluated by V20, V30, V40, and the mean dose to normal liver (MDTNL). Univariate analysis was performed to identify the significant dose changes. Among the 23 patients, the liver V20, V30, V40, and MDTNL showed significant differences between Dplan and Dadjusted, with average values of these parameters increased by 4.1%, 4.7%, 4.5%, and 3.9 Gy, respectively (p < 0.05). The adjusted liver dose in 21 patients (91%) was higher than the planned value. For patients without and with RILD,the MDTNL was increased on average by 3.5 Gy and 4.7 Gy, and normal tissue complication probability (NTCP) increased on average by 2.8% and 7.5%, respectively. Our study found that the adjusted cumulative dose based on calculations using pretreatment mCBCT differs significantly from planned dose; the use of the dosimetric results of the initial plan was found to be less predictive of RILD as compared with Dadjusted. Determination of a reconstructed Dadjusted using the mCBCT scans are more accurate in predicting RILD and has the potential to reduce the risk of RILD.

Safety and Efficacy of Accelerated Hypofractionation and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma Patients With Varying Degrees of Hepatic Impairment

To report the toxicities and outcomes for stereotactic body radiation therapy (SBRT) and accelerated hypofractionated radiation therapy (AHRT) in patients with Child-Pugh (CP) class A, B, or C and albumin-bilirubin (ALBI) score 1, 2, or 3 hepatocellular carcinoma. We retrospectively reviewed the data from 146 patients with hepatocellular carcinoma who had undergone SBRT (50Gy in 5 fractions) or AHRT (45Gy in 18 fractions). The primary endpoint was liver toxicity, defined as an increase in the CP score of ≥2 within 6months of radiation therapy. The secondary endpoints of ALBI change, overall survival, and local control were also calculated. The median follow-up was 23months (range 1-59). Most received SBRT (72%), and 28% received AHRT. Of all 146 patients, 45 (31%) had a CP score elevation of ≥2 within 6months of radiation therapy (RT) (27 patients [28%] with baseline CP-A/B7 and 18 [35%] with baseline CP-B8/B9/C cirrhosis; P = .45). On multivariate analysis, neither baseline CP nor ALBI score was predictive of toxicity. No patient with a decline in liver functionality of CP ≥2 within 6months of RT returned to baseline at later time points. Eleven grade 4 toxicities were observed. The mean change in the raw ALBI score at ∼6months was similar for all baseline ALBI groups. Twenty-two patients underwent orthotopic liver transplantation after RT, 13 of whom had baseline CP-B8/B9/C liver functionality. For all patients, the 1- and 2-year treated-lesion local control was greater for SBRT than for AHRT (2-year 94% vs 65%, P<.0001). The tolerability of SBRT or AHRT as measured by a CP score decline of ≥2 within 6months of RT was similar across baseline liver functionality groups. Compared with AHRT, SBRT was associated with superior local control. Because thetrue tolerability of limited-volume RT for patients with CP-B or CP-C cirrhosis is unknown, prospective trials validating its safety and efficacy are warranted.

Abstract IA25: Targeted therapies for hepatocellular carcinoma

Abstract In 2008, the multikinase inhibitor Sorafenib consistently proved to extend the survival of patients with Hepatocellular Carcinoma (HCC) that were treated in the advanced stage and had a good liver function, and it became the first agent to be specifically approved for this indication (ref). Although Sorafenib was a paradigm shift in the field, systemic therapy of HCC remains a major unmet need. The mechanism of action of Sorafenib is still poorly understood and the same is true for the mechanism of resistance after initial response, which usually reveals as disease stabilization for a few months. Molecular biomarkers predicting response and resistance to Sorafenib are also hardly defined. Furthermore, all subsequent novel targeted agents or regimens tested in large randomized controlled trials both in the first-line and second-line setting have been unable to reach or improve the magnitude of benefit obtained with Sorafenib. Strategies under study have included the blockade of other pro-angiogenic signals such as the FGFR pathway using Brivanib, proliferative signals such as the EGFR pathway using Erlotinib, or cell growth, proliferation, angiogenesis and apoptosis signals arising from the PI3K-Akt-mTOR pathway using Everolimus. The relevance of targeting these pathways is still not completely understood since biomarker data have not been reported, including EGFR and FGFR expression in tumor specimens. Besides, a number of trials have definitively shown the lack of efficacy of Doxorubicin, used for decades as a systemic therapy for HCC patients without formal scientific evidence. And no survival benefit was proven for combination chemotherapy based on 5-fluorouracil and oxaliplatin. The door was then opened to a more focused approach in which only patients with an altered targeted pathway are deemed candidates for a given agent. The anticancer activity of the c-met tyrosine kinase inhibitor Tivantinib was suggested in a randomized, placebo-controlled trial in the second-line setting where patients with high c-met expression survived significantly longer if they received Tivantinib. Patient enrichment based on molecular targets has been incorporated into the clinical development of other agents such as a monoclonal antibody that binds to glypican-3 or Refametinib a tyrosine kinase inhibitor that targets the MAPK (Ras-Raf-MEK-ERK) pathway. Agents targeting novel signaling pathways including TGF-β and FGF19, but also less explored pathways such as Wntβ-catenin, Hedgehog or Notch are being studied for the treatment of HCC. We will soon learn whether or not this more selective approach translates into positive results. Identification of driver molecular events in an individual patient using markers from tumor biopsies has proven successful in other tumors including breast or lung cancer. However, the reliability of this strategy has been challenged by studies showing intratumoural heterogeneity in various malignancies at advanced stages. HCC needs to be explored in this regard. Citation Format: Bruno Sangro. Targeted therapies for hepatocellular carcinoma [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA25.

Analysis of the factors affecting the safety of robotic stereotactic body radiation therapy for hepatocellular carcinoma patients.

ObjectiveThe objective of this study was to investigate the safety of robotic stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) patients and its related factors.MethodsA total of 74 HCC patients with Child–Turcotte–Pugh (CTP) Class A were included in a multi-institutional, single-arm Phase II trial (NCT 02363218) between February 2013 and August 2016. All patients received SBRT treatment at a dose of 45 Gy/3f. The liver function was compared before and after SBRT treatment by the analysis of adverse hepatic reactions and changes in CTP classification.ResultsAfter SBRT treatment, eight patients presented with decreases in CTP classification and 13 patients presented with ≥ grade 2 hepatic adverse reactions. For patients presenting with ≥ grade 2 hepatic adverse reactions, the total liver volume of ≤1,162 mL and a normal liver volume (total liver volume – gross tumor volume [GTV]) of ≤1,148 mL were found to be independent risk factors and statistically significant (P<0.05).ConclusionThe total liver volume and normal liver volume are associated with the occurrence of ≥ grade 2 hepatic adverse reactions after SBRT treatment on HCC patients. Therefore, if the fractionated scheme of 45 Gy/3f is applied in SBRT for HCC patients, a total liver volume >1,162 mL and a normal liver volume >1,148 mL should be ensured to improve therapeutic safety.

Abstract 3504: High expression of lncRNA-ATB and miR-21 as a biomarker in human hepatocellular carcinoma

Abstract Non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have emerged as novel gene-regulators. The aim of this study was to determine the clinical relevancies of 2 lncRNAs (lncRNA-ATB and MEG3) and 2 miRNAs (miR-21 and miR-31) in hepatocellular carcinoma (HCC). We analyzed clinical specimens from 100 pairs of HCC and matched normal liver (NL) tissues. MiRNAs and lncRNAs expression levels were evaluated by quantitative real-time PCR. In addition, we determined the clinical significance of the ncRNAs expression in matching tissue and serum exosome samples from HCC patients. MiR-21 significantly increased in HCC (P&amp;lt;0.01) compared to corresponding NL tissues. LncRNA-ATB was significantly up-regulated in HCC (P&amp;lt;0.05); however, lncRNA-MEG3 was down-regulated in HCC (P&amp;lt;0.05) tissues. In addition, expression of miR-21 and lncRNA-ATB was significantly associated with the tumor size and poor prognosis of HCC patients. More importantly, expression of serum exosomal lncRNA-ATB and miR-21 was more significantly associated with HCC progression and poor patients survival compared to its’ tissue expression. We conclude that non-coding RNAs (lncRNA-ATB and miR-21) expression has the potential to serve as biomarkers for prognosis and targeted therapy in HCC patients. Citation Format: Eunhye Lee, Gyeonghwa Kim, Se Young Jang, Yong-Hun Choi, Yu Rim Lee, Won Young Tak, Young Oh Kweon, Soo Young Park, Keun Hur. High expression of lncRNA-ATB and miR-21 as a biomarker in human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3504. doi:10.1158/1538-7445.AM2017-3504

Circulating SCCA–IgM complex is a useful biomarker to predict the outcome of therapy in hepatocellular carcinoma patients

Introduction: Hepatocellular carcinoma (HCC) develops in about 3–4% of cirrhotic patients every year. The squamous cell carcinoma antigen (SCCA) has been found elevated in liver cancer specimens by immunohistochemistry, and detected in complex with IgM (SCCA-IgM) in the serum of patients with HCC. The aim of this study was to evaluate the ability of serological SCCA-IgM levels to predict the efficacy of HCC therapy.Materials and methods: From April 2012 to April 2014, 131 patients with a new diagnosis of HCC were enrolled. The HCC diagnosis was made according to the EASL guidelines. The patients were staged and treated according to the BCLC Staging System: BCLC stages A and B were treated with locoregional therapy, and BCLC stage C was treated with Sorafenib. Response to therapy was evaluated according to the mRECIST criteria. Serum SCCA-IgM levels were determined by a commercially available ELISA kit at basal time (T0) and after one month of treatment (T1).Results: At baseline and one month into therapy, SCCA-IgM levels were significantly lower (p value <.05) in patients who responded to therapy compared to those who did not respond (median SCCA-IgM level [25th + 75th percentile] at T0:115.1 AU/mL [50.0 + 174.4] vs. 149.1 AU/mL [111.3 + 198.8]; median SCCA-IgM level [25th + 75th percentile] at T1: 113.4 AU/mL [50.0 + 194.2] vs. 170.6 AU/mL [111.7 + 344.2]).Conclusion: Our study suggests that the SCCA-IgM determination could be helpful in predicting the response to therapy in patients with HCC.

High number of PD-1 positive tumoral lymphocytes as a potent biomarker for adopting cytokine-induced killer cells in hepatocellular carcinoma.

e15680 Background: Adjuvant cytokine-induced killer cell (CIK) treatment has shown potential in reducing recurrence rate and prolong survival of patients with hepatocellular carcinoma (HCC). We aim to evaluate the PD-1/PD-L1 expression in tumor cells and tumor infiltrative lymphocytes in HCC patients and their correlation with survival benefit from cytokine-induced killer cell therapy. Methods: Between 2004 and 2011, 290 HCC patients received curative section were retrospectively enrolled by one-to-one propensity score matching, including 145 cases received adjuvant CIK cell transfusion after surgery (Surgery-CIK group), and 145 cases underwent surgery only (Surgery only group). Immunohistochemistry (IHC) was used to measure the PD-1 and PD-L1 expression in formalin fixed paraffin embedded tissue of all subjects; IHC of CD4, CD8 and Foxp3 were also conducted in the surgery-CIK group to explore their correlation with PD1/PD-L1 expression and survival of HCC patients. Results: The surgery-CIK group had significantly improved overall survival (OS; HR 0.55, 95% CI 0.33-0.92) and disease-free survival (DFS; HR 0.59, 95% CI 0.42-0.83) as compared to the surgery-only group. In the surgery-CIK group, univariate analysis showed both high PD-L1 expression and a high number of PD-1+ TILs were significantly associated with improved OS, while only the high number of PD-1+ TILs was associated with improved DFS. Multivariate analyses showed a high number of PD-1+ TILs was the only independent factor predicting favorable OS (HR 0.19, 95% CI 0.08-0.45) and DFS (HR 0.40, 95% CI 0.24-0.66) in the surgery-CIK group. By contrast, in the surgery-only group, no significant associations between PD-1/PD-L1 expression and survival of patients were identified. Conclusions: A high number of PD-1+ TILs can serve as a potent biomarker to adopt CIK cell therapy in HCC patients after curative resection.

간문맥 종양혈전을 동반한 간세포암종의 예후 인자

Background/Aims: Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) exhibits poor prognosis. The aim of this study is to evaluate factors associated with survival of HCC patients with PVTT to suggest better therapeutic options. MethodsPatients with HCC which were newly diagnosed at three tertiary hospitals between January 2004 and December 2012, were reviewed retrospectively. Among them, Barcelona Clinic of Liver Cancer stage C patients with PVTT were identified. Factors affecting overall survival (OS) were analyzed and efficacies of the treatment modalities were compared. ResultsFour hundred sixty five patients with HCC and PVTT were included. Liver function, tumor burden, presence of extrahepatic tumor, alfa fetoprotein, and treatment modalities were significant factors associated with OS. Treatment outcomes were different according to the initial modalities. OS of the patients who received hepatic resection, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), sorafenib, systemic cytotoxic chemotherapy, radiation therapy (without combination), and supportive care were 27.8, 7.1, 6.7, 5.3, 2.5, 3.0, 1.8, and 0.9 months, respectively (P<0.001). Curative-intent treatments such as hepatic resection or RFA were superior to noncurativeintent treatments (P<0.001). TACE or HAIC was superior to sorafenib or systemic chemotherapy (P<0.001). Combining radiotherapy to TACE or HAIC did not provide additional benefit on OS (P=0.096). ConclusionsTreatment modalities as well as baseline factors significantly influenced on OS of HCC patients with PVTT. Whenever possible, curative intent treatments should be preferentially considered. If unable, locoregional therapy would be a better choice than systemic therapy in HCC patients with PVTT.

Prognostic factors of sorafenib therapy in hepatocellular carcinoma patients with failure of transarterial chemoembolization.

There is no approved therapy for patients with failed transarterial chemoembolization (TACE) and progression of hepatocellular carcinoma. We aimed to investigate the efficacy and prognostic factors in patients with TACE failure who received sorafenib rescue therapy. We investigated 54 patients who met the criteria of TACE failure as defined by the international guidelines of Europe and Japan. Sorafenib was used as a rescue therapy. Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier methods, and multivariate analysis was performed to find prognostic factors. The patients were followed for a median 5.5months, and the median duration of sorafenib administration was 3.3months. The presence of main (or lobar) portal vein invasion (PVI) (3.7 versus 8.4months, p=0.004), dose reduction of sorafenib (4.0 versus 8.8months, p=0.002) and Child-Pugh class B (5.3 versus 8.9months, p=0.004) were associated with shorter OS compared to the presence of segmental PVI (or absence of macroscopic vascular invasion, MVI), full dosage of sorafenib and Child-Pugh class A, respectively. The presence of main (or lobar) PVI was associated with poorer PFS compared to the presence of segmental PVI (or absence of MVI) (2.1 versus 3.8months p=0.010). Sorafenib is a potential rescue therapy in patients with TACE failure. However, the clinical benefits need to be further evaluated for patients with main (or lobar) PVI or those treated with reduced doses of sorafenib.

The preventive effect of the impaired liver function for antiemetic therapy against chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients.

Transarterial chemoembolization and hepatic arterial infusion chemotherapy are recommended for the treatment in patients with intermediate stage of hepatocellular carcinoma. Impaired liver function was sometime observed in patients with hepatocellular carcinoma after transarterial chemoembolization or hepatic arterial infusion chemotherapy. However, what kinds of factors deeply influence in impaired liver function are not clear. A retrospective study was performed to evaluate the risk factors of impaired liver function in cisplatin-naïve patients treated with these therapies using cisplatin. Prior to and 2 months after these therapies, we analyzed the liver function by Child-Pugh score in these patients. For assessing the severity of chemotherapy-induced nausea and vomiting, we utilized the Common Terminology Criteria for Adverse Events ver. 4.0. In hepatocellular carcinoma patients received these therapies using cisplatin, the cancer stage and treatment without neurokinin-1 (NK1) antagonist were found to be independent risk factors of the impaired liver function. The treatment with NK1 antagonist was effective in reducing chemotherapy-induced nausea and vomiting and patients treated with NK1 antagonist kept their liver functions after cisplatin-used these therapies. The treatment with NK1 antagonist was effective in chemotherapy-induced nausea and vomiting and prevented the impaired liver function associated with cisplatin-used these therapies in hepatocellular carcinoma patients.

Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients

ABSTRACTThe recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine.

Therapeutic Strategies in HCC: Radiation Modalities.

Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with 131I Lipiodol or 90Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment.

A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma

Background:To date, no adjuvant treatment has been shown to have a clear benefit in patients with hepatocellular carcinoma (HCC). In this prospective phase I/IIa study, we evaluated the safety and efficacy of adjuvant dendritic cell (DC) therapy in HCC patients who received primary treatment for HCC.Methods:Twelve HCC patients who had no viable tumour after primary treatments were included. Dendritic cell vaccines pulsed with cytoplasmic transduction peptide-attached alpha-fetoprotein, glypican-3 and melanoma-associated antigen 1 recombinant fusion proteins were injected subcutaneously near to inguinal lymph nodes. Adverse effects, time to progression (TTP), and associated immune responses were evaluated after DC vaccination.Results:Nine of 12 patients had no tumour recurrence up to 24 weeks after DC vaccination. Among a total of 144 adverse events, 129 events (89.6%) were regarded as adverse drug reactions, all of which were grade 1 or 2. The majority of patients showed enhanced anti-tumour immune responses after DC vaccination. Recurrence-free patients exhibited relatively stronger anti-tumour immune responses than patients who developed recurrence after DC vaccination, as evidenced by lymphocyte proliferation and IFN-γ ELISPOT assays. The median time of TTP was 36.6 months in the DC-vaccination group and 11.8 months in the control group (hazard ratio, 0.41; 95% confidence interval, 0.18–0.95; P=0.0031 by log-rank test).Conclusions:Adjuvant DC vaccine for HCC was safe and well tolerated in phase I/IIa study, and preliminary efficacy data are encouraging to warrant further clinical study in patients with HCC after primary treatments.

Abstract C149: Next-generation sequencing of biopsy-free circulating tumor DNA revealed frequent actionable alterations in advanced hepatocellular carcinoma

Abstract Background: Treatment options for advanced hepatocellular carcinoma (HCC) are limited. Tumor biopsy is not routinely performed in HCC and involves risks. As such, genomic analysis of HCC specimens for matched-targeted therapies is not often an option. The utility of cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) to identify somatic alterations and target therapy in HCC patients has not yet been characterized. Methods: We prospectively evaluated 14 patients with advanced hepatocellular carcinoma (January 2015 - June 2015) using a ctDNA NGS panel of 68 genes (Guardant360). The test sequences complete exons for single nucleotide variants (SNVs) in 68 genes, amplifications of 16 genes, fusion events in ALK/RET/ROS1/NTRK1, and specific insertion/deletion mutations. The mutant allele fraction for detected alterations is calculated relative to wild type in cell-free DNA. The test is sensitive to a single fragment of mutated ctDNA in a 10 ml blood sample, and analytic specificity is &amp;gt;99.9999%. All patients signed informed consent. When appropriate, patients were presented at the UCSD Moores Cancer Center Molecular Tumor Board. Results: All patients (100%) had somatic alterations (SNVs and/or amplifications) (average = 3.6 alterations per patient [range, 1-8]) with a median mutant allele fraction of 0.29% (range 0.1% - 37.77%). Point mutations were identified in the following genes: TP53 (N = 8 patients), CTNNB1 (4), PTEN (1), CDKN2A (1), ARID1A (1), and MET (1); amplifications were identified in CDK6 (2), EGFR (2), MYC (2), BRAF (1), RAF1 (1), FGFR1 (1), CCNE1 (1), PIK3CA (1), and ERBB2/HER2 (1). Eleven patients (79%) had at least one actionable alteration identified. The patient with a CDKN2A inactivating mutation and a CTNNB1 activating mutation was treated with palbociclib (CDK4/6 inhibitor) and celecoxib (COX-2/Wnt inhibitor); des gamma-carboxy prothrombin level decreased by 84% over 2 months (1410 to 242 ng/ml [normal: 0.0 - 7.4 ng/ml]) (alpha fetoprotein (AFP) low at baseline). Another patient with a PTEN inactivating mutation and a MET activating mutation received sirolimus (mTOR inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% in one month (8320 ng/ml to 3045 ng/ml [normal: 0-15 ng/ml]). (Imaging studies are pending). Conclusion: ctDNA profiling is feasible in advanced HCC, and may provide a tissue biopsy-free alternative in these difficult-to-biopsy patients. Two patients who received matched-targeted therapy demonstrated rapid biomarker response. Further study of clinical validity and utility is ongoing. Citation Format: Sadakatsu Ikeda, Kimberly Banks, Richard B. Lanman, Razelle Kurzrock. Next-generation sequencing of biopsy-free circulating tumor DNA revealed frequent actionable alterations in advanced hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C149.

Abstract CT115: Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients

Abstract Background and purpose: In a phase I trial for advanced hepatocellular carcinoma (HCC), glypican-3(GPC3)-derived peptide vaccination was well-tolerated, and immune responses and antitumor efficacy were noted. The recurrence rates of HCC are still high and immunotherapy, as an adjuvant therapy, is expected. Therefore, we have conducted a phase II study of GPC3 peptide vaccine as an adjuvant therapy for HCC patients. Study design: Forty one patients with initial HCC, who had undergone surgery or radiofrequency ablation (RFA), were analyzed in this phase II, open-label, single-arm trial.Ten vaccinations were performed for one year after curative treatment. The primary endpoints were 1- and 2-year recurrence rates. The secondary endpoints were safety and immune responses. We have evaluated GPC3-specific CTL response in PBMCs by IFN-γ enzyme-linked immunospot (ELISPOT) assay. We have evaluated the expression of GPC3 in the 33 primary tumors and 11 recurrence tumors, that could be obtained, by immunohistochemical analysis, and the phenotype of CTLs in recurrence tumor and vaccine site by flow cytometry. Results: GPC3 peptide vaccine showed no severe adverse events. 1-year and 2-year recurrence rates of the 41 patients treated with the vaccination were 24.4% and 53.7%. In this study, 35 patients had received surgery and 6 patients RFA therapy. We analyzed the case-control study to evaluate the reduction in the risk of post-operative recurrence by vaccination. Thirty three patients with initial HCC who underwent curative resection in the same period were selected as control group. The recurrence rate tended to be lower in 35 patients treated with surgery and the vaccination than in 33 patients with surgery alone (28.6% and 54.3% vs 39.4% and 54.5% at 1 year and 2 year, p = 0.346, 0.983). In the patients with GPC3 positive tumor, the recurrence rate was significantly lower in 25 patients treated with surgery and the vaccination than in 21 patients with surgery alone (24% and 48% vs 52.4% and 61.9% at 1 year and 2 year, p = 0.047, 0.387), and there was no significant difference in clinical background. There were not the correlation between the relapse free survival and the antigen-specific immune response as measured by IFN-γ ELISPOT assay. Two of 11 case appeared to lack GPC3 expression in the recurrence tumor, although GPC3 was expressed in the primary HCC tissue before GPC3 peptide vaccine. In the other case, GPC3 peptide specific CTLs had infiltrated into recurrence tumor, and the expression of PD-1 among CD8 positive T cells, was higher in recurrence tumor and vaccine site than in PBMCs. Conclusions: GPC3 peptide vaccine for patient with GPC3 positive tumor could improve 1-year recurrence rates. This study showed GPC3 expression of the primary tumor could be the biomarker for a larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine. Citation Format: Yu Sawada, Toshiaki Yoshikawa, Kazuya Ofuji, Mayuko Yoshimura, Nobuhiro Tsuchiya, Mari Takahashi, Daisuke Nobuoka, Shoichi Mizuno, Itaru Endo, Tetsuya Nakatsura. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT115. doi:10.1158/1538-7445.AM2015-CT115

Changes in CD4 and CD8 after Interventional Management of Hepatocellular Carcinoma

Background and study aim : Hepato-cellular carcinoma (HCC) has many curative choices which in some circumstances are equal to or even better than surgery. These strategies for treatment of HCC may induce certain local effects which trigger distinct immunological responses that may have a systemic impact on the natural history of the tumour itself. These responses are validated through the measurement of specific immune cells in the systemic circulation. In this study, we tried to observe and analyze changes in the peripheral immune cells that accompany and follow HCC ablation by different procedures of radiological intervention and compare our results with literature. So, this study may be useful with other criteria in the guidelines for the selection of the optimal therapeutic strategy for each patient. . Patients and Methods: This study was conducted on about 50patients diagnosed with HCC who were referred to Tropical Medicine Department at Mansoura University Hospital, Egypt and 20 healthy volunteers as a control. The therapeutic strategy was selected according to the tumor stage and general condition. RFA was performed for12 cases, PEI for 13, MWA for12 and TACE for 13 cases. All Patients were subjected to full history taking, clinical examination, liver function tests, anti HCV antibodies and HBS antigen by 3rd generation ELISA, serum alpha fetoprotein, abdominal ultrasonography, triphasic abdominal computerized tomo-graphy and lymphocyte subset assay by flow cytometry 1 day before, and 3 weeks after the treatment. Results: Regarding the immunological status between control and HCC patients, there was a demonstrable difference in the number of cells in both groups, as the control group had higher levels of CD4+ and CD8+ values. In the RFA group, CD4+ cells and CD4/CD8 ratio remarkably increased after treatment (P <0.001), and the CD8+ cells significantly decreased (P <0.002) with concomitant increase in the CD4+/CD8+ ratio (P<0.001). In the PEI group, CD4+ cells markedly increased after treatment (P<0.001), but there were no significant differences in CD8+ cells and CD4/CD8 ratio. In the MWA group, CD4+ cells markedly increased after treatment (P<0.001), with increase in CD4/CD8 ratio (P<0.007) but there were no significant differences in CD8+ cells. In the TACE group, the CD4+ cells and CD4/CD8 ratio dramatically decreased after treatment (P<0.001), and the CD8+ cells increased significantly (P<0.001). Conclusion: Our study has proved to find a relationship between immunity and different models of therapy in HCC patients and demonstrated a positive attitude towards increasing immune cells following ablation technique.

Pancreatic Atrophy in Hepatocellular Carcinoma Patients Receiving Long-Term Treatment with Sorafenib

Objective: To date, sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). Pancreatic atrophy has recently been reported in 2 patients as a novel side effect after long-term sorafenib treatment. Methods: We retrospectively analyzed clinical and radiological data of patients with advanced HCC with long-term treatment of sorafenib (median 279 days, range 153-826 days). Pancreata were semi-manually segmented section by section to calculate the pancreas volumes before and under sorafenib treatment. Results: Sorafenib reduced pancreatic volume in 18/19 (95%) HCC patients with a mean pancreatic volume loss of 25% (p = 0.002). Pancreatic volume loss depended on the dose (r = 0.36) and exposure time of sorafenib (r = 0.35) and was detectable as early as after 3 months of sorafenib treatment and already after a cumulative sorafenib dose of <100 g. Median overall survival was 13.2 months (range 7.8-31.3 months) but did not correlate with sorafenib-induced pancreatic volume reduction (hazard ratio 1.002, 95% confidence interval 0.981-1.060, p = 0.24). Conclusion: We could confirm pancreatic atrophy as a novel adverse event of sorafenib therapy in HCC patients, correlating with sorafenib dose and exposure time.

P0382 : Angiotensin II type 1 receptor antagonists as adjuvant therapy for hepatocellular carcinoma patients treated with radiofrequency ablation

P0382 : Angiotensin II type 1 receptor antagonists as adjuvant therapy for hepatocellular carcinoma patients treated with radiofrequency ablation