Publications by authors named "Ronald Herbst"

77 Publications

Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR.

Mol Cancer Ther 2021 03;20(3):541-552

Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland.

Resistance to antibody-drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine. 361-PBDr cells were over 20-fold less sensitive to SG3199 compared with parental cells and were cross-resistant to other PBD warhead and ADCs conjugated with PBDs. Proteomic profiling revealed that downregulation of Schlafen family member 11 (SLFN11), a putative DNA/RNA helicase, sensitizing cancer cells to DNA-damaging agents, was associated with PBD resistance. Confirmatory studies demonstrated that siRNA knockdown of SLFN11 in multiple tumor cell lines conferred reduced sensitivity to SG3199 and PBD-conjugated ADCs. Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0351DOI Listing
March 2021

Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment.

Clin Cancer Res 2020 12 17;26(23):6284-6298. Epub 2020 Aug 17.

AstraZeneca, Oncology R&D Unit, Gaithersburg, Maryland.

Purpose: While immune checkpoint inhibitors such as anti-PD-L1 are rapidly becoming the standard of care in the treatment of many cancers, only a subset of treated patients have long-term responses. IL12 promotes antitumor immunity in mouse models; however, systemic recombinant IL12 had significant toxicity and limited efficacy in early clinical trials.

Experimental Design: We therefore designed a novel intratumoral IL12 mRNA therapy to promote local IL12 tumor production while mitigating systemic effects.

Results: A single intratumoral dose of mouse (m)IL12 mRNA induced IFNγ and CD8 T-cell-dependent tumor regression in multiple syngeneic mouse models, and animals with a complete response demonstrated immunity to rechallenge. Antitumor activity of mIL12 mRNA did not require NK and NKT cells. mIL12 mRNA antitumor activity correlated with TH1 tumor microenvironment (TME) transformation. In a PD-L1 blockade monotherapy-resistant model, antitumor immunity induced by mIL12 mRNA was enhanced by anti-PD-L1. mIL12 mRNA also drove regression of uninjected distal lesions, and anti-PD-L1 potentiated this response. Importantly, intratumoral delivery of mRNA encoding membrane-tethered mIL12 also drove rejection of uninjected lesions with very limited circulating IL12p70, supporting the hypothesis that local IL12 could induce a systemic antitumor immune response against distal lesions. Furthermore, in patient tumor slice cultures, human IL12 mRNA (MEDI1191) induced dose-dependent IL12 production, downstream IFNγ expression and TH1 gene expression.

Conclusions: These data demonstrate the potential for intratumorally delivered IL12 mRNA to promote TH1 TME transformation and robust antitumor immunity..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0472DOI Listing
December 2020

Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

J Immunol 2020 07 20;205(1):102-112. Epub 2020 May 20.

Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742;

To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes (IC). This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis. Transcriptomic analysis of TLR stimulation in the presence of IC predicted the downstream activation of AKT and the inhibition of GSK3. Consequently, we pretreated LPS-stimulated human macrophages with small molecule inhibitors of GSK3 to partially phenocopy the regulatory effects of stimulation in the presence of IC. The upregulation of DC-STAMP and matrix metalloproteases was observed on these cells and may represent potential biomarkers for this regulatory activation state. To demonstrate the presence of these anti-inflammatory, growth-promoting macrophages in a human infectious disease, biopsies from patients with leprosy (Hanseniasis) were analyzed. The lepromatous form of this disease is characterized by hypergammaglobulinemia and defective cell-mediated immunity. Lesions in lepromatous leprosy contained macrophages with a regulatory phenotype expressing higher levels of DC-STAMP and lower levels of IL-12, relative to macrophages in tuberculoid leprosy lesions. Therefore, we propose that increased signaling by FcγR cross-linking on TLR-stimulated macrophages can paradoxically promote the resolution of inflammation and initiate processes critical to tissue growth and repair. It can also contribute to infectious disease progression.
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http://dx.doi.org/10.4049/jimmunol.1901382DOI Listing
July 2020

Retraction Note: Microglia-dependent synapse loss in type I interferon-mediated lupus.

Nature 2020 02;578(7793):177

Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, 02115, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41586-020-1949-xDOI Listing
February 2020

The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort.

J Transl Med 2019 11 4;17(1):357. Epub 2019 Nov 4.

University Paris Descartes, Paris, France.

Background: The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care.

Methods: The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString PanCancer IO360™ CodeSet using nCounter technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these.

Results: TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2).

Conclusions: These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.
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http://dx.doi.org/10.1186/s12967-019-2100-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829827PMC
November 2019

Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies.

J Immunother Cancer 2019 09 11;7(1):244. Epub 2019 Sep 11.

R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK.

Background: Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically "cold" tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated.

Methods: The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models.

Results: Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8 T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models.

Conclusion: Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.
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http://dx.doi.org/10.1186/s40425-019-0724-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739946PMC
September 2019

The Immunoscore: Colon Cancer and Beyond.

Clin Cancer Res 2020 01 14;26(2):332-339. Epub 2019 Aug 14.

INSERM, Laboratory of Integrative Cancer Immunology, Équipe Labellisée Ligue Contre le Cancer, Sorbonne Université, Université Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; Centre de Recherche des Cordeliers, Paris, France.

Tumors evolve in close interaction with their microenvironment, which encompasses a continual tension between the developing tumor and the host immune system. Clinical trials have shown that appropriate enhancement of a tumor immune response can lead to long-lasting clinical responses and patient benefit. Understanding the contribution of the immune contexture, in addition to the molecular subtype across different tumor indications, is a significant knowledge gap with limited sagacity to drive rational immunotherapy combinations. To better inform clinical studies, we must first strive to understand the multifaceted elements of the tumor-immune interaction, the spatiotemporal interplay of numerous different immune cell types, in conjunction with an understanding of the oncogenic drivers and mutations that may lead to presentation of neoepitopes and could drive changes within the tumor microenvironment. In this review, we discuss the Immunoscore and its probable universal characteristic. The overlay of immune quantification with the molecular segments of disease and how this may benefit identification of patients at high risk of tumor recurrence will be discussed. The Immunoscore may translate to provide a tumor agnostic method to define immune fitness of a given tumor and predict and stratify patients who will benefit from certain therapies (in particular immune therapies) and, ultimately, help save the lives of patients with cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1851DOI Listing
January 2020

A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity.

Sci Transl Med 2019 04;11(489)

Viela Bio, Gaithersburg, MD 20878, USA.

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67 dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.
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http://dx.doi.org/10.1126/scitranslmed.aar6584DOI Listing
April 2019

Proposal for a Combined Histomolecular Algorithm to Distinguish Multiple Primary Adenocarcinomas from Intrapulmonary Metastasis in Patients with Multiple Lung Tumors.

J Thorac Oncol 2019 05 2;14(5):844-856. Epub 2019 Feb 2.

Department of Biochemistry, Unit of Pharmacogenetic and Molecular Oncology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM UMR-S1147, Paris Sorbonne Cite University, Paris, France.

Introduction: Multiple nodules in the lung are being diagnosed with an increasing frequency thanks to high-quality computed tomography imaging. In patients with lung cancer, this situation represents up to 10% of patients who have an operation. For clinical management, it is important to classify the disease as intrapulmonary metastasis or multiple primary lung carcinoma to define TNM classification and optimize therapeutic options. In the present study, we evaluated the respective and combined input of histological and molecular classification to propose a classification algorithm for multiple nodules.

Methods: We studied consecutive patients undergoing an operation with curative intent for lung adenocarcinoma (N = 120) and harboring two tumors (N = 240). Histological diagnosis according to the WHO 2015 classification and molecular profiling using next-generation sequencing targeting 22 hotspot genes allowed classification of samples as multiple primary lung adenocarcinomas or as intrapulmonary metastasis.

Results: Next-generation sequencing identified molecular mutations in 91% of tumor pairs (109 of 120). Genomic and histological classification showed a fair agreement when the κ test was used (κ = 0.43). Discordant cases (30 of 109 [27%]) were reclassified by using a combined histomolecular algorithm. EGFR mutations (p = 0.03) and node involvement (p = 0.03) were significantly associated with intrapulmonary metastasis, whereas KRAS mutations (p = 0.00005) were significantly associated with multiple primary lung adenocarcinomas. EGFR mutations (p = 0.02) and node involvement (p = 0.004) were the only independent prognostic factors.

Conclusion: We showed that combined histomolecular algorithm represents a relevant tool to classify multifocal lung cancers, which could guide adjuvant treatment decisions. Survival analysis underlined the good prognosis of EGFR-mutated adenocarcinoma in patients with intrapulmonary metastasis.
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http://dx.doi.org/10.1016/j.jtho.2019.01.017DOI Listing
May 2019

Discovery and characterization of potent IL-21 neutralizing antibodies via a novel alternating antigen immunization and humanization strategy.

PLoS One 2019 25;14(1):e0211236. Epub 2019 Jan 25.

Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland, United States of America.

Interleukin-21 (IL-21), a member of the common cytokine receptor γ chain (γc) family, is secreted by CD4+ T cells and natural killer T cells and induces effector function through interactions with the IL-21 receptor (IL-21R)/γc complex expressed on both immune and non-immune cells. Numerous studies suggest that IL-21 plays a significant role in autoimmune disorders. Therapeutic intervention to disrupt the IL-21/IL-21R/γc interaction and inhibit subsequent downstream signal transduction could offer a treatment paradigm for these diseases. Potent neutralizing antibodies reported in the literature were generated after extensive immunizations with human IL-21 alone and in combination with various adjuvants. To circumvent the laborious method of antibody generation while targeting a conserved functional epitope, we designed a novel alternating-antigen immunization strategy utilizing both human and cynomolgus monkey (cyno) IL-21. Despite the high degree of homology between human and cyno IL-21, our alternating-immunization strategy elicited higher antibody titers and more potent neutralizing hybridomas in mice than did the immunization with human IL-21 antigen alone. The lead hybridoma clone was humanized by grafting the murine complementarity-determining regions onto human germline framework templates, using a unique rational design. The final humanized and engineered antibody, MEDI7169, encodes only one murine residue at the variable heavy/light-chain interface, retains the sub-picomolar affinity for IL-21, specifically inhibits IL-21/IL-21R-mediated signaling events and is currently under clinical development as a potential therapeutic agent for autoimmune diseases. This study provides experimental evidence of the immune system's potential to recognize and respond to shared epitopes of antigens from distinct species, and presents a generally applicable, novel method for the rapid generation of exceptional therapeutic antibodies using the hybridoma platform.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211236PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347146PMC
October 2019

Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells.

Cell 2018 12 29;175(7):1731-1743.e13. Epub 2018 Nov 29.

Innate Pharma, 117 Avenue de Luminy, 13009 Marseille, France; Aix Marseille Université, INSERM, CNRS, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France; Service d'Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France. Electronic address:

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8 T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8 T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.
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http://dx.doi.org/10.1016/j.cell.2018.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292840PMC
December 2018

Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses.

Ann Rheum Dis 2019 02 20;78(2):228-237. Epub 2018 Nov 20.

Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA.

Objective: Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development.

Methods: VIB9600 was humanised and optimised from the IV.3 Ab. Binding affinity and specificity were determined by Biacore and ELISA. Confocal microscopy, Flow Cytometry-based assays and binding competition assays were used to assess the mode of action of the antibody. In vitro cell-based assays were used to demonstrate suppression of IC-mediated inflammatory responses. In vivo target suppression and efficacy was demonstrated in FcγRIIA-transgenic mice. Single-dose pharmacokinetic (PK)/pharmacodynamic study multiple dose Good Laboratory Practice (GLP) toxicity studies were conducted in non-human primates.

Results: We generated a humanised effector-deficient anti-FcγRIIA antibody (VIB9600) that potently blocks autoantibody and IC-mediated proinflammatory responses. VIB9600 suppresses FcγRIIA activation by blocking ligand engagement and by internalising FcγRIIA from the cell surface. VIB9600 inhibits IC-induced type I interferons from plasmacytoid dendritic cells (involved in SLE), antineutrophil cytoplasmic antibody (ANCA)-induced production of reactive oxygen species by neutrophils (involved in ANCA-associated vasculitis) and IC-induced tumour necrosis factor α and interleukin-6 production (involved in rheumatoid arthritis). In FcγRIIA transgenic mice, VIB9600 suppressed antiplatelet antibody-induced thrombocytopaenia, acute anti-GBM Ab-induced nephritis and anticollagen Ab-induced arthritis. VIB9600 also exhibited favourable PK and safety profiles in cynomolgus monkey studies.

Conclusions: VIB9600 is a specific humanised antibody antagonist of FcγRIIA with null effector function that warrants further clinical development for the treatment of IC-mediated diseases.
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http://dx.doi.org/10.1136/annrheumdis-2018-213523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352406PMC
February 2019

Improved Therapeutic Window in -mutant Tumors with Antibody-linked Pyrrolobenzodiazepine Dimers with and without PARP Inhibition.

Mol Cancer Ther 2019 01 23;18(1):89-99. Epub 2018 Oct 23.

Oncology Research, MedImmune, Gaithersburg, Maryland.

Pyrrolobenzodiazepine dimers (PBD) form cross-links within the minor groove of DNA causing double-strand breaks (DSB). DNA repair genes such as and play important roles in homologous recombination repair of DSB. We hypothesized that PBD-based antibody-drug conjugates (ADC) will have enhanced killing of cells in which homologous recombination processes are defective by inactivation of or genes. To support this hypothesis, we found 5T4-PBD, a PBD-dimer conjugated to anti-5T4 antibody, elicited more potent antitumor activity in tumor xenografts that carry defects in DNA repair due to mutations compared with wild-type xenografts. To delineate the role of mutations in determining sensitivity to PBD, we used siRNA knockdown and isogenic knockout models to demonstrate that deficiency markedly increased cell sensitivity to PBD-based ADCs. To understand the translational potential of treating patients with deficiency using PBD-based ADCs, we conducted a "mouse clinical trial" on 23 patient-derived xenograft (PDX) models bearing mutations in or Of these PDX models, 61% to 74% had tumor stasis or regression when treated with a single dose of 0.3 mg/kg or three fractionated doses of 0.1 mg/kg of a PBD-based ADC. Furthermore, a suboptimal dose of PBD-based ADC in combination with olaparib resulted in significantly improved antitumor effects, was not associated with myelotoxicity, and was well tolerated. In conclusion, PBD-based ADC alone or in combination with a PARP inhibitor may have improved therapeutic window in patients with cancer carrying mutations.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0314DOI Listing
January 2019

SLC46A3 as a Potential Predictive Biomarker for Antibody-Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads.

Clin Cancer Res 2018 12 21;24(24):6570-6582. Epub 2018 Aug 21.

Oncology Research, MedImmune, Gaithersburg, Maryland.

Purpose: Antibody-drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. Currently, there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance.

Experimental Design: The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, . The functional relevance of SLC46A3, a lysosomal transporter of noncleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EPHA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for . expression was also examined in patient-derived xenograft and models of acquired T-DM1 resistance and multiple myeloma bone marrow samples by RT-PCR.

Results: Loss of expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of , suggesting that expression of may be more predictive of activity than target antigen levels alone. Interrogation of primary multiple myeloma samples indicated a range of expression, including samples with undetectable levels like multiple myeloma cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs.

Conclusions: Our findings support as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1300DOI Listing
December 2018

Antitumor Activity of MEDI3726 (ADCT-401), a Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting PSMA, in Preclinical Models of Prostate Cancer.

Mol Cancer Ther 2018 10 31;17(10):2176-2186. Epub 2018 Jul 31.

Spirogen, London, United Kingdom.

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase that is highly expressed in nearly all prostate cancers with the highest expression in metastatic castration-resistant prostate cancer (mCRPC). The prevalence of increased surface expression and constitutive internalization of PSMA make it an attractive target for an antibody-drug conjugate (ADC) approach to treating patients with mCRPC. MEDI3726 (previously known as ADCT-401) is an ADC consisting of an engineered version of the anti-PSMA antibody J591 site specifically conjugated to the pyrrolobenzodiazepine (PBD) dimer tesirine. MEDI3726 specifically binds the extracellular domain of PSMA and, once internalized, releases the PBD dimer to crosslink DNA and trigger cell death. , MEDI3726 demonstrated potent and specific cytotoxicity in a panel of PSMA-positive prostate cancer cell lines, consistent with internalization and DNA interstrand crosslinking. , MEDI3726 showed robust antitumor activity against the LNCaP and the castration-resistant CWR22Rv1 prostate cancer cell line xenografts. MEDI3726 also demonstrated durable antitumor activity in the PSMA-positive human prostate cancer patient-derived xenograft (PDX) LuCaP models. This activity correlated with increased phosphorylated Histone H2AX in tumor xenografts treated with MEDI3726. MEDI3726 is being evaluated in a phase I clinical trial as a treatment for patients with metastatic castrate-resistant prostate cancer (NCT02991911). .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0982DOI Listing
October 2018

Baseline Plasma Cell Gene Signature Predicts Improvement in Systemic Sclerosis Skin Scores Following Treatment With Inebilizumab (MEDI-551) and Correlates With Disease Activity in Systemic Lupus Erythematosus and Chronic Obstructive Pulmonary Disease.

Arthritis Rheumatol 2018 12 22;70(12):2087-2095. Epub 2018 Oct 22.

MedImmune, Gaithersburg, Maryland.

Objective: B cells impact the progression of systemic sclerosis (SSc; scleroderma) through multiple pathogenic mechanisms. CD19 inhibition in mice reduced skin thickness, collagen production, and autoantibody levels, consistent with CD19 expression on plasma cells (PCs), the source of antibody production. PC depletion could effectively reduce collagen deposition and inflammation in SSc; therefore, we investigated the effects of PC depletion on SSc disease activity.

Methods: A PC gene signature was evaluated in SSc skin biopsy samples in 2 phase I clinical trials. We assessed microarray data from tissue from public studies of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), dermatomyositis (DM), systemic lupus erythematosus (SLE), and atopic dermatitis, as well as blood from a phase IIb clinical trial in SLE.

Results: The PC signature was elevated in SSc skin specimens compared to healthy donor skin (P = 2.28 × 10 ) and correlated with the baseline modified Rodnan skin thickness score (MRSS) (r = 0.64, P = 0.0004). Patients with a high PC signature at baseline showed greater improvement in the MRSS (mean ± SD change 35 ± 16%; P = 6.30 × 10 ) following anti-CD19 treatment with inebilizumab (MEDI-551) than did patients with a low PC signature at baseline (mean ± SD change 8 ± 12%; P = 0.104). The PC signature was overexpressed in tissue from patients with SLE, DM, COPD, interstitial lung disease, and IPF relative to controls (all fold change >2; P < 0.001). The PC signature also differed significantly between SLE patients with mild-to-moderate disease and those with severe disease (SLE Disease Activity Index cutoff at 10) (fold change 1.44; P = 3.90 × 10 ) and correlated significantly with the degree of emphysema in COPD (r = 0.53, P = 7.55 × 10 ).

Conclusion: Our results support the notion that PCs have a role in the pathogenesis of SSc and other autoimmune or pulmonary indications. An elevated pretreatment PC signature was associated with increased benefit from MEDI-551 in SSc.
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http://dx.doi.org/10.1002/art.40656DOI Listing
December 2018

Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer.

Oncotarget 2018 May 1;9(33):22960-22975. Epub 2018 May 1.

Oncology Research, MedImmune, LLC, Gaithersburg, Maryland, United States of America.

Despite recent advances in treatment, breast cancer remains the second-most common cause of cancer death among American women. A greater understanding of the molecular characteristics of breast tumors could ultimately lead to improved tumor-targeted treatment options, particularly for subsets of breast cancer patients with unmet needs. Using an unbiased genomics approach to uncover membrane-localized tumor-associated antigens (TAAs), we have identified glial cell line derived neurotrophic factor (GDNF) family receptor α 1 (GFRA1) as a breast cancer TAA. Immunohistochemistry (IHC) revealed that GFRA1 displays a limited normal tissue expression profile coupled with overexpression in specific breast cancer subsets. The cell surface localization as determined by fluorescence-activated cell sorting (FACS) and the rapid internalization kinetics of GFRA1 makes it an ideal target for therapeutic exploitation as an antibody-drug conjugate (ADC). Here, we describe the development of a pyrrolobenzodiazepine (PBD)-armed, GFRA1-targeted ADC that demonstrates cytotoxicity in GFRA1-positive cell lines and patient-derived xenograft (PDX) models. The safety profile of the rat cross-reactive GFRA1-PBD was assessed in a rat toxicology study to find transient cellularity reductions in the bone marrow and peripheral blood, consistent with known off-target effects of PBD ADC's. These studies reveal no evidence of on-target toxicity and support further evaluation of GFRA1-PBD in GFRA1-positive tumors.
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http://dx.doi.org/10.18632/oncotarget.25160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955426PMC
May 2018

, and Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma.

Clin Cancer Res 2018 11 15;24(22):5710-5723. Epub 2018 May 15.

Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France.

By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained. We showed that distinct combinations of , and mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of mutations without co-occurring or alterations (-mut/--WT), independently of mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16-0.63, < 0.001) was observed in anti-PD-1-treated patients harboring -mut/--WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Our study reveals that different combinations of , and mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0163DOI Listing
November 2018

Characterisation of innate lymphoid cell populations at different sites in mice with defective T cell immunity.

Wellcome Open Res 2017 14;2:117. Epub 2017 Dec 14.

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

: Innate lymphoid cells (ILCs) have now been identified within most tissues of the body and current evidence indicates that this family of cells play a fundamental role in maintaining tissue homeostasis. However, few studies have compared the ILC populations between several tissues. : We sought to generate a comprehensive characterisation of the ILC populations in different tissues of C57BL/6 WT and genetically modified mice targeting costimulatory pathways, using transcription factor expression to define specific groups. : Consistent with studies individually describing the ILC composition in different tissues, our analysis revealed different ILC groups dominate the ILC population in different tissues. Additionally, we observed a population of  IL-7Rα Id2 cells lacking expression of lineage markers but also lacking expression of GATA-3, RORgt or T-bet. This population was most evident in ear skin where it outnumbered the defined ILC groups, however, further experiments demonstrated that detection of these cells was influenced by how the tissue was digested, raising concerns as to its real nature. Since both ILC2 and ILC3 express ICOS, we then investigated the requirement for ICOS:ICOSL interactions in the homeostasis of ILC populations at these sites. Surprisingly, no significant differences were detected in the number of ILC1, ILC2 or ILC3 between WT and ICOSL mice in any tissue, indicating that this pathway is not required for ILC homeostasis at these sites. These data were compared with CD80 CD86 mice given evidence of CD28 expression by some ILC and ILC crosstalk with activated T cells. Notably, the absence of CD28 ligands resulted in a significant increase in ILC2 and ILC3 numbers in the intestine. : Together, these data provide new insight into ILC composition in different tissues in both WT and genetically modified mice where key costimulatory pathways are genetically deleted, providing a useful resource for further research into ILC biology.
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http://dx.doi.org/10.12688/wellcomeopenres.13199.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854988PMC
December 2017

Impaired Tumor-Infiltrating T Cells in Patients with Chronic Obstructive Pulmonary Disease Impact Lung Cancer Response to PD-1 Blockade.

Am J Respir Crit Care Med 2018 10;198(7):928-940

1 Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown.

Objectives: To study the impact of COPD on the immune contexture of non-small cell lung cancer.

Methods: We performed in-depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patient survival (n = 435). Tumor-infiltrating T lymphocyte (TIL) exhaustion by flow cytometry (n = 50) was also investigated. The effectiveness of an anti-PD-1 (programmed cell death-1) treatment (nivolumab) was evaluated in 39 patients with advanced-stage non-small cell lung cancer. All data were analyzed according to patient COPD status.

Measurements And Main Results: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD patients. Interestingly, a negative prognostic value of PD-L1 (programmed cell death ligand 1) expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD patients. Finally, data obtained on 39 patients with advanced-stage non-small cell lung cancer treated by an anti-PD-1 antibody showed longer progression-free survival in COPD patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD patients.

Conclusions: COPD is associated with an increased sensitivity of CD8 tumor-infiltrating T lymphocytes to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.
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http://dx.doi.org/10.1164/rccm.201706-1110OCDOI Listing
October 2018

T follicular helper-like cells contribute to skin fibrosis.

Sci Transl Med 2018 03;10(431)

Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.

Systemic sclerosis (SSc) is a debilitating inflammatory and fibrotic disease that affects the skin and internal organs. Although the pathophysiology of SSc remains poorly characterized, mononuclear cells, mainly macrophages and T cells, have been implicated in inflammation and fibrosis. Inducible costimulator (ICOS), which is expressed on a subset of memory T helper (T) and T follicular helper (T) cells, has been shown to be increased in SSc and associated with disease pathology. However, the identity of the relevant ICOS T cells and their contribution to inflammation and fibrosis in SSc are still unknown. We show that CD4 ICOS-expressing T cells with a T-like phenotype infiltrate the skin of patients with SSc and are correlated with dermal fibrosis and clinical disease status. ICOS T-like cells were found to be increased in the skin of graft-versus-host disease (GVHD)-SSc mice and contributed to dermal fibrosis via an interleukin-21- and matrix metalloproteinase 12-dependent mechanism. Administration of an anti-ICOS antibody to GVHD-SSc mice prevented the expansion of ICOS T-like cells and inhibited inflammation and dermal fibrosis. Interleukin-21 neutralization in GVHD-SSc mice blocked disease pathogenesis by reducing skin fibrosis. These results identify ICOS T-like profibrotic cells as key drivers of fibrosis in a GVHD-SSc model and suggest that inhibition of these cells could offer therapeutic benefit for SSc.
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http://dx.doi.org/10.1126/scitranslmed.aaf5307DOI Listing
March 2018

Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression.

J Clin Invest 2018 02 16;128(2):805-815. Epub 2018 Jan 16.

Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1- and PD-1-deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti-PD-1 alone or in combination with anti-CTLA-4. Thus, PD-L1-expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade.
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http://dx.doi.org/10.1172/JCI96113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785251PMC
February 2018

Molecular-based diagnosis of multiple sclerosis and its progressive stage.

Ann Neurol 2017 Nov;82(5):795-812

Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Objective: Biomarkers aid diagnosis, allow inexpensive screening of therapies, and guide selection of patient-specific therapeutic regimens in most internal medicine disciplines. In contrast, neurology lacks validated measurements of the physiological status, or dysfunction(s) of cells of the central nervous system (CNS). Accordingly, patients with chronic neurological diseases are often treated with a single disease-modifying therapy without understanding patient-specific drivers of disability. Therefore, using multiple sclerosis (MS) as an example of a complex polygenic neurological disease, we sought to determine whether cerebrospinal fluid (CSF) biomarkers are intraindividually stable, cell type-, disease- and/or process-specific, and responsive to therapeutic intervention.

Methods: We used statistical learning in a modeling cohort (n = 225) to develop diagnostic classifiers from DNA-aptamer-based measurements of 1,128 CSF proteins. An independent validation cohort (n = 85) assessed the reliability of derived classifiers. The biological interpretation resulted from in vitro modeling of primary or stem cell-derived human CNS cells and cell lines.

Results: The classifier that differentiates MS from CNS diseases that mimic MS clinically, pathophysiologically, and on imaging achieved a validated area under the receiver operating characteristic curve (AUROC) of 0.98, whereas the classifier that differentiates relapsing-remitting from progressive MS achieved a validated AUROC of 0.91. No classifiers could differentiate primary progressive from secondary progressive MS better than random guessing. Treatment-induced changes in biomarkers greatly exceeded intraindividual and technical variabilities of the assay.

Interpretation: CNS biological processes reflected by CSF biomarkers are robust, stable, disease specific, or even disease stage specific. This opens opportunities for broad utilization of CSF biomarkers in drug development and precision medicine for CNS disorders. Ann Neurol 2017;82:795-812.
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http://dx.doi.org/10.1002/ana.25083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743213PMC
November 2017

Targeting ADAM17 inhibits human colorectal adenocarcinoma progression and tumor-initiating cell frequency.

Oncotarget 2017 Sep 10;8(39):65090-65099. Epub 2017 May 10.

Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.

ADAM17 (a disintegrin and metalloproteinase 17)/TACE (TNFα converting enzyme) has emerged as a potential therapeutic target in colorectal cancer (CRC) and other cancers, due in part to its role in regulating various tumor cell surface proteins and growth factors and cytokines in the tumor microenvironment. The emergence of MEDI3622, a highly potent and specific antibody-based ADAM17 inhibitor, has allowed testing of the concept that targeting ADAM17 may be an important new therapeutic approach for CRC patients. We demonstrate that MEDI3622 is highly efficacious on tumor growth in multiple human CRC PDX models, resulting in improved survival of animals bearing tumor xenografts. MEDI3622 was further found to impact Notch pathway activity and tumor-initiating cells. The promising preclinical activity seen here supports further clinical investigation of this treatment approach to improve therapeutic outcome for patients diagnosed with metastatic CRC, including patients with KRAS-mutant tumors for whom other therapeutic options are currently limited.
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http://dx.doi.org/10.18632/oncotarget.17780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630314PMC
September 2017

IL-22 Increases Permeability of Intestinal Epithelial Tight Junctions by Enhancing Claudin-2 Expression.

J Immunol 2017 11 22;199(9):3316-3325. Epub 2017 Sep 22.

Department of Oncology Research, MedImmune, Gaithersburg, MD 20878; and

Dysfunction of the epithelial barrier is a hallmark of inflammatory intestinal diseases. The intestinal epithelial barrier is maintained by expression of tight junctions that connect adjacent epithelial cells and seal the paracellular space. IL-22 is critical for the maintenance of intestinal barrier function through promoting antipathogen responses and regeneration of epithelial tissues in the gut. However, little is known about the effects of IL-22 on the regulation of tight junctions in the intestinal epithelium. In this study we report that IL-22 signals exclusively through the basolateral side of polarized Caco-2 cell monolayers. IL-22 treatment does not affect the flux of uncharged macromolecules across cell monolayers but significantly reduces transepithelial electrical resistance (TEER), indicating an increase of paracellular permeability for ions. IL-22 treatment on Caco-2 monolayers and on primary human intestinal epithelium markedly induces the expression of Claudin-2, a cation-channel-forming tight junction protein. Furthermore, treatment of IL-22 in mice upregulates Claudin-2 protein in colonic epithelial cells. Knocking down Claudin-2 expression with small interfering RNA reverses the reduction of TEER in IL-22-treated cells. Moreover, IL-22-mediated upregulation of Claudin-2 and loss of TEER can be suppressed with the treatment of JAK inhibitors. In summary, our results reveal that IL-22 increases intestinal epithelial permeability by upregulating Claudin-2 expression through the JAK/STAT pathway. These results provide novel mechanistic insights into the role of IL-22 in the regulation and maintenance of the intestinal epithelial barrier.
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http://dx.doi.org/10.4049/jimmunol.1700152DOI Listing
November 2017

Effects of ICOS+ T cell depletion via afucosylated monoclonal antibody MEDI-570 on pregnant cynomolgus monkeys and the developing offspring.

Reprod Toxicol 2017 12 13;74:116-133. Epub 2017 Sep 13.

Toxicology, Research & Development, MedImmune Inc., One MedImmune Way, Gaithersburg, MD 20854, United States.

MEDI-570 is a fully human afucosylated monoclonal antibody (MAb) against Inducible T-cell costimulator (ICOS), highly expressed on CD4+ T follicular helper (T) cells. Effects of MEDI-570 were evaluated in an enhanced pre-postnatal development toxicity (ePPND) study in cynomolgus monkeys. Administration to pregnant monkeys did not cause any abortifacient effects. Changes in hematology and peripheral blood T lymphocyte subsets in maternal animals and infants and the attenuated infant IgG immune response to keyhole limpet hemocyanin (KLH) were attributed to MEDI-570 pharmacology. Adverse findings included aggressive fibromatosis in one dam and two infant losses in the high dose group with anatomic pathology findings suggestive of atypical lymphoid hyperplasia. The margin of safety relative to the no observed adverse effect level (NOAEL) for the highest planned clinical dose in the Phase 1a study was 7. This study suggests that women of child bearing potential employ effective methods of contraception while being treated with MEDI-570.
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http://dx.doi.org/10.1016/j.reprotox.2017.08.018DOI Listing
December 2017

Microglia-dependent synapse loss in type I interferon-mediated lupus.

Nature 2017 06 14;546(7659):539-543. Epub 2017 Jun 14.

Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
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http://dx.doi.org/10.1038/nature22821DOI Listing
June 2017

Oncolytic VSV Primes Differential Responses to Immuno-oncology Therapy.

Mol Ther 2017 08 2;25(8):1917-1932. Epub 2017 Jun 2.

MedImmune, LLC, One Medimmune Way, Gaithersburg, MD 20878, USA. Electronic address:

Vesicular stomatitis virus encoding the IFNβ transgene (VSV-IFNβ) is a mediator of potent oncolytic activity and is undergoing clinical evaluation for the treatment of solid tumors. Emerging preclinical and clinical data suggest treatment of tumors with oncolytic viruses may sensitize tumors to checkpoint inhibitors and increase the anti-tumor immune response. New generations of immuno-oncology molecules including T cell agonists are entering clinical development and could be hypothesized to enhance the activity of oncolytic viruses, including VSV-IFNβ. Here, we show that VSV-IFNβ exhibits multiple mechanisms of action, including direct cell killing, stimulation of an innate immune response, recruitment of CD8 T cells, and depletion of T regulatory cells. Moreover, VSV-IFNβ promotes the establishment of a CD8 T cell response to endogenous tumor antigens. Our data demonstrate a significant enhancement of anti-tumor function for VSV-IFNβ when combined with checkpoint inhibitors, but not OX40 agonists. While the addition of checkpoint inhibitors to VSV-IFNβ generated robust tumor growth inhibition, it resulted in no increase in viral replication, transgene expression, or immunophenotypic changes beyond treatment with VSV-IFNβ alone. We hypothesize that tumor-specific T cells generated by VSV-IFNβ retain activity due to a lack of immune exhaustion when checkpoint inhibitors were used.
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http://dx.doi.org/10.1016/j.ymthe.2017.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542805PMC
August 2017