scholarly journals Combinatorial Approaches for Cancer Treatment Using Oncolytic Viruses: Projecting the Perspectives through Clinical Trials Outcomes

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1271
Author(s):  
Alexander Malogolovkin ◽  
Nizami Gasanov ◽  
Alexander Egorov ◽  
Marianna Weener ◽  
Roman Ivanov ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Treatment ◽  
Immune Checkpoint ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Conventional Radiotherapy ◽  
Indispensable Tool

Recent cancer immunotherapy breakthroughs have fundamentally changed oncology and revived the fading hope for a cancer cure. The immune checkpoint inhibitors (ICI) became an indispensable tool for the treatment of many malignant tumors. Alongside ICI, the application of oncolytic viruses in clinical trials is demonstrating encouraging outcomes. Dozens of combinations of oncolytic viruses with conventional radiotherapy and chemotherapy are widely used or studied, but it seems quite complicated to highlight the most effective combinations. Our review summarizes the results of clinical trials evaluating oncolytic viruses with or without genetic alterations in combination with immune checkpoint blockade, cytokines, antigens and other oncolytic viruses as well. This review is focused on the efficacy and safety of virotherapy and the most promising combinations based on the published clinical data, rather than presenting all oncolytic virus variations, which are discussed in comprehensive literature reviews. We briefly revise the research landscape of oncolytic viruses and discuss future perspectives in virus immunotherapy, in order to provide an insight for novel strategies of cancer treatment.

scholarly journals Prospects of immune checkpoint blockade and vaccine-based immunotherapy for glioblastoma

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Stefanie Tietze ◽  
Susanne Michen ◽  
Gabriele Schackert ◽  
Achim Temme
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Primary Brain Tumor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Therapeutic Vaccines ◽  
Dismal Prognosis ◽  
Tumor Parenchyma ◽  
Immunosuppressive Microenvironment

Abstract Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor endowed with a dismal prognosis. Nowadays, immunotherapy in a particular immune checkpoint blockade and therapeutic vaccines are being extensively pursued. Yet, several characteristics of GBM may impact such immunotherapeutic approaches. This includes tumor heterogeneity, the relatively low mutational load of primary GBM, insufficient delivery of antibodies to tumor parenchyma and the unique immunosuppressive microenvironment of GBM. Moreover, standard treatment of GBM, comprising temozolomide chemotherapy, radiotherapy and in most instances the application of glucocorticoids for management of brain edema, results in a further increased immunosuppression. This review will provide a brief introduction to the principles of vaccine-based immunotherapy and give an overview of the current clinical studies, which employed immune checkpoint inhibitors, oncolytic viruses-based vaccination, cell-based and peptide-based vaccines. Recent experiences as well as the latest developments are reviewed. Overcoming obstacles, which limit the induction and long-term immune response against GBM when using vaccination approaches, are necessary for the implementation of effective immunotherapy of GBM.

scholarly journals Immune checkpoint blockade in the treatment of malignant tumor: current statue and future strategies

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wenwen Yang ◽  
Caining Lei ◽  
Shaoming Song ◽  
Wutang Jing ◽  
Chuanwei Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Malignant Tumor ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Response ◽  
Inhibitory Molecule

AbstractAfter being stagnant for decades, there has finally been a paradigm shift in the treatment of cancer with the emergence and application of immune checkpoint inhibitors (ICIs). The most extensively utilized ICIs are targeting the pathways involving programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). PD-1, as an crucial immune inhibitory molecule, by and large reasons the immune checkpoint response of T cells, making tumor cells get away from immune surveillance. Programmed cell death ligand-1 (PD-L1) is exceptionally expressed in most cancers cells and approves non-stop activation of the PD-1 pathway in the tumor microenvironment. PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, inhibit hostile to regulatory signals, and restore the activity of T cells, thereby bettering immune response. The current researchers assume that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), and other emerging biomarkers. Although malignant tumors can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, formulating a customized medication model and discovering biomarkers that can predict efficacy are the new trend in the new era of malignant tumor immunotherapy. This review summarizes the mechanism of action of PD-1/PD-L1 inhibitors, their clinical outcomes on various malignant tumors, their efficacy biomarkers, as well as predictive markers of irAEs.

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 Checkpoint inhibition in myeloma

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 528-533 ◽  
Author(s):  
Don M. Benson
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Inhibition ◽  
The Past ◽  
Complementary Approach ◽  
Fundamental Biology ◽  
System Interfaces

Abstract Historically, attempts at cancer immunotherapy have emphasized strategies designed to stimulate or augment the immune system into action. In the past decade, a complementary approach has developed, that of releasing immune cells from inhibitory restraint. Discoveries in the fundamental biology of how immunity is regulated, how the immune system interfaces with malignancy, and how cancer cells may exploit these processes to evade detection have all been translated into the rapidly growing field of therapeutic immune checkpoint inhibition for cancer. Myeloma is a malignancy associated with significant immune dysfunction imparted both by the disease itself as well as by many of the immunosuppressive therapies that have been used in the past. The growing body of preclinical data regarding immunoregulatory mechanisms that appear active in myeloma has begun to be translated to clinical trials targeting these signaling axes. This review will attempt to summarize the current understanding of the basic biology of several immune checkpoint pathways that may be important in myeloma and provide an up-to-date overview of recent and ongoing clinical trials of immune checkpoint inhibitors in myeloma. Finally, several current challenges and possible future directions of immune checkpoint blockade in myeloma will be reviewed.

scholarly journals Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yalei Zhang ◽  
Ye Li ◽  
Kun Chen ◽  
Ling Qian ◽  
Peng Wang
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Tumor Resistance ◽  
Systemic Delivery ◽  
Future Directions ◽  
Immunosuppressive Tumor Microenvironment ◽  
Proinflammatory Factors

AbstractIt has been intensively reported that the immunosuppressive tumor microenvironment (TME) results in tumor resistance to immunotherapy, especially immune checkpoint blockade and chimeric T cell antigen therapy. As an emerging therapeutic agent, oncolytic viruses (OVs) can specifically kill malignant cells and modify immune and non-immune TME components through their intrinsic properties or genetically incorporated with TME regulators. Strategies of manipulating OVs against the immunosuppressive TME include serving as a cancer vaccine, expressing proinflammatory factors and immune checkpoint inhibitors, and regulating nonimmune stromal constituents. In this review, we summarized the mechanisms and applications of OVs against the immunosuppressive TME, and strategies of OVs in combination with immunotherapy. We also introduced future directions to achieve efficient clinical translation including optimization of preclinical models that simulate the human TME and achieving systemic delivery of OVs.

scholarly journals Checkpoint blockade in Hodgkin and non-Hodgkin lymphoma

2017 ◽  
Vol 1 (26) ◽  
pp. 2643-2654 ◽  
Author(s):  
Reid W. Merryman ◽  
Philippe Armand ◽  
Kyle T. Wright ◽  
Scott J. Rodig
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Constitutive Expression ◽  
Clinical Trial Design ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

AbstractClassical Hodgkin lymphoma (cHL) is characterized by nearly universal genetic alterations in 9p24.1, resulting in constitutive expression of PD-1 ligands. This likely underlies the unique sensitivity of cHL to PD-1 blockade, with response rates of ∼70% in relapsed/refractory disease. There are now numerous clinical trials testing PD-1 inhibitors in earlier stages of treatment and in combination with many other therapies. In general, non-Hodgkin lymphomas (NHLs) do not display a high frequency of 9p24.1 alterations and do not share cHL’s vulnerability to PD-1 blockade. However, a few entities have genetic or immunologic features that may predict sensitivity to immune checkpoint blockade. These include primary mediastinal B cell lymphoma, primary central nervous system lymphoma, and primary testicular lymphoma, which harbor frequent alterations in 9p24.1, as well as Epstein Barr virus (EBV)–infected lymphomas, where EBV infection leads to increased PD-L1 expression. Although these subtypes may be specifically vulnerable to PD-1 blockade, the majority of NHLs appear to be minimally sensitive to PD-1 blockade monotherapy. Current investigations in NHL are therefore focusing on targeting other checkpoints or studying PD-1–based combination therapy. Looking forward, additional insight into the most common mechanisms of resistance to immune checkpoint inhibitors will be important to guide rational clinical trial design. In this review, we describe the biological basis for checkpoint blockade in cHL and NHL and summarize the clinical data generated to date. Guided by our rapidly evolving understanding of the pathobiology of various lymphoma subtypes, we are hopeful that the role of checkpoint inhibitors in lymphoma treatment will continue to grow.

Surface engineering of oncolytic adenovirus for combinations of immune checkpoint blockade and virotherapy

2021 ◽  
Author(s):  
Peng Lv ◽  
Xiaomei Chen ◽  
Shiying Fu ◽  
En Ren ◽  
Chao Liu ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Surface Engineering ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Adenovirus ◽  
Checkpoint Blockade

Advances in the development of modern cancer immunotherapy and immune checkpoint inhibitors have dramatically changed the landscape of cancer treatment. However, most cancer patients are refractory to immune checkpoint inhibitors...

scholarly journals The State of Immunotherapy in Hepatobiliary Cancers

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2096
Author(s):  
Farhan Z. Ilyas ◽  
Joal D. Beane ◽  
Timothy M. Pawlik
Keyword(s):  
Clinical Trials ◽  
Adoptive Transfer ◽  
Immune Checkpoint ◽  
Therapeutic Approach ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Oncolytic Viruses ◽  
Curative Intent ◽  
Important Approach

Hepatobiliary cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC), are lethal cancers with limited therapeutic options. Curative-intent treatment typically involves surgery, yet recurrence is common and many patients present with advanced disease not amenable to an operation. Immunotherapy represents a promising approach to improve outcomes, but the immunosuppressive tumor microenvironment of the liver characteristic of hepatobiliary cancers has hampered the development and implementation of this therapeutic approach. Current immunotherapies under investigation include immune checkpoint inhibitors (ICI), the adoptive transfer of immune cells, bispecific antibodies, vaccines, and oncolytic viruses. Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two ICIs that have demonstrated utility in HCC, and newer immune checkpoint targets are being tested in clinical trials. In advanced CCA and GBC, PD-1 ICIs have resulted in antitumor responses, but only in a minority of select patients. Other ICIs are being investigated for patients with CCA and GBC. Adoptive transfer may hold promise, with reports of complete durable regression in metastatic CCA, yet this therapeutic approach may not be generalizable. Alternative approaches have been developed and promising results have been observed, but clinical trials are needed to validate their utility. While the treatment of hepatobiliary cancers involves unique challenges that these cancers present, the progress seen with ICIs and adoptive transfer has solidified immunotherapy as an important approach in these challenging patients with few other effective treatment options.

scholarly journals Immune Checkpoint Inhibitors in Triple Negative Breast Cancer Treatment: Promising Future Prospects

2021 ◽  
Vol 10 ◽  
Author(s):  
Remy Thomas ◽  
Ghaneya Al-Khadairi ◽  
Julie Decock
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Future Prospects

Immunotherapy has emerged as the fifth pillar of cancer treatment alongside surgery, radiotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors are the current superheroes of immunotherapy, unleashing a patient’s own immune cells to kill tumors and revolutionizing cancer treatment in a variety of cancers. Although breast cancer was historically believed to be immunologically silent, treatment with immune checkpoint inhibitors has been shown to induce modest responses in metastatic breast cancer. Given the inherent heterogeneity of breast tumors, this raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define the likelihood of inducing a potent and durable anti-tumor immune response. In this review, we will focus on triple negative breast cancer as immunogenic breast cancer subtype, and specifically discuss the relevance of tumor mutational burden, the plethora and diversity of tumor infiltrating immune cells in addition to the immunoscore, the presence of immune checkpoint expression, and the microbiome in defining immune checkpoint blockade response. We will highlight the current immune checkpoint inhibitor treatment options, either as monotherapy or in combination with standard-of-care treatment modalities such as chemotherapy and targeted therapy. In addition, we will look into the potential of immunotherapy-based combination strategies using immune checkpoint inhibitors to enhance both innate and adaptive immune responses, or to establish a more immune favorable environment for cancer vaccines. Finally, the review will address the need for unambiguous predictive biomarkers as one of the main challenges of immune checkpoint blockade. To conclude, the potential of immune checkpoint blockade for triple negative breast cancer treatment could be enhanced by exploration of aforementioned factors and treatment strategies thereby providing promising future prospects.

scholarly journals Beyond Tumor PD-L1: Emerging Genomic Biomarkers for Checkpoint Inhibitor Immunotherapy

2020 ◽  
pp. e47-e57 ◽  
Author(s):  
Galina G. Lagos ◽  
Benjamin Izar ◽  
Naiyer A. Rizvi
Keyword(s):  
Immune Response ◽  
Clinical Practice ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Tumor Subtypes ◽  
Mutation Burden ◽  
Specific Tumor ◽  
Sequencing Platforms

Despite the success of immune checkpoint blockade as a strategy for activating an antitumor immune response and promoting cancer regression, only a subset of patients have durable clinical benefit. Efforts are ongoing to identify robust biomarkers that can effectively predict treatment response to immune checkpoint inhibitors (ICIs). Although PD-L1 expression is useful for stratifying patients, it is an imperfect tool. Comprehensive next-generation sequencing platforms that are readily used in clinical practice to identify a tumor’s potentially actionable genetic alterations also reveal tumor genomic features, including tumor mutation burden (TMB), that may impact the response to ICIs. High TMB enhances tumor immunogenicity through increased numbers of tumor neoantigens that may promote an immune response. Defective DNA repair, leading to microsatellite instability, is an endogenous mechanism for increased tumor TMB that augments response to anti–PD-1 blockade. Alternatively, DNA damage from exogenous factors is responsible for high TMB seen in melanoma, lung cancer, and urothelial carcinoma, among tumor subtypes with higher response rates to ICIs. In this review, we summarize data supporting the use of TMB as a biomarker as well as its known limitations. We also highlight specific tumor suppressor genes and oncogenes that are under investigation as biomarkers for ICI response and resistance. Efforts are ongoing to delineate which genomic tumor characteristics can eventually be utilized in clinical practice to ascertain the benefit of ICIs for an individual patient.

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