A Study to Investigate ONCOS-102 in Combination With Durvalumab in Subjects With Advanced Peritoneal Malignancies
Ontology highlight
ABSTRACT:
DISEASE(S): Ovarian Cancer,Appendiceal Cancer,Colorectal Cancer,Appendiceal Neoplasms
PROVIDER: 2229839 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:An unmet need in cancer treatment is identification of biomarkers of response to PD-1 or PD-L1 immune checkpoint inhibitors that predict therapeutic outcomes in patients with non–small-cell lung carcinoma (NSCLC) and urothelial cancer (UC). Expression of PD-L1 measured by immunohistochemistry has limited capacity for predicting outcomes of immune checkpoint therapy because expression of this biomarker does not correlate highly with treatment response. In addition, PD-L1 as measured on tumor cells, which has been approved by the FDA for both companion and complementary diagnostic utility, does not necessarily reflect anti-tumor activity of tumor-infiltrating lymphocytes. Results presented in this report demonstrate that gene expression levels of four interferon gamma (IFNγ)-inducible mRNAs correlate with improved clinical outcomes in patients with NSCLC or UC treated with the PD-L1 inhibitor durvalumab. This IFNγ gene signature may augment the predictive value of PD-L1 and other biomarkers in identifying cancer patients most likely to respond to therapy with durvalumab or other immune checkpoint inhibitors.
2018-02-14 | GSE110390 | GEO
Project description:T cells in cutaneous T-cell lymphoma (CTCL) are functionally exhausted, expressing immune inhibitory molecules such as PD1 and PD-L1. Durvalumab selectively targets PD-L1 on exhausted T cells and distinct cells within the CTCL tumor microenvironment (TME) and may restore an anti-tumor immune response. The oral immunomodulator lenalidomide, which has shown activity in CTCL, may enhance immune checkpoint blockade by durvalumab. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab in patients with refractory/advanced CTCL (NCT03011814). Primary objectives were to assess safety and tolerability and identify the maximum tolerated dose/recommended phase 2 dose. Secondary and tertiary objectives were to investigate efficacy and the effects on the TME. Thirteen patients enrolled in sequential cohorts received fixed dose durvalumab and dose escalation of lenalidomide. Thirteen patients were evaluable for toxicities and 12 for response in phase 1. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1-3 (DLT evaluation period). The most frequent AEs were tumor flare, fatigue, neutropenia and leukopenia. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Median cycles of treatment were 11 (range, 3-42+). Median duration of response was 25.5 (range 8-36.5) months. Anti-PD-L1/lenalidomide showed clinical activity; there were 7 partial responses, 4 stable disease and 1 progressive disease. Adaptive and innate immune signatures potentially predictive of response seen in gene expression profiling of serial skin samples were downregulation of TNF-alpha signaling via NFκB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders vs up-regulation of MYC targets and pro-inflammatory pathways in non-responders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment status and response.
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Project description:Modelling combined virotherapy and immunotherapy:strengthening the antitumour immune response mediated byIL-12 and GM-CSF expression
Adrianne L. Jennera, Chae-Ok Yunb, Arum Yoonb, Adelle C. F. Costercand Peter S. Kimaa
School of Mathematics and Statistics, University of Sydney, Sydney, Australia;bDepartment ofBioengineering, Hanyang University, Seoul, Korea;cSchool of Mathematics and Statistics, University of NewSouth Wales, Sydney, Australia
ABSTRACT
Combined virotherapy and immunotherapy has been emergingas a promising and effective cancer treatment for some time.Intratumoural injections of an oncolytic virus instigate an immunereaction in the host, resulting in an influx of immune cells tothe tumour site. Through combining an oncolytic viral vector withimmunostimulatory cytokines an additional antitumour immuneresponse can be initiated, whereby immune cells induce apoptosisin both uninfected and virus infected tumour cells. We developa mathematical model to reproduce the experimental results fortumour growth under treatment with an oncolytic adenovirus co-expressing the immunostimulatory cytokines interleukin 12 (IL-12)and granulocyte-monocyte colony stimulating factor (GM-CSF). Byexploring heterogeneity in the immune cell stimulation by thetreatment, we find a subset of the parameter space for the immunecell induced apoptosis rate, in which the treatment will be lesseffective in a short time period. Therefore, we believe the bivariatenature of treatment outcome, whereby tumours are either completelyeradicated or grow unbounded, can be explained by heterogeneity inthis immune characteristic. Furthermore, the model highlights theapparent presence of negative feedback in the helper T cell and APCstimulation dynamics, when IL-12 and GM-CSF are co-expressed asopposed to individually expressed by the viral vector.
2020-01-09 | MODEL1912120003 | BioModels
Project description:Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations do not respond to anti-PD-1 (L1) as well as tumors without an EGFR mutation. We showed in a xenograft mouse model of EGFR-mutated NSCLC that, neither durvalumab nor oleclumab alone inhibited tumor growth compared to the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth and increased gene expressions that corresponded to inflammation and T cell function in tumors treated. We used microarrays to study gene expressions that corresponded to enhanced immune response in antibody-treated mice.
2022-02-23 | GSE190731 | GEO
Project description:Immune checkpoint blockade with anti–PD-1/L1 or anti–CTLA-4 therapies has shown promising results across multiple cancer types, but the mechanisms within the tumor microenvironment (TME) have not been fully characterized. We used single-cell RNA sequencing to investigate the effects of anti–PD-L1 monoclonal antibody (mAb) durvalumab (D) alone and combined with an anti–CTLA-4 mAb, tremelimumab (T), on distinct subsets of immune cells. Upon treatment with D or D+T, two NSCLC tumors showed elevated IFNγ responses, although they differed in magnitude of response but differed in other areas. Our results highlight that D and D+T in the TME have some consistent effects across tumors but also exhibit tumor-specific effects depending on composition and functional state of immune cells in the TME at time of treatment. This complex tumor-specific interplay of diverse immune subtypes in the TME is critical to better understand patient response to immunotherapy.
2021-09-01 | GSE131933 | GEO
Project description:Background:
* Immune-based approaches in colorectal cancer have unfortunately with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage
* Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death via the induction of innate and adaptive immune responses
* Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed against programmed death-ligand 1 (PD-L1).
* The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition.
Objective:
-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer.
Eligibility:
* Histologically confirmed metastatic colorectal cancer.
* Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab based chemotherapy.
* Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
* Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy.
* Willingness to undergo mandatory tumor biopsy.
Design:
-The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in combination with immune checkpoint inhibition in patients with metastatic colorectal cancer.
| 2248442 | ecrin-mdr-crc
Project description:<p>Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.</p>
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Project description:Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mphage) or macrophage CSF (M-CSF)-induced human monocyte-derived Mphage (M-Mphage) are distinct in terms of the resistance to Mycobacterium tuberculosis (M. tuberculosis). To elucidate the role of molecules involved in the functional differences between these Mphages, we investigated the gene expression profiles using microarray. After culture of CD14+ monocytes with CSFs, Mphages were cultured with or without BCG (GM-Mf-BCG and M-Mf-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mphages were selected and evaluated for antimycobacterial activity and superoxide production. FN1 and FCGR2B were the most up-regulated genes in GM-Mphage and M-Mphage, respectively. After the stimulation with BCG, 3 chemokine genes (Osteopontin (SPP1), CXC chemokine ligand 7 (CXCL7), and CC chemokine ligand 11 (CCL11)) were highly expressed in M-Mphage-BCG when compared to those in GM-Mf-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mphage with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mphages were higher than those of GM-Mphages without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediates production in Mphages.
2005-10-05 | GSE3408 | GEO
Project description:GM-CSF is involved in immune complex (IC)-mediated arthritis. However, little is known about what is the cellular source of GM-CSF and how it is regulated during IC-mediated inflammation. Using novel GM-CSF reporter mice, we show that NK cells produce GM-CSF during an IC-mediated model of inflammatory arthritis. NK cells promoted STIA in a GM-CSF-dependent manner, as deletion of NK cells and selective removal of GM-CSF production by NK cells abrogated disease. Furthermore, we show that myeloid cell activation by GM-CSF is restrained by induction of JAK/STAT checkpoint inhibitor cytokine-inducible SH2-containing protein, CIS. Myeloid cells from CIS-deficient mice had exaggerated responses to GM-CSF, and these mice develop exacerbated STIA. Our data suggest that tissue NK cells may amplify joint inflammation in arthritis via GM-CSF production and thus represent a novel target in IC-mediated pathology. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor and strategies that boost its function may provide an alternative anti-inflammatory approach.
2020-02-19 | PXD012794 | Pride