Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

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Overview of Current Progress in Immune Checkpoint Inhibitor Therapy for Advanced Hepatocellular Carcinoma

Technology in Cancer Research & Treatment ◽

10.1177/1533033820947486 ◽

2020 ◽

Vol 19 ◽

pp. 153303382094748

Author(s):

Xinlun Dai ◽

Shupeng Wang ◽

Chunyuan Niu ◽

Bai Ji ◽

Yahui Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Immune Checkpoint ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

Inhibitory Signaling

Hepatocellular carcinoma (HCC) remains to a common cause of tumor mortality worldwide and represents the most common type of lethal hepatic malignancy. The incidence of HCC is swiftly increasing in western countries and southeast Asia. Despite poor prognosis, traditional treatments for advanced HCC appear to be minimally effective or even useless since patients are usually diagnosed in the advanced stage of disease. In recent years, immune checkpoint blockade has shown promising results in multiple pre-clinical and clinical trials of different solid tumors, including advanced HCC. Novel drugs targeting immune checkpoints, such as nivolumab (anti-PD-1), durvalumab (anti-PD-L1), and tremelimumab (anti-CTLA-4) have been shown to be highly effective and relatively safe in monotherapy or in combination treatment of advanced liver cancer. Unlike other immunotherapies, this approach can rouse human anti-tumor immunity by relieving T-cell exhaustion and inhibiting the evasion of HCC by blocking co-inhibitory signaling transduction accurately. In this review, we will provide current knowledge of several major immune checkpoints and summarize recent data from clinical trials that applied immune checkpoint inhibitors alone or in combination. In addition, this review will discuss the limitations and future prospective of immune checkpoint-targeted therapy for advanced HCC.

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Next generation of immune checkpoint inhibitors and beyond

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01056-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Julian A. Marin-Acevedo ◽

ErinMarie O. Kimbrough ◽

Yanyan Lou

Keyword(s):

Cell Death ◽

Immune System ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Immune Checkpoints ◽

Host Immune System ◽

Immune Recognition

AbstractThe immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.

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Treating tumors with immune checkpoint inhibitors: Rationale and limitations

Trends in Immunotherapy ◽

10.24294/ti.v1.i1.20 ◽

2017 ◽

Vol 1 (1) ◽

pp. 2 ◽

Cited By ~ 1

Author(s):

Judith Anna Seidel ◽

Atsushi Otsuka ◽

Kenji Kabashima

Keyword(s):

Immune Responses ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Programmed Cell Death 1 ◽

Human Use ◽

Blocking Antibodies ◽

Medical Advances

Immune checkpoints are essential for preventing immunopathology but can also obstruct anti-tumor immune responses. Recent medical advances in blocking these mechanisms have therefore opened promising avenues in the treatment of cancer. Various blocking antibodies targeting the immune checkpoints programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now approved for human use. This review summarizes the properties of PD-1 and CTLA-4 in physiological and tumor settings, and examines the treatment efficacy, side effects and biomarkers of their inhibitors. Future avenues in the application and development of immune checkpoint inhibitors for the treatment of cancer are also explored.

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Overview and management of toxicities of immune checkpoint-blocking drugs

Forum of Clinical Oncology ◽

10.1515/fco-2016-0004 ◽

2016 ◽

Vol 7 (1) ◽

pp. 28-37 ◽

Cited By ~ 1

Author(s):

Panagiota Economopoulou ◽

Amanda Psyrri

Keyword(s):

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Cancer Management ◽

New Methods ◽

Organ Specific ◽

Clinical Benefits ◽

Immune Oncology ◽

Cell Death Protein

Abstract Immunotherapy is considered to be the most important breakthrough in cancer management in the past few years. This success was based on the scientific understanding of immune mechanisms due to improvement in preclinical science and the introduction of new methods of investigation. Immune checkpoint inhibitors (ICIs) are among the most promising drugs in the field of immune-oncology; they represent monoclonal antibodies that modulate the effects of immune checkpoints, such as cytotoxic T lymphocyte Antigen 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), which are co-inhibitory signals responsible for immune suppression. Despite clinical benefits, ICIs are immune activating agents that are associated with a number of important side effects (immune-related adverse events-irAEs), attributed to organ-specific inflammation. Herein, we review the toxicities of ICIs, highlighting the importance of early identification and management.

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Neutrophils in the era of immune checkpoint blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002242 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002242

Author(s):

Julien Faget ◽

Solange Peters ◽

Xavier Quantin ◽

Etienne Meylan ◽

Nathalie Bonnefoy

Keyword(s):

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Neutrophil Infiltration ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Cancer Management ◽

Origin Function ◽

And Function

The immune checkpoint blockade-based immunotherapies are revolutionizing cancer management. Tumor-associated neutrophils (TANs) were recently highlighted to have a pivotal role in modulating the tumor microenvironment and the antitumor immune response. However, these cells were largely ignored during the development of therapies based on programmed cell death receptor or ligand-1 and cytotoxic T lymphocyte antigen-4 immune checkpoint inhibitors (ICIs). Latest evidences of neutrophil functional diversity in tumor raised many questions and suggest that targeting these cells can offer new treatment opportunities in the context of ICI development. Here, we summarized key information on TAN origin, function, and plasticity that should be considered when developing ICIs and provide a detailed review of the ongoing clinical trials that combine ICIs and a second compound that might affect or be affected by TANs. This review article synthetizes important notions from the literature demonstrating that: (1) Cancer development associates with a profound alteration of neutrophil biogenesis and function that can predict and interfere with the response to ICIs, (2) Neutrophil infiltration in tumor is associated with key features of resistance to ICIs, and (3) TANs play an important role in resistance to antiangiogenic drugs reducing their clinical benefit when used in combination with ICIs. Finally, exploring the clinical/translational aspects of neutrophil impact on the response to ICIs offers the opportunity to propose new translational research avenues to better understand TAN biology and treat patients.

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Prognostic Role of Immune Checkpoint Regulators in Cholangiocarcinoma: A Pilot Study

Journal of Clinical Medicine ◽

10.3390/jcm10102191 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2191

Author(s):

Lu Cao ◽

Prashanth Prithviraj ◽

Ritu Shrestha ◽

Revati Sharma ◽

Matthew Anaka ◽

...

Keyword(s):

Overall Survival ◽

Pilot Study ◽

Immune Checkpoint ◽

Drug Targets ◽

Checkpoint Inhibitors ◽

Prognostic Significance ◽

Immune Checkpoints ◽

Poor Overall Survival ◽

Mesenchymal Transition

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy associated with steadily increasing incidence and poor prognosis. Ongoing clinical trials are assessing the effectiveness and safety of a few immune checkpoint inhibitors (ICIs) in CCA patients. However, these ICI treatments as monotherapies may be effective for a proportion of patients with CCA. The prevalence and distribution of other immune checkpoints (ICs) in CCA remain unclear. In this pilot study, we screened databases of CCA patients for the expression of 19 ICs and assessed the prognostic significance of these ICs in CCA patients. Notably, expression of immune modulator IDO1 and PD-L1 were linked with poor overall survival, while FASLG and NT5E were related to both worse overall survival and progression-free survival. We also identified immune modulators IDO1, FASLG, CD80, HAVCR2, NT5E, CTLA-4, LGALS9, VTCN1 and TNFRSF14 that synergized with PD-L1 and correlated with worse patient outcomes. In vitro studies revealed that the expression of ICs was closely linked with aggressive CCA subpopulations, such as cancer stem cells and cells undergoing TGF-β and TNF-α-mediated epithelial-to-mesenchymal transition. These findings suggest that the aforementioned IC molecules may serve as potential prognostic biomarkers and drug targets in CCA patients, leading to lasting and durable treatment outcomes.

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Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

Thai Journal of Hepatology ◽

10.30856/th.jhep2018vol1iss1_07 ◽

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

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Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

Current Cancer Drug Targets ◽

10.2174/1568009620666200520084415 ◽

2020 ◽

Vol 20 (9) ◽

pp. 720-727

Author(s):

Jianguo Qiu ◽

Wei Tang ◽

Chengyou Du

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Immune Checkpoint ◽

Graft Rejection ◽

Checkpoint Inhibitors ◽

Liver Graft ◽

Immune Checkpoints ◽

Term Survival ◽

Liver Preservation ◽

Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

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From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽

10.3390/molecules26082278 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2278

Author(s):

Afshin Derakhshani ◽

Zeinab Rostami ◽

Hossein Safarpour ◽

Mahdi Abdoli Shadbad ◽

Niloufar Sadat Nourbakhsh ◽

...

Keyword(s):

Single Cell ◽

Signaling Pathways ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cancer Development ◽

Immune Checkpoints ◽

Single Cell Sequencing ◽

Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

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Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001945 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001945 ◽

Cited By ~ 1

Author(s):

Jeffrey Sum Lung Wong ◽

Gerry Gin Wai Kwok ◽

Vikki Tang ◽

Bryan Cho Wing Li ◽

Roland Leung ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Acquired Resistance ◽

Survival Rates ◽

Advanced Hepatocellular Carcinoma ◽

Primary Resistance ◽

Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

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