scholarly journals DRES-08. CLINICAL SIGNIFICANCE OF HYPERMUTATION IN GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi73-vi73
Author(s):  
Mehdi Touat ◽  
Yvonne Li ◽  
Adam Boynton ◽  
Liam Spurr ◽  
Bryan Iorgulescu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Alkylating Agents ◽  
Standard Of Care ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Molecular Characteristics ◽  
Clinical Value

Abstract BACKGROUND Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB). METHODS We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments. RESULTS Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSIONS Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas

scholarly journals OS9.1 Clinical significance of hypermutation in gliomas

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii18-iii18 ◽  
Author(s):  
M Touat ◽  
Y Li ◽  
A Boynton ◽  
L Spurr ◽  
B Iorglescu ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Alkylating Agents ◽  
Standard Of Care ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Molecular Characteristics

Abstract BACKGROUND Among patients with glioma, little is known about the clinical significance of hypermutation. We sought to define the determinants of hypermutation in gliomas, and to assess the value of this biomarker for predicting response to standard of care and immune checkpoint blockade. MATERIAL AND METHODS We performed comprehensive molecular characterization of 2420 pediatric and adult gliomas with clinical annotation. We determined the clinical and molecular characteristics associated with hypermutation, and assessed the relationship between hypermutation and clinical response to cancer therapies. RESULTS Overall, 114 hypermutated gliomas were identified. Hypermutation occurred predominantly in therapy-responsive subtypes characterized by methylated MGMT promoter, IDH1/2mutation or 1p/19q co-deletion. Hypermutation was almost always associated with prior treatment with temozolomide and molecular defects in DNA mismatch repair (MMR), which were identified in one-third of IDH1/2-mutated recurrent gliomas and was associated with shorter survival in multivariate analyses (hazard ratio 2.11 [95% CI 1.24–3.6], P=0.006). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSION This study establishes that mutation burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas.

scholarly journals P2.04-44 Combined Immune Checkpoint Blockade in Mesothelioma: In Vivo Investigation of in Vitro Data

2019 ◽  
Vol 14 (10) ◽  
pp. S725
Author(s):  
E. Marcq ◽  
J. Van Audenaerde ◽  
J. De Waele ◽  
J. Jacobs ◽  
J. Van Loenhout ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals The Current Landscape of Immune Checkpoint Blockade in Metastatic Lung Squamous Cell Carcinoma

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1392
Author(s):  
Hong Yuan ◽  
Jing Liu ◽  
Jun Zhang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Unmet Need ◽  
Lung Squamous Cell Carcinoma ◽  
Standard Of Care ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Programmed Death

In addition to surgery, chemotherapy, radiotherapy, and targeted therapy, immunotherapy has emerged as a standard pillar of cancer treatment. Immune checkpoint inhibitors (ICIs) such as targeting programmed death-1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have been integrated into standard-of-care regimens for patients with advanced lung squamous cell carcinoma (LUSC), who were previously limited by the lack of treatment options. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Recent successes and failures of immune checkpoint blockade-based combination therapies have provided significant insights into implementing combination strategies in LUSC. Therefore, there is an urgent need to correctly select patients who are more likely to respond to immunotherapy and understand the mechanisms of primary or acquired resistance. In this review, we aim at summarizing the emerging clinical data on the promise and challenge of ICIs, discussing the unmet need of potential biomarkers for predicting response or resistance to immunotherapy, and providing an overview of the current immune landscape and future directions in advanced LUSC.

scholarly journals Cannabinoids Inhibited Pancreatic Cancer via P-21 Activated Kinase 1 Mediated Pathway

2020 ◽  
Vol 21 (21) ◽  
pp. 8035
Author(s):  
Yang Yang ◽  
Nhi Huynh ◽  
Chelsea Dumesny ◽  
Kai Wang ◽  
Hong He ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Pancreatic Stellate Cells ◽  
Inhibitory Effects ◽  
Anti Cancer ◽  
Pancreatic Tumour ◽  
Mouse Study

The anti-cancer effects of cannabinoids including CBD (Cannabidiol) and THC ((−)-trans-∆9-tetrahydrocannabinol) have been reported in the case of pancreatic cancer (PC). The connection of these cannabinoids to KRas oncogenes that mutate in more than 90% of PC, and their effects on PD-L1, a key target of immune checkpoint blockade, have not been thoroughly investigated. Using cell lines and mouse models of PC, the effects of CBD and THC on cancer growth, the interaction between PC cells and a stromal cell, namely pancreatic stellate cells (PSCs), and the mechanism(s) involved were determined by cell-based assays and mouse study in vivo. CBD and THC inhibited the proliferation of PC, PSC, and PSC-stimulated PC cells. They also suppressed pancreatic tumour growth in mice. Furthermore, CBD and/or THC reduced the expression of PD-L1 by either PC or PSC cells. Knockout of p-21 activated kinase 1 (PAK1, activated by KRas) in PC and PSC cells and, in mice, dramatically decreased or blocked these inhibitory effects of CBD and/or THC. These results indicated that CBD and THC exerted their inhibitions on PC and PSC via a p-21 activated kinase 1 (PAK1)-dependent pathway, suggesting that CBD and THC suppress Kras activated pathway by targeting PAK1. The inhibition by CBD and THC of PD-L1 expression will enhance the immune checkpoint blockade of PC.

scholarly journals KALRN mutations promote antitumor immunity and immunotherapy response in cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000293
Author(s):  
Mengyuan Li ◽  
Yuxiang Ma ◽  
You Zhong ◽  
Qian Liu ◽  
Canping Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Patients With Cancer ◽  
In Vivo Experiments ◽  
Damage Repair

Backgroundkalirin RhoGEF kinase (KALRN) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer.MethodsWe explored the correlation between KALRN mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between KALRN mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy.ResultsAntitumor immune signatures were more enriched in KALRN-mutated than KALRN-wildtype cancers. Moreover, KALRN mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in KALRN-mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between KALRN mutations and increased antitumor immunity was associated with the fact that KALRN mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors.ConclusionsThe KALRN mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.

scholarly journals B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

2018 ◽  
Author(s):  
Johannes Griss ◽  
Wolfgang Bauer ◽  
Christine Wagner ◽  
Margarita Maurer-Granofszky ◽  
Martin Simon ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Checkpoint ◽  
Cd8 T Cell ◽  
Immune Checkpoint Blockade ◽  
Human Melanoma ◽  
Checkpoint Blockade ◽  
Inflammatory Factors ◽  
T Effector Cells

Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses. Here we show that tumor-associated B cells are vital to tumor associated inflammation. Autologous B cells were directly induced by melanoma conditioned medium, expressed pro- and anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro. We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.

scholarly journals Targeting MUS81 promotes the anticancer effect of WEE1 inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chengguo Li ◽  
Qian Shen ◽  
Peng Zhang ◽  
Tao Wang ◽  
Weizhen Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Anticancer Effect ◽  
Gastric Cancer Cells ◽  
Therapeutic Value

Abstract Background Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated. Methods Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined. Results In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the WEE1 inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the WEE1 inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells. Conclusions Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of WEE1 inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells.

scholarly journals Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer

2021 ◽  
Vol 9 (11) ◽  
pp. e002917
Author(s):  
Shaoming Zhu ◽  
A-Hong Ma ◽  
Zheng Zhu ◽  
Elio Adib ◽  
Ting Rao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Pi3k Pathway ◽  
Immune Checkpoint Blockade ◽  
Mechanisms Of Action ◽  
Mtor Pathway ◽  
Checkpoint Blockade ◽  
Q Value ◽  
Secondary Resistance ◽  
Pi3k Inhibition

BackgroundImmune checkpoint blockade (ICB) induces durable response in approximately 20% of patients with advanced bladder urothelial cancer (aUC). Over 50% of aUCs harbor genomic alterations along the phosphoinositide 3-kinase (PI3K) pathway. The goal of this project was to determine the synergistic effects and mechanisms of action of PI3K inhibition and ICB combination in aUC.MethodsAlterations affecting the PI3K pathway were examined in The Cancer Genome Atlas (TCGA) and the Cancer Dependency Map databases. Human and mouse cells with Pten deletion were used for in vitro studies. C57BL/6 mice carrying syngeneic tumors were used to determine in vivo activity, mechanisms of action and secondary resistance of pan-PI3K inhibition, ICB and combination.ResultsAlterations along the PI3K pathway occurred in 57% of aUCs in TCGA. CRISPR (clustered regularly interspaced short palindromic repeats) knockout of PIK3CA induced pronounced inhibition of cell proliferation (p=0.0046). PI3K inhibition suppressed cancer cell growth, migration and colony formation in vitro. Pan-PI3K inhibition, antiprogrammed death 1 (aPD1) therapy and combination improved the overall survival (OS) of syngeneic mice with PTEN-deleted tumors from 27 days of the control to 48, 37, and 65 days, respectively. In mice with tumors not containing a PI3K pathway alteration, OS was prolonged by the combination but not single treatments. Pan-PI3K inhibition significantly upregulated CD80, CD86, MHC-I, and MHC-II in dendritic cells, and downregulated the transforming growth factor beta pathway with a false discovery rate-adjusted q value of 0.001. Interferon alpha response was significantly upregulated with aPD1 therapy (q value: <0.001) and combination (q value: 0.027). Compared with the control, combination treatment increased CD8+ T-cell infiltration (p=0.005), decreased Treg-cell infiltration (p=0.036), and upregulated the expression of multiple immunostimulatory cytokines and granzyme B (p<0.01). Secondary resistance was associated with upregulation of the mammalian target of rapamycin (mTOR) pathway and multiple Sprr family genes.ConclusionsThe combination Pan-PI3K inhibition and ICB has significant antitumor effects in aUC with or without activated PI3K pathway and warrants further clinical investigation. This combination creates an immunostimulatory tumor milieu. Secondary resistance is associated with upregulation of the mTOR pathway and Sprr family genes.

scholarly journals Modeling Immune Checkpoint Inhibitor Efficacy in Syngeneic Mouse Tumors in an Ex Vivo Immuno-Oncology Dynamic Environment

2020 ◽  
Vol 21 (18) ◽  
pp. 6478
Author(s):  
Daniel T. Doty ◽  
Julia Schueler ◽  
Vienna L. Mott ◽  
Cassie M. Bryan ◽  
Nathan F. Moore ◽  
...  
Keyword(s):  
Real Time ◽  
Mouse Models ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Confocal Imaging ◽  
Checkpoint Blockade ◽  
Syngeneic Mouse

The immune checkpoint blockade represents a revolution in cancer therapy, with the potential to increase survival for many patients for whom current treatments are not effective. However, response rates to current immune checkpoint inhibitors vary widely between patients and different types of cancer, and the mechanisms underlying these varied responses are poorly understood. Insights into the antitumor activities of checkpoint inhibitors are often obtained using syngeneic mouse models, which provide an in vivo preclinical basis for predicting efficacy in human clinical trials. Efforts to establish in vitro syngeneic mouse equivalents, which could increase throughput and permit real-time evaluation of lymphocyte infiltration and tumor killing, have been hampered by difficulties in recapitulating the tumor microenvironment in laboratory systems. Here, we describe a multiplex in vitro system that overcomes many of the deficiencies seen in current static histocultures, which we applied to the evaluation of checkpoint blockade in tumors derived from syngeneic mouse models. Our system enables both precision-controlled perfusion across biopsied tumor fragments and the introduction of checkpoint-inhibited tumor-infiltrating lymphocytes in a single experiment. Through real-time high-resolution confocal imaging and analytics, we demonstrated excellent correlations between in vivo syngeneic mouse and in vitro tumor biopsy responses to checkpoint inhibitors, suggesting the use of this platform for higher throughput evaluation of checkpoint efficacy as a tool for drug development.

Sign in / Sign up

Export Citation Format

Share Document