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

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.

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Treatment Progress of Immune Checkpoint Blockade Therapy for Glioblastoma

Frontiers in Immunology ◽

10.3389/fimmu.2020.592612 ◽

2020 ◽

Vol 11 ◽

Author(s):

Na Zhang ◽

Li Wei ◽

Meng Ye ◽

Chunsheng Kang ◽

Hua You

Keyword(s):

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Resistance Mechanism ◽

Primary Brain Tumor ◽

Immune Checkpoint Blockade ◽

Brain Parenchyma ◽

Checkpoint Blockade ◽

Research Progress ◽

Recent Success

Glioblastoma (GBM) is a highly malignant and aggressive primary brain tumor mostly prevalent in adults and is associated with a very poor prognosis. Moreover, only a few effective treatment regimens are available due to their rapid invasion of the brain parenchyma and resistance to conventional therapy. However, the fast development of cancer immunotherapy and the remarkable survival benefit from immunotherapy in several extracranial tumor types have recently paved the way for numerous interventional studies involving GBM patients. The recent success of checkpoint blockade therapy, targeting immunoinhibitory proteins such as programmed cell death protein-1 and/or cytotoxic T lymphocyte-associated antigen-4, has initiated a paradigm shift in clinical and preclinical investigations, and the use of immunotherapy for solid tumors, which would be a potential breakthrough in the field of drug therapy for the GBM treatment. However clinical trial showed limited benefits for GBM patients. The main reason is drug resistance. This review summarizes the clinical research progress of immune checkpoint molecules and inhibitors, introduces the current research status of immune checkpoint inhibitors in the field of GBM, analyzes the molecular resistance mechanism of checkpoint blockade therapy, proposes corresponding re-sensitive strategies, and describes a reference for the design and development of subsequent clinical studies on immunotherapy for GBM.

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Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy

Science Translational Medicine ◽

10.1126/scitranslmed.aao1641 ◽

2018 ◽

Vol 10 (422) ◽

pp. eaao1641 ◽

Cited By ~ 102

Author(s):

Marie-Claude Bourgeois-Daigneault ◽

Dominic Guy Roy ◽

Amelia Sadie Aitken ◽

Nader El Sayes ◽

Nikolas Tim Martin ◽

...

Keyword(s):

Breast Cancer ◽

Surgical Resection ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Neoadjuvant Treatment ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Oncolytic Viruses

Triple-negative breast cancer (TNBC) is an aggressive disease for which treatment options are limited and associated with severe toxicities. Immunotherapeutic approaches like immune checkpoint inhibitors (ICIs) are a potential strategy, but clinical trials have demonstrated limited success in this patient cohort. Clinical studies using ICIs have revealed that patients with preexisting anticancer immunity are the most responsive. Given that oncolytic viruses (OVs) induce antitumor immunity, we investigated their use as an ICI-sensitizing approach. Using a therapeutic model that mimics the course of treatment for women with newly diagnosed TNBC, we demonstrate that early OV treatment coupled with surgical resection provides long-term benefits. OV therapy sensitizes otherwise refractory TNBC to immune checkpoint blockade, preventing relapse in most of the treated animals. We suggest that OV therapy in combination with immune checkpoint blockade warrants testing as a neoadjuvant treatment option in the window of opportunity between TNBC diagnosis and surgical resection.

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Rethinking immune checkpoint blockade: ‘Beyond the T cell’

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001460 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001460 ◽

Cited By ~ 1

Author(s):

Xiuting Liu ◽

Graham D Hogg ◽

David G DeNardo

Keyword(s):

Immune System ◽

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Antitumor Immunity ◽

Checkpoint Inhibitors ◽

Clinical Success ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

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Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Nature Communications ◽

10.1038/s41467-019-12361-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 30

Author(s):

Haoxin Li ◽

Kevin Bullock ◽

Carino Gurjao ◽

David Braun ◽

Sachet A. Shukla ◽

...

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Resistance Mechanism ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Adaptive Resistance ◽

Metabolic Monitoring ◽

Pd1 Blockade ◽

To Receive ◽

Cell Death Protein

Abstract Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase (IDO/TDO) inhibitors.

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Synergy between hemagglutinin 2 (HA2) subunit of influenza fusogenic membrane glycoprotein and oncolytic Newcastle disease virus suppressed tumor growth and further enhanced by Immune checkpoint PD-1 blockade

Cancer Cell International ◽

10.1186/s12935-020-01476-5 ◽

2020 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Seyed Mohammad Miri ◽

Mir Saeed Ebrahimzadeh ◽

Elahe Abdolalipour ◽

Mahsa Yazdi ◽

Hassan Hosseini Ravandi ◽

...

Keyword(s):

Cervical Cancer ◽

Gene Therapy ◽

Newcastle Disease Virus ◽

Tumor Cells ◽

Disease Virus ◽

Newcastle Disease ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Oncolytic Viruses

Abstract Background Newcastle disease virus (NDV) has shown noticeable oncolytic properties, especially against cervical cancer. However, in order to improve the spread rate and oncotoxicity of the virus, employment of other therapeutic reagents would be helpful. It has been shown that some viral fusogenic membrane glycoproteins (FMGs) could facilitate viral propagation and increase the infection rate of tumor cells by oncolytic viruses. Additionally, immune checkpoint blockade has widely been investigated for its anti-tumor effects against several types of cancers. Here, we investigated for the first time whether the incorporation of influenza hemagglutinin-2 (HA2) FMG could improve the oncolytic characteristics of NDV against cervical cancer. Next, we added anti-PD-1 mAb to our therapeutic recipe to assess the complementary role of immune checkpoint blockade in curbing tumor progression. Methods For this purpose, TC-1 tumor cells were injected into the mice models and treatment with NDV, iNDV, HA2, NDV-HA2, iNDV-HA2 began 10 days after tumor challenge and was repeated at day 17. In addition, PD-1 blockade was conducted by injection of anti-PD-1 mAb at days 9 and 16. Two weeks after the last treatment, sample mice were sacrificed and treatment efficacy was evaluated through immunological and immunohistochemical analysis. Moreover, tumors condition was monitored weekly for 6 weeks intervals and the tumor volume was measured and compared within different groups. Results The results of co-treatment with NDV and HA2 gene revealed that these agents act synergistically to induce antitumor immune responses against HPV-associated carcinoma by enhancement of E7-specific lymphocyte proliferation, inducement of CD8+ T cell cytotoxicity responses, increase in splenic cytokines and granzyme B, decrease in immunosuppressive cytokines and E6 oncogene expression, and upregulation of apoptotic proteins expression, in comparison with control groups. Moreover, incorporation of PD-1 blockade as the third side of our suggested therapy led to noticeable regression in tumor size and augmentation of cytokine responses. Conclusions The invaluable results of synergy between NDV virotherapy and HA2 gene therapy suggest that tumor-selective cell killing by oncolytic NDV can be enhanced by combining with FMG gene therapy. Moreover, the adjunction of the PD-1 blockade proves that checkpoint blockade can be considered as an effective complementary therapy for the treatment of cervical cancer.

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Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice

Cancers ◽

10.3390/cancers11111689 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1689 ◽

Cited By ~ 10

Author(s):

Edoardo Giannini ◽

Andrea Aglitti ◽

Mauro Borzio ◽

Martina Gambato ◽

Maria Guarino ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Practice ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Critical Evaluation ◽

Real Life ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Immune Checkpoints

Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.

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Dermatologic adverse events with immune checkpoint blockade: Systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.84 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 84-84

Author(s):

Kushal Naha ◽

Lakshmi Manogna Chintalacheruvu ◽

Donald C. Doll ◽

Sowjanya Naha

Keyword(s):

Adverse Effects ◽

Adverse Events ◽

Confidence Interval ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Randomized Controlled ◽

Dermatologic Adverse Events

84 Background: Immune checkpoint blockade is known to be associated with various dermatologic adverse events. However, these adverse effects have not been studied in a systematic manner. This is especially relevant considering the rapidly increasing number of immune checkpoint inhibitors that are now available. Methods: We searched for eligible studies in PubMed and Google scholar. We reviewed randomized controlled trials involving cancer patients treated with immune checkpoint inhibitors - PD1 inhibitors, PDL1 inhibitors and CTLA4 inhibitors and for dermatologic adverse effects. A total of 47 randomized controlled trials involving 11875 patients met eligibility criteria for our study. Results: Incidence rate of all grade dermatologic adverse effects was 40.6% (95% confidence interval [CI], 39.4-41.7%). Most common adverse effects included pruritus (17.3%) (95% confidence interval [CI] 16.6-18.1%), undifferentiated rash (15.1%) (95% confidence interval [CI] 14.4-15.9%), vitiligo (3.6%) (95% confidence interval [CI] 3.2-3.9%), maculopapular rash (2.3%) (95% confidence interval [CI] 2.1-2.6%), stomatitis (0.7%) (95% confidence interval [CI] 0.55-0.92%) and dry skin (0.7%) (95% confidence interval [CI] 0.5-0.8%). Less common adverse events include palmoplantar erythrodysesthesia, pemphigoid skin reactions, lichen planus and hyperhidrosis. Grade 3 and higher adverse effects were seen in 1.3% of patients (95% confidence interval [CI] 1.1-1.6%). Conclusions: A wide range of dermatologic adverse effects can be seen with immune checkpoint blockade. While the majority of these events are of grade 1-2, they can occasionally be severe and even life threatening. Patients receiving immune checkpoint blockade should be closely monitored for dermatologic adverse effects.

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SLAMF8, a novel biomarker for personalized immune checkpoint blockade therapy in gastrointestinal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14078 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14078-e14078

Author(s):

Qun Zhang ◽

Lei Cheng ◽

Jing Hu ◽

Li Li ◽

Mi Yang ◽

...

Keyword(s):

Gastric Cancer ◽

Immune Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Gene Signature ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Normal Tissues ◽

Ebv Infection

e14078 Background: Immune checkpoint inhibitors have brought great breakthroughs in cancer therapy. Activated immune response is known to be the prerequisite for exerting immunotherapy efficacy. Epstein-Barr virus (EBV) infection is associated with longer survival in gastric cancer (GC) patients due to enhanced anti-tumor immune response, and therefore it was reportedly played an important role in modulating immune checkpoint blockade therapy efficacy. However, molecular dimensions underlying the good response to immune checkpoint inhibitors in presence of EBV infection are still unclear. The aim of this study is to identify a gene signature related to EBV induced anti-tumor immune response, and select a tag gene from this signature to predict which patients are most likely to benefit from immune checkpoint blockade therapy. Methods: Two large transcriptome datasets from Gene Expression Omnibus(GEO) database (GSE51575 and GSE62254) were used to screen gene signature for EBV infected gastric cancer tissues. We further selected genes that showed a trend towards differential co-expression independent of EBV infection status. The tag gene of this differential co-expression signature was finally identified by bioinformatics analysis. To make an external validation, we performed RNA sequencing in 20 colorectal caner (CRC) tissues and 20 GC tissues, respectively. Meanwhile, tissue microarrays of CRC cohort (36 paired tumor and normal tissues) and GC cohort (75 paired tumor and normal tissues) were used to analyze the association of SLAMF8 with CD8 protein expression by immunohistochemistry (IHC). Results: Analysis of GEO datasets indicated 788 genes as feature gene cluster for EBV-positive gastric cancer, from which 290 genes were selected to be characterized by differential co-expression in either EBV-positive or EBV-negative gastric cancers. SLAMF8 was identified as the tag gene for this differential co-expression signature. This signature, tagged by SLAMF8, was successfully validated by our RNA sequencing data in presence of its good performance in dividing CRC and GC patients into two subsets. Moreover, we observed a significant association between SLAMF8 and CD8 expression in our CRC and GC tissue samples, in terms of either mRNA or protein level. Conclusions: SLAMF8, a potential indicator for T cell‐mediated immune response induced by EBV infection, may be served as a biomarker for individualized immune checkpoint blockade therapy in gastrointestinal cancer. Further SLAMF8 guided drug sensitivity tests are warranted to validate our results.

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Immunotherapy for cholangiocarcinoma: a 2021 update

Immunotherapy ◽

10.2217/imt-2021-0126 ◽

2021 ◽

Author(s):

Nikolaos Charalampakis ◽

Georgios Papageorgiou ◽

Sergios Tsakatikas ◽

Rodanthi Fioretzaki ◽

Christo Kole ◽

...

Keyword(s):

Cell Therapy ◽

Cancer Patients ◽

Immune Checkpoint ◽

Cancer Vaccines ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Adoptive Cell Therapy ◽

Oncolytic Viruses ◽

Dismal Prognosis ◽

Rare Malignancy

Cholangiocarcinoma (CCA) is a rare malignancy with generally dismal prognosis. Immunotherapy has revolutionized the management of cancer patients during the last decade, offering durable responses with an acceptable safety profile, but there are still no significant advances regarding CCA. Novel immunotherapeutic methods, such as cancer vaccines, oncolytic viruses, adoptive cell therapy and combinations of immune checkpoint inhibitors with other agents are currently under investigation and may improve prognosis. Efforts to find robust biomarkers for response are also ongoing. In this review, we discuss the rationale for the use of immunotherapy in CCA and available clinical data. Ongoing trials will also be presented, as well as key findings from each study.

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Role of Immune Checkpoint Blockade in the Treatment for Human Hepatocellular Carcinoma

Digestive Diseases ◽

10.1159/000480258 ◽

2017 ◽

Vol 35 (6) ◽

pp. 618-622 ◽

Cited By ~ 6

Author(s):

Naoshi Nishida ◽

Masatoshi Kudo

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Molecular Targeting ◽

Advanced Hepatocellular Carcinoma ◽

Targeting Therapy ◽

Molecular Targeting Therapy

With the development of molecular targeting therapy, several treatment options for advanced hepatocellular carcinoma (HCC) have become available in cases where curative and other palliative treatments, such as radiofrequency ablation, surgical resection, and transarterial chemoembolization, are not applicable. However, with the detection of a variety of mutations in cancer-related genes in a single tumor, molecular heterogeneity is commonly observed in HCC. Therefore, mutations in the major cellular signaling pathways underlie the development of resistance to molecular targeting agents. On the contrary, immune checkpoint inhibitors have proven effective in patients who are refractory to conventional treatments and molecular targeting therapy. Several clinical trials are currently investigating the efficacy of immune checkpoint inhibitors both individually and in combination with other types of anticancer agents. In this review, we focus on the potential of immune checkpoint blockade in the treatment of human HCC.

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