scholarly journals Novel immune checkpoints beyond PD-1 in advanced melanoma

2021 ◽  
Author(s):  
Nina Zila ◽  
Christoph Hoeller ◽  
Verena Paulitschke
Keyword(s):  
Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Short Review ◽  
Therapy Resistance ◽  
Advanced Melanoma ◽  
Immune Checkpoints ◽  
Malignant Diseases ◽  
Foreseeable Future ◽  
Cell Responses ◽  
Therapeutic Landscape

SummaryIn malignant diseases, targeting of immune checkpoints successfully changed the therapeutic landscape and helped to unleash anti-tumor T cell responses, resulting in durable clinical outcomes, but only in up to 50% of patients. The success of these therapies and the need to overcome intrinsic and acquired therapy resistance stimulated research to identify new pathways and targets. Numerous clinical trials are currently evaluating novel checkpoint inhibitors or recently developed strategies like modulating the tumor microenvironment, mostly in combination with approved therapies. This short review briefly discusses promising therapeutic targets, currently still under investigation, with the chance to realize clinical application in the foreseeable future.

scholarly journals The therapeutic landscape of advanced melanoma

2020 ◽  
Vol 13 (3) ◽  
pp. 306-308 ◽  
Author(s):  
Erika Richtig
Keyword(s):  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Short Review ◽  
Advanced Melanoma ◽  
Oncolytic Viruses ◽  
Therapeutic Landscape ◽  
The World ◽  
Melanoma Treatment ◽  
Tumor Entities

Summary The therapeutic landscape of advanced and metastatic melanoma has changed dramatically in the last ten years. Targeted therapies as well as checkpoint inhibitors and oncolytic viruses have launched a broad revolution within this field. First presented at ASCO 2011, changes in melanoma treatment giving “light at the end of the tunnel” have also changed the treatment of many other tumor entities. So oncologists all over the world can offer their patients these treatment options with higher efficacy than we ever had. But despite all optimism we are still losing about half of our patients with metastatic melanoma along the way. In this short review the therapeutic landscape of advanced melanoma is described.

scholarly journals Clinical and Molecular Characteristics Associated with Survival in Advanced Melanoma Treated with Checkpoint Inhibitors

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Sunil Badami ◽  
Sunil Upadhaya ◽  
Ravi Kanth Velagapudi ◽  
Pushyami Mikkilineni ◽  
Ranju Kunwor ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Random Effect ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Melanoma ◽  
Cochrane Library ◽  
Molecular Characteristics ◽  
Significant Heterogeneity

Background. We performed meta-analysis to gather more evidence regarding clinical-molecular subgroups associated with better overall survival (OS) in advanced melanoma treated with checkpoint inhibitors. Materials and Methods. We performed a systematic search of PubMed, Scopus, Cochrane Library, and clinical trial.gov. Randomized clinical trials that compared a checkpoint inhibitor (nivolumab or pembrolizumab) with investigator choice chemotherapy or ipilimumab were included in our study. Hazard ratios (HR) and confidence interval (CI) were calculated for progression-free survival (PFS) and OS for each subgroup using generic inverse model along with the random effect method. Results. A total of 6 clinical trials were eligible for the meta-analysis. OS was prolonged in wild BRAF subgroup (HR 0.65, 95% CI 0.49-0.85, p 0.002), Programmed cell death subgroup (PD-1+) (HR 0.57, 95% CI 0.41-0.80, p 0.001), and high lactate dehydrogenase (LDH) level subgroup (HR 0.60, 95% CI 0.38-0.95, p 0.03). Similarly, we found increased OS in eastern cooperative oncology group (ECOG) 1, males and age >65 years subgroups. Conclusions. Checkpoint inhibitors significantly increased OS in patients with wild BRAF, positive PD-1, and high LDH. However, results should be interpreted keeping in mind associated significant heterogeneity. The results of this study should help in designing future clinical trials.

scholarly journals Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuki Nakamori ◽  
Eun Jeong Park ◽  
Motomu Shimaoka
Keyword(s):  
Clinical Trials ◽  
T Lymphocytes ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Specific Treatment ◽  
Multiple Organ ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Drug Candidates ◽  
Immune Paralysis

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.

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

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.

scholarly journals Targeting Immune Signaling Checkpoints in Acute Myeloid Leukemia

2019 ◽  
Vol 8 (2) ◽  
pp. 236 ◽  
Author(s):  
Krzysztof Giannopoulos
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Negative Control ◽  
Immune Checkpoints ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by the targeting of negative control checkpoints. The two best-known inhibitory immune checkpoints are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1). In AML, PD-1 expression is observed in T-cell subpopulations, including T regulatory lymphocytes. Increased PD-1 expression on CD8+ T lymphocytes may be one of the factors leading to dysfunction of cytotoxic T cells and inhibition of the immune response during the progressive course of AML. Upregulation of checkpoint molecules was observed after alloHSCT and therapy with hypomethylating agents, pointing to a potential clinical application in these settings. Encouraging results from recent clinical trials (a response rate above 50% in a relapsed setting) justify further clinical use. The most common clinical trials employ two PD-1 inhibitors (nivolumab and pembrolizumab) and two anti-PD-L1 (programmed death-ligand 1) monoclonal antibodies (atezolizumab and durvalumab). Several other inhibitors are under development or in early phases of clinical trials. The results of these clinical trials are awaited with great interest in, as they may allow for the established use of checkpoint inhibitors in the treatment of AML.

scholarly journals Immunotherapy in endometrial cancer: rationale, practice and perspectives

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Wenyu Cao ◽  
Xinyue Ma ◽  
Jean Victoria Fischer ◽  
Chenggong Sun ◽  
Beihua Kong ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Cancer Vaccines ◽  
Molecular Basis ◽  
Checkpoint Inhibitors ◽  
Molecular Classification ◽  
Adoptive Cell Transfer ◽  
Immune Checkpoints ◽  
Effective Strategies ◽  
Tumor Research

AbstractTumor immunotherapy has attracted more and more attention nowadays, and multiple clinical trials have confirmed its effect in a variety of solid tumors. Immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), and lymphocyte-promoting cytokines are the main immunotherapy methods. Endometrial cancer (EC) is one of the most frequent tumors in women and the prognosis of recurrent or metastatic EC is poor. Since molecular classification has been applied to EC, immunotherapy for different EC subtypes (especially POLE and MSI-H) has gradually attracted attention. In this review, we focus on the expression and molecular basis of the main biomarkers in the immunotherapy of EC firstly, as well as their clinical application significance and limitations. Blocking tumor immune checkpoints is one of the most effective strategies for cancer treatment in recent years, and has now become the focus in the field of tumor research and treatment. We summarized clinical date of planned and ongoing clinical trials and introduced other common immunotherapy methods in EC, such as cancer vaccine and ACT. Hormone aberrations, metabolic syndrome (MetS) and p53 mutant and that affect the immunotherapy of endometrial cancer will also be discussed in this review.

scholarly journals Prospects and Challenges for T Cell-Based Therapies of HCC

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1651
Author(s):  
Norman Woller ◽  
Sophie Anna Engelskircher ◽  
Thomas Wirth ◽  
Heiner Wedemeyer
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Therapy Resistance ◽  
Full Potential ◽  
Viral Origin ◽  
Cell Therapies ◽  
Cell Responses ◽  
Cell Immunity ◽  
Tumor Progress

The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.

scholarly journals Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1558
Author(s):  
Matthias Ocker ◽  
Christian Mayr ◽  
Tobias Kiesslich ◽  
Sebastian Stintzing ◽  
Daniel Neureiter
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Human Tumor ◽  
Standard Of Care ◽  
Immune Checkpoints ◽  
Published Data ◽  
Ablative Techniques

Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic “door” to improve outcome and response rate for patients with HCC. Methods: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail. Results: Overall, our knowledge of the role of immune checkpoints in HCC is dramatically increased in the last years. Experimental and pre-clinical findings could be translated to phase 1 and 2 clinical trials and became standard of care. Local ablative techniques of HCC could improve the effectivity of immune checkpoint inhibitors in situ. Conclusions: This review demonstrates the importance of immunomodulatory treatment strategies of HCC, whereby the “best treatment code” of immune checkpoint drugs, combination with ablative techniques and of timing must be evaluated in coming clinical trials.

scholarly journals Determinants of Resistance to Checkpoint Inhibitors

2020 ◽  
Vol 21 (5) ◽  
pp. 1594 ◽  
Author(s):  
Linda Tran ◽  
Dan Theodorescu
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Recurrence ◽  
Therapeutic Agents ◽  
Advanced Melanoma ◽  
Combination Therapies ◽  
Resistant Disease ◽  
Inhibitory Pathways

The development of immune checkpoint inhibitors (ICIs) has drastically altered the landscape of cancer treatment. Since approval of the first ICI for the treatment of advanced melanoma in 2011, several therapeutic agents have been Food and Drug Administration (FDA)-approved for multiple cancers, and hundreds of clinical trials are currently ongoing. These antibodies disrupt T-cell inhibitory pathways established by tumor cells and thus re-activate the host’s antitumor immune response. While successful in many cancers, several types remain relatively refractory to treatment or patients develop early recurrence. Hence, there is a great need to further elucidate mechanisms of resistant disease and determine novel, effective, and tolerable combination therapies to enhance efficacy of ICIs.

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