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 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 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 Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 271
Author(s):  
Philippe Rochigneux ◽  
Brice Chanez ◽  
Bernadette De Rauglaudre ◽  
Emmanuel Mitry ◽  
Christian Chabannon ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
T Cells ◽  
Early Phase ◽  
Kinase Inhibitors ◽  
Adoptive Cell Therapy ◽  
Adoptive Cell Transfer ◽  
Immune Checkpoints ◽  
Systemic Treatments ◽  
Engineered T Cells

The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials.

scholarly journals Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines

2021 ◽  
Vol 8 ◽  
Author(s):  
Kue Peng Lim ◽  
Nur Syafinaz Zainal
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
Cancer Vaccine ◽  
Cancer Vaccines ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Rapid Development ◽  
Activated T Cells ◽  
Specific Cytotoxicity

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.

scholarly journals The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions

2020 ◽  
Vol 13 (11) ◽  
pp. 389 ◽  
Author(s):  
Karam Khaddour ◽  
Tanner Johanns ◽  
George Ansstas
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Glioblastoma Multiforme ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Adoptive Cell Transfer ◽  
High Morbidity ◽  
Future Directions ◽  
Treatment Approaches

Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.

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 Vaccinations for Colorectal Cancer: Progress, Strategies, and Novel Adjuvants

2019 ◽  
Vol 20 (14) ◽  
pp. 3403 ◽  
Author(s):  
Stephen Jiang ◽  
David Good ◽  
Ming Q. Wei
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Immune System ◽  
Cancer Vaccines ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Host Proteins ◽  
Signalling Molecules ◽  
Low Toxicity ◽  
Made In

Although cancer is a leading cause of death, significant breakthroughs have been made in its treatment in recent years. In particular, increasingly effective cancer vaccines are being developed, including some for colorectal cancer. There are also currently a variety of compounds that can act as adjuvants, such as signalling molecules called cytokines. Other adjuvants target and inhibit the specific mechanisms by which cancers evade the immune system. One of them is a galectin inhibitor, which targets galectins—proteins produced by cancer cells that can cause the death of immune cells. Likewise, immune checkpoint inhibitors affect immune checkpoints—natural host proteins that usually control inflammation but can be exploited by cancers to weaken the body’s defences. Equally, regulatory T cells may contribute to the progression of cancer by inhibiting the functions of other T cells. The main advantages of cancer vaccines include their low toxicity and their ability to strengthen the immune system. Nevertheless, significant limitations include their slow effects and their inability to treat cancer at times due to immunosuppression. Ultimately, ongoing trials provide hope for the development of more effective methods of immunotherapeutic inoculation that can target a greater variety of cancers.

scholarly journals Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints

2021 ◽  
Vol 11 ◽  
Author(s):  
Yaolin Xu ◽  
Lijie He ◽  
Qiang Fu ◽  
Junzhe Hu
Keyword(s):  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Mitochondrial Biogenesis ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Nucleotide Metabolism ◽  
Metabolic Reprogramming ◽  
Immune Checkpoints

Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.

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