P2.06-25 Combined Immune Checkpoint Blockade in Malignant Pleural Mesothelioma: In Vivo Validation of in Vitro Results

TPS9078 Background: While the role of surgery in limited-stage (stage I-III) malignant pleural mesothelioma (MPM) is controversial, many centers have adopted an aggressive tri-modality approach incorporating (neo)adjuvant chemotherapy, surgical resection and radiotherapy. Despite this, most patients relapse and die from their disease. Immune checkpoint blockade (ICB) has shown promise in advanced MPM, but the mechanisms of response and resistance remain elusive. Improving the mechanistic understanding of ICB in MPM while concurrently optimizing the treatment strategy for limited-stage MPM are two urgent unmet needs. This multicenter multi-arm phase I/II study seeks to evaluate the safety and feasibility of neoadjuvant ICB in resectable MPM, incorporating novel genomic and immunologic analyses to deliver mechanistic insight into the biology of ICB in MPM. Methods: Patients with surgically resectable stage I-III treatment-naïve epithelioid or biphasic MPM receive neoadjuvant treatment with nivolumab every 2 weeks for 3 doses with or without 1 dose of ipilimumab (arm A: nivolumab monotherapy; arm B: nivolumab + ipilimumab). After macroscopic complete resection, patients receive optional investigator-choice adjuvant chemotherapy +/- radiation. Following this, patients will receive up to 1 year of adjuvant nivolumab. Feasibility and safety are co-primary endpoints of this study with feasibility defined by a delay in surgery of ≤24 days from the preplanned surgical date and safety defined by adverse events according to CTCAE v5.0. Bayesian-designed stopping rules have been implemented for feasibility and safety. Secondary endpoints include assessment of pathologic response and radiographic response using RECIST 1.1 for MPM. Correlative analyses will be performed on tissue specimens obtained pre- and post-ICB, as well as blood obtained pre, during, and post-ICB. Key correlates include multiplex immunofluorescence and longitudinal ctDNA assessment. Whole exome sequencing, T-cell receptor sequencing, and the MANAFEST functional neoantigen assay will be utilized to identify neoantigen-specific T-cell clonotypes and track these clonotypes temporally (during/post ICB) and spatially (across immune compartments). Single-cell RNA sequencing will be used to characterize the functionality of expanded T-cell clonotypes. Accrual to arm B will commence following complete accrual to arm A with a planned total enrollment of 30 patients. This study is open with 1 patient enrolled at the time of submission. Clinical trial information: NCT03918252.

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DRES-08. CLINICAL SIGNIFICANCE OF HYPERMUTATION IN GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.296 ◽

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

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OS9.1 Clinical significance of hypermutation in gliomas

Neuro-Oncology ◽

10.1093/neuonc/noz126.059 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii18-iii18 ◽

Cited By ~ 1

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.

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

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2019.08.1549 ◽

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

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Blocking the GITR-GITRL pathway to overcome resistance to therapy in sarcomatoid malignant pleural mesothelioma

Communications Biology ◽

10.1038/s42003-021-02430-5 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Meilin Chan ◽

Licun Wu ◽

Zhihong Yun ◽

Trevor D. McKee ◽

Michael Cabanero ◽

...

Keyword(s):

Tumor Growth ◽

Malignant Pleural Mesothelioma ◽

Neutralizing Antibodies ◽

Pleural Mesothelioma ◽

Spheroid Formation ◽

Resistance To Therapy ◽

Sarcomatoid Mesothelioma

AbstractMalignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are particularly resistant to therapy. We investigated the role of the GITR-GITRL pathway in mediating the resistance to therapy. We found that GITR and GITRL expressions were higher in the sarcomatoid cell line (CRL5946) than in non-sarcomatoid cell lines (CRL5915 and CRL5820), and that cisplatin and Cs-137 irradiation increased GITR and GITRL expressions on tumor cells. Transcriptome analysis demonstrated that the GITR-GITRL pathway was promoting tumor growth and inhibiting cell apoptosis. Furthermore, GITR+ and GITRL+ cells demonstrated increased spheroid formation in vitro and in vivo. Using patient derived xenografts (PDXs), we demonstrated that anti-GITR neutralizing antibodies attenuated tumor growth in sarcomatoid PDX mice. Tumor immunostaining demonstrated higher levels of GITR and GITRL expressions in non-epithelioid compared to epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation therapy followed by surgery, the intensity of GITR expression after radiation negatively correlated with survival in non-epithelioid MPM patients. In conclusion, the GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. Blocking the GITR-GITRL pathway could be a new therapeutic target for non-epithelioid mesothelioma.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21218035 ◽

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.

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KALRN mutations promote antitumor immunity and immunotherapy response in cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000293 ◽

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.

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