Advanced Nanotechnology for Enhancing Immune Checkpoint Blockade Therapy

Immune checkpoint receptor signaling pathways constitute a prominent class of “immune synapse,” a cell-to-cell connection that represses T-lymphocyte effector functions. As a possible evolutionary countermeasure against autoimmunity, this strategy is aimed at lowering potential injury to uninfected cells in infected tissues and at minimizing systemic inflammation. Nevertheless, tumors can make use of these strategies to escape immune recognition, and consequently, such mechanisms represent chances for immunotherapy intervention. Recent years have witnessed the advance of pharmaceutical nanotechnology, or nanomedicine, as a possible strategy to ameliorate immunotherapy technical weaknesses thanks to its intrinsic biophysical properties and multifunctional modifying capability. To improve the long-lasting response rate of checkpoint blockade therapy, nanotechnology has been employed at first for the delivery of single checkpoint inhibitors. Further, while therapy via single immune checkpoint blockade determines resistance and a restricted period of response, strong interest has been raised to efficiently deliver immunomodulators targeting different inhibitory pathways or both inhibitory and costimulatory pathways. In this review, the partially explored promise in implementation of nanotechnology to improve the success of immune checkpoint therapy and solve the limitations of single immune checkpoint inhibitors is debated. We first present the fundamental elements of the immune checkpoint pathways and then outline recent promising results of immune checkpoint blockade therapy in combination with nanotechnology delivery systems.

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Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade

Frontiers in Oncology ◽

10.3389/fonc.2021.617335 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yanna Lei ◽

Xiaoying Li ◽

Qian Huang ◽

Xiufeng Zheng ◽

Ming Liu

Keyword(s):

Immune Checkpoint ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Unmet Need ◽

Predictive Biomarkers ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Cancer Therapies ◽

Sustained Improvement ◽

The Past

Over the past decade, immune checkpoint blockade (ICB) therapy has revolutionized the outlook for oncology with significant and sustained improvement in the overall patient survival. Unlike traditional cancer therapies, which target the cancer cells directly, ICB acts on the immune system to enhance anti-tumoral immunity. However, the response rate is still far from satisfactory and most patients are refractory to such treatment. Unfortunately, the mechanisms underlying such heterogeneous responses between patients to ICB therapy remain unclear. In addition, escalating costs of cancer care and unnecessary immune-related adverse events also are pertinent considerations with applications of ICB. Given these issues, identifying explicit predictive biomarkers for patient selection is an urgent unmet need to increase the efficacy of ICB therapy. The markers can be classified as tumor related and non-tumor-related biomarkers. Although substantial efforts have been put into investigating various biomarkers, none of them has been found to be sufficient for effectively stratifying patients who may benefit from immunotherapy. The present write up is an attempt to review the various emerging clinically relevant biomarkers affecting the efficacy of immune checkpoint inhibitors, as well as the limitations associated with their clinical application.

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

Innovative Surgical Sciences ◽

10.1515/iss-2020-0034 ◽

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.

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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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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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Chemo4MetPanc: A phase II study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment naïve pancreas adenocarcinoma (PDAC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps454 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS454-TPS454

Author(s):

Ilenia Pellicciotta ◽

Emily Linda Alouani ◽

Alexander Raufi ◽

Samuel M Pan ◽

Jianhua Hu ◽

...

Keyword(s):

Immune Checkpoint ◽

Response Rate ◽

Treatment Options ◽

The United States ◽

Neoplastic Cell ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Open Label ◽

Pancreas Adenocarcinoma ◽

Treatment Naïve

TPS454 Background: Pancreas adenocarcinoma (PDAC) is an aggressive cancer projected to be the second leading cause of cancer-related death in the United States by 2030 for which improved treatment options are desperately needed. Immune checkpoint blockade (ICB) for PDAC has failed as monotherapy in early phase clinical trials likely due to a highly immunosuppressive tumor microenvironment. The CXCR4/CXCL12 axis is a key immune evasion mechanism thought to deter CD8+ T-cells (CTLs) from infiltrating the tumor. We performed a large seven arm survival and biopsy/necropsy study in KPC mice (KrasLSL.G12D/+;p53R172H/+;Pdx1Cretg/+) where we demonstrate that addition of gemcitabine to CXCR4 inhibition in combination with ICB, enhanced tumor stabilization and neoplastic cell death, and improved survival by 50 percent. Multiplex immunofluorescence indicated an increased CTL to regulatory T-cell ratio and clustering of CTLs around neoplastic cells. Presented here is a trial-in progress that will evaluate combination of a CXCR4 inhibitor, ICB, and chemotherapy in treatment naïve patients with PDAC. Methods: This is a multicenter, single arm, open-label phase 2 study of combination motixafortide 1.25mg/kg SC monotherapy for 5 days during priming followed by twice weekly, cemiplimab 350mg IV once every 21 days, gemcitabine 1000mg/m2 IV with nab-paclitaxel 125mg/m2 IV on days 1, 8, and 15 every 28 days. Patients with histologically confirmed metastatic PDAC who have not received prior therapy will be enrolled. The primary endpoint is overall response rate by 16 weeks. A response rate greater than 45% by 16 weeks is considered promising, whereas a response rate of less than 23% is considered not promising. We will use a Simon optimal 2-stage design, where we will enroll 10 patients in the first stage. If 3 or more patients meet the endpoint in the first stage, the study will be expanded to a total of 40 patients. If a total of 14 or more patients achieve CR or PR by 16 weeks, the agent will be considered promising and worthy of further study. Secondary endpoints include safety, mPFS, disease control rate (DCR), and mOS. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, and generation of patient derived organoids for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the stage I portion of the study. Clinical trial information: NCT04543071.

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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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