scholarly journals Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events during Sorafenib Therapy for Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 426
Author(s):  
Josep Corominas ◽  
Victor Sapena ◽  
Marco Sanduzzi-Zamparelli ◽  
Cristina Millán ◽  
Esther Samper ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Adverse Events ◽  
Immune Suppression ◽  
Immune Checkpoints ◽  
Advanced Hepatocellular Carcinoma ◽  
Activation Markers ◽  
Immune Exhaustion ◽  
Increased Risk ◽  
Dermatologic Adverse Events

Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1+ cells express activation markers, T DNAM-1+ cells induce immune suppression and show immune exhaustion. This is the first study to report an association between immune checkpoints expression in circulating immune cells and the increased incidence of eDAEs. Our results support the hypothesis for an off-target role of sorafenib in immune modulation. We also describe a novel association between DNAM-1 and immune exhaustion in T cells.

scholarly journals Immunotherapy of HBV-related advanced hepatocellular carcinoma with short-term HBV-specific TCR expressed T cells: results of dose escalation, phase I trial

2021 ◽  
Author(s):  
Fanping Meng ◽  
Jinfang Zhao ◽  
Anthony Tanoto Tan ◽  
Wei Hu ◽  
Si-Yu Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Dose Escalation ◽  
Immunosuppressive Agents ◽  
Advanced Hepatocellular Carcinoma ◽  
T Cell Therapy

Abstract Background & aims Immunotherapy with hepatitis B virus (HBV)-specific TCR redirected T (HBV-TCR-T) cells in HBV-related hepatocellular carcinoma (HBV-HCC) patients after liver transplantation was reported to be safe and had potential therapeutic efficacy. We aim to investigate the safety of HBV-TCR-T-cell immunotherapy in advanced HBV-HCC patients who had not met the criteria for liver transplantation. Methods We enrolled eight patients with advanced HBV-HCC and adoptively transferred short-lived autologous T cells expressing HBV-specific TCR to perform an open-label, phase 1 dose-escalation study (NCT03899415). The primary endpoint was to evaluate the safety of HBV-TCR-T-cell therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) during the dose-escalation process. The secondary endpoint was to assess the efficacy of HBV-TCR-T-cell therapy by evaluating the anti-tumor responses using RECIST criteria (version 1.1) and the overall survival. Results Adverse events were observed in two participants among the 8 patients enrolled. Only one patient experienced a Grade 3 liver-related adverse event after receiving a dose of 1 × 105 HBV-TCR-T cells/kg, then normalized without interventions with immunosuppressive agents. Among the patients, one achieved a partial response lasting for 27.7 months. Importantly, most of the patients exhibited a reduction or stabilization of circulating HBsAg and HBV DNA levels after HBV-TCR-T-cell infusion, indicating the on-target effects. Conclusions The adoptive transfer of HBV-TCR-T cells into advanced HBV-HCC patients were generally safe and well-tolerated. Observations of clinical efficacy support the continued development and eventual application of this treatment strategy in patients with advanced HBV-related HCC. Clinical trials registration This study was registered at ClinicalTrials.gov (NCT03899415).

Real-world efficacy and safety of immune checkpoint inhibitors in advanced hepatocellular carcinoma: Experience of a tertiary Asian center.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 559-559
Author(s):  
Kennedy Ng ◽  
Lawrence Wen Jun Wong ◽  
Su Pin Choo ◽  
David Wai-Meng Tai ◽  
Sze Huey Tan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trial ◽  
Adverse Events ◽  
Real World ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Efficacy And Safety ◽  
Advanced Hcc ◽  
Increased Risk

559 Background: Immune checkpoint inhibitor (ICI) use in advanced hepatocellular carcinoma (HCC) is increasing. Real-world data on efficacy and safety however is lacking, more so when used in patients who fall out of standard clinical trial criteria. Methods: We conducted a retrospective review of all patients with advanced HCC seen at our centre who received at least one dose of an ICI between May 2015 - June 2018. Data cutoff was 31 Dec 2018. Responses were evaluated using RECIST v1.1 criteria. Results: 114 patients fulfilled inclusion criteria. Median age was 66 years and 88.6% were male. 96.5% had an ECOG PS of 0 – 1. 64.9% received an ICI within a clinical trial setting. 62.3% received monotherapy ICI. 19.6% of patients had Child-Pugh B disease on initiation of ICI, and 69.3% had an ALBI Grade of 2. 50.0% were known to have hepatitis B and 11.4% had hepatitis C. Baseline HBV VL ranged from undetectable to 8210000 IU/mL. 30.7% received prior systemic treatment, most commonly sorafenib (82.9%). Over a median follow-up duration of 5.7 months (0.03 - 42.4), ORR was 18.4%, and disease control rate (DCR) was 51.8%. Median PFS was 2.6 months (1.7 - 3.9), and median OS was 13.9 months (7.0 - 16.2). 5 patients (23.8%) had response duration of more than 18 months. 35.1% received further systemic therapy after ICI. On multivariable analyses, age ≥ 65 years, higher albumin level and lower bilirubin level were associated with increased OS. 68.0% of patients experienced adverse events (AEs) of any grade, 12.0% of these being grade 3 - 4. No grade 5 adverse events were observed. Use of antiviral therapy was associated with a lower risk of hepatic AEs (p = 0.04) whilst high baseline HBV VL was not associated with an increased risk of reactivation or hepatic AEs. Conclusions: In the real-world setting, responses and adverse event profiles to ICI use are comparable to those observed in clinical trials despite a more heterogenous population base. The expansion of indications for ICI use in advanced HCC beyond current approvals warrants greater study.

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

A phase II study of sorafenib and yttrium-90 glass microspheres for advanced hepatocellular carcinoma, BCLC stage C.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4083-4083
Author(s):  
Ahmed Omar Kaseb ◽  
Reham Abdel-Wahab ◽  
Ravi Murthy ◽  
Manal Hassan ◽  
Kanwal Pratap Singh Raghav ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Adverse Events ◽  
Local Therapy ◽  
Phase Iii ◽  
Response To Treatment ◽  
Cancer Center ◽  
Advanced Hepatocellular Carcinoma ◽  
Combined Use ◽  
Elevated Liver Enzymes ◽  
Yttrium 90

4083 Background: Combined use of sorafenib and local therapy for treating unresectable hepatocellular carcinoma (HCC) is not well established. Notably, most common cause of death in HCC is liver failure, therefore we tested the promise of controlling the local tumors even in the setting of advanced/metastatic disease to improve survival. Our study aimed to assess the efficacy and safety of combined use of sorafenib and yttrium-90 resin microspheres (Y90 RMS) in unresectable HCC defined as Barcelona Clinic Liver Cancer class C. Methods: Between October 2013 and August 2016 we enrolled 40 advanced stage HCC patients, 38 patients were treated with sorafenib followed (after 4 weeks) with Y90 RMS at MD Anderson Cancer Center. Survival analysis was done to evaluate median overall survival (OS) and progression-free survival (PFS). We used modified Response Evaluation Criteria in Solid Tumors (RECIST) to assess response to treatment and the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 to evaluate the grading of treatment related toxicity. Results: The majority of our patients were males (74%), white (47%), 66% of patients had underlying liver cirrhosis, 26% had vascular invasion, and 26% had extrahepatic disease. The estimated median OS and 95% confidence interval (CI) in months was 18.46 (12.29 – NA) and the estimated PFS was 12.29 months (5.72 – 18.79). Stable disease (SD) was observed in 44.74% of patients, while 28.95% achieved partial response (PR). Grade III-IV adverse events included fatigue (n = 3), hyperbilirubinemia (n = 2), thrombocytopenia (n = 1), proteinuria (n = 1), hyponatremia (n = 1), elevated liver enzymes (n = 4), hypertension (n = 4), diarrhea (n = 1), nausea (n = 1) and vomiting (n = 2). Conclusions: This is the first prospective study to evaluate sorafenib followed by Y90 in HCC. Our study included patients with metastatic HCC and showed that combined use of sorafenib and Y90 was tolerable and was associated with longer OS and PFS compared to previous studies which evaluated sorafenib alone. However, future randomized phase III studies are warranted to assess sorafenib+/-Y90 in metastatc disease setting. Clinical trial information: NCT01900002.

scholarly journals Differential Dermatologic Adverse Events Associated With Checkpoint Inhibitor Monotherapy and Combination Therapy: A Meta-Analysis of Randomized Control Trials

2021 ◽  
Vol 12 ◽  
Author(s):  
Yang Ge ◽  
Huiyun Zhang ◽  
Nathaniel Weygant ◽  
Jiannan Yao
Keyword(s):  
Relative Risk ◽  
Combination Therapy ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
High Grade ◽  
Treatment Regimens ◽  
Increased Risk ◽  
Significant Difference ◽  
Dermatologic Adverse Events

Background: As immune checkpoint inhibitors (ICIs) transition to the forefront of cancer treatment, a better understanding of immune related adverse events (IRAEs) is essential to promote safe clinical practice. Dermatologic adverse events are the most common IRAEs and can lead to drug withdrawal and decreased quality of life. This meta-analysis aimed to investigate the risk of the most prevalent dermatologic adverse events (pruritus and rash) among various ICI treatment regimens.Methods: A systematic search of electronic databases was performed to identify qualified randomized controlled trials (RCTs). Data for any grade and high grade pruritus and rash were extracted for meta-analysis. Two reviewers independently assessed methodological quality. The relative risk summary and 95% confidence interval were calculated.Results: 50 RCTs involving 29941 patients were analyzed. The risk of pruritus (2.15 and 4.21 relative risk respectively) and rash (1.61 and 3.89 relative risk respectively) developing from CTLA-4 or PD-1/-L1 inhibitor were increased compared to placebo, but this effect was not dose-dependent. PD-1/-L1 plus CTLA-4 inhibitor was associated with increased risk of pruritus (1.76 and 0.98 relative risk respectively) and rash (1.72 and 1.37 relative risk respectively) compared to either monotherapy. Compared with CTLA-4 inhibitor, PD-1/-L1 inhibitor had a significantly decreased risk of pruritus and rash in both monotherapy and combination therapy (0.65 and 0.29 relative risk respectively). No significant difference was found between PD-1/-L1 inhibitor combined with chemotherapy and PD-1/-L1 monotherapy in any grade and high grade rash (0.84 and 1.43 relative risk respectively). In subgroup analyses, PD-1 inhibitor was associated with reduced risk of pruritus and rash compared to PD-L1 inhibitor.Conclusion: Our meta-analysis demonstrates a better safety profile for PD-1/-L1 inhibitor compared to CTLA-4 inhibitor in terms of pruritus and rash among both monotherapy and multiple combination therapies. PD-L1 inhibitor may contribute to an increased risk of pruritus and rash compared to PD-1 inhibitor.

scholarly journals Combination of Sorafenib, Camrelizumab, Transcatheter Arterial Chemoembolization, and Stereotactic Body Radiation Therapy as a Novel Downstaging Strategy in Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Case Series Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Yun Huang ◽  
Zeyu Zhang ◽  
Weijun Liao ◽  
Kuan Hu ◽  
Zhiming Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Adverse Events ◽  
Tumor Thrombus ◽  
Stereotactic Body Radiation Therapy ◽  
Transcatheter Arterial Chemoembolization ◽  
Case Series ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Arterial Chemoembolization

Background and AimAlthough the treatment effect and availability of therapeutic options for advanced hepatocellular carcinoma (HCC) are limited, the downstaging strategy may improve patient prognosis. This study aimed to investigate the potential of combination therapy as a downstaging strategy for treating advanced HCC with portal vein tumor thrombus (PVTT).MethodsThis retrospective case series included patients having advanced HCC with PVTT, who received the combination therapy of sorafenib, camrelizumab, transcatheter arterial chemoembolization (TACE), and stereotactic body radiation therapy (SBRT) from January 2019 to December 2019 in Xiangya Hospital, Central South University. The downstaging rate, treatment responses, progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities were evaluated.ResultsOf the 13 patients, HCC downstaging was achieved in 4 (33.3%) patients who later received hepatectomy. The overall response rate was 41.7%, and the disease control rate was 50.0%. The median PFS time was 15.7 months, with a 1-year PFS rate of 58.3%, whereas the median OS was not reached after 1 year (1-year OS, 83.3%). No severe adverse events or grade 3–4 adverse effect was observed in 12 of the 13 enrolled patients; therapy had to be discontinued in only one patient due to adverse events, who was excluded from the study. The most common adverse effect was fever (n = 4, 33.3%), followed by skin reaction (n = 3, 25%).ConclusionA combination therapy comprising sorafenib, camrelizumab, TACE, and SBRT is an effective downstaging strategy for advanced HCC with PVTT and is associated with few adverse events.

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