scholarly journals Emerging dynamics pathways of response and resistance to PD-1 and CTLA-4 blockade: tackling uncertainty by confronting complexity

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Allan Relecom ◽  
Maysaloun Merhi ◽  
Varghese Inchakalody ◽  
Shahab Uddin ◽  
Darawan Rinchai ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Mechanisms Of Action ◽  
Checkpoint Blockade ◽  
Adaptive Resistance ◽  
Insight Into

AbstractImmune checkpoint inhibitors provide considerable therapeutic benefit in a range of solid cancers as well as in a subgroup of hematological malignancies. Response rates are however suboptimal, and despite considerable efforts, predicting response to immune checkpoint inhibitors ahead of their administration in a given patient remains elusive. The study of the dynamics of the immune system and of the tumor under immune checkpoint blockade brought insight into the mechanisms of action of these therapeutic agents. Equally relevant are the mechanisms of adaptive resistance to immune checkpoint inhibitors that have been uncovered through this approach. In this review, we discuss the dynamics of the immune system and of the tumor under immune checkpoint blockade emanating from recent studies on animal models and humans. We will focus on mechanisms of action and of resistance conveying information predictive of therapeutic response.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
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.

scholarly journals Metabolomic adaptations and correlates of survival to immune checkpoint blockade

2019 ◽  
Vol 10 (1) ◽  
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.

scholarly journals 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 ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1689 ◽  
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.

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

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.

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

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.

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

2017 ◽  
Vol 35 (6) ◽  
pp. 618-622 ◽  
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.

scholarly journals Understanding Checkpoint Inhibitors in Cancer Therapy, Mechanisms of Action, Resistance and Future Challenges

2020 ◽  
pp. 1-13
Author(s):  
Harman Saman ◽  
Harman Saman ◽  
Shahab Uddin ◽  
Syed Raza ◽  
Raj Shrimali ◽  
...  
Keyword(s):  
Immune System ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Mechanisms Of Action ◽  
Programmed Death ◽  
Future Challenges

The immune system is the human body’s natural defence against mutated cells produced as the result of DNA replicative error or by the effect of carcinogens, a process rereferred to as immune surveillance. ‘Escaping’ of cancer cells from immune surveillance leads to tumor development, metastasis and progression. Avoiding detection and destruction by the immune system are the result of cancer cells evolution, caused primarily by cancer cells’ genomic instability. On the other hand, scientists attempted for decades to exploit the anticancer effect of the immune system with limited success. However, better understanding of the mechanisms behind the cancer cells’ ability to avoid detection and suppression by the immune system resulted in the development of immune checkpoint inhibitors, a form of immunotherapy, first approved by the Food and Drug Administration (FDA) in 2011. This article reviews the pathways involved in anticancer immune response, evading and supressing of the immune system by cancer cells mechanisms of action and successes of immune checkpoint inhibitors (ICI), particularly programmed death1 (PD-1) and programmed death-ligand (PD-L1) inhibitors as well as mechanisms that result in resistance of cancer cells to ICI.

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...

237 In vitro potency assays for immune checkpoint blockade using human primary cells, murine huGEMM immune cells and patient-derived tumor organoids

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A254-A254
Author(s):  
Xuefei Yan ◽  
Hongjuan Zhang ◽  
Jun Zhou ◽  
Jia Zheng ◽  
Shuang Zhu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Culture System ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Tumor Organoids

BackgroundThe demand of evaluating potency of immune checkpoint modulators is steadily growing for immune-oncology drug development.MethodsWe aimed to establish a platform to assess the effects of immune checkpoint blockade using human primary immune cells, humanized murine primary immune cells, and co-cultures of tumor cells or patient-derived tumor organoids with immune cells.ResultsFirst, we validated the potency of immune checkpoint blockade, such as anti-PD-1 antibodies, using mixed lymphocyte reaction (MLR) assay and T cell activation assay by in vitro stimulation. Secondly, we introduced tumor cell lines into co-culture system with immune cells and validate the potency assay by measuring cytokine production and tumor cell killing by allogenic T cells. Thirdly we used huGEMM mouse-derived immune cells to replace human primary immune cells in potency assays. HuGEMM mice express engineered human immune checkpoint targets on immune cells and they can serve as an excellent resource of primary immune cells to test the drug candidates targeting human checkpoints in vitro. Last, we developed a patient-derived tumor organoid co-culture system with immune cells. We profiled the expression of immune inhibitory molecules on the tumor organoids and assessed the potency of immune checkpoint inhibitors.ConclusionsIn summary, we have established an extensive in vitro platform to evaluate the potency of the next generation of immune checkpoint inhibitors.

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