597 In situ vaccination with oncolytic vesicular stomatitis virus improves anti-tumor immune response and outcome in bladder cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A632-A632
Author(s):  
Coby Rangsitratkul ◽  
Christine Lawson ◽  
Lee-Hwa Tai
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Cell Lines ◽  
Vesicular Stomatitis Virus ◽  
Cd8 T Cells ◽  
Solid Cancer ◽  
Bcg Therapy ◽  
Vesicular Stomatitis ◽  
Human Immune ◽  
Bladder Sparing

BackgroundThe majority of nonmuscle invasive bladder cancer (NMIBC) cases progress towards muscle invasive disease. Transurethral resection followed by chemotherapy and/or BCG immunotherapy can stall progression in the minority of NMIBC cases. Cystectomy prior to muscle invasion provides the best option for survival. However, bladder removal significantly affects morbidity and quality of life. There are no effective treatment options for patients with chemo/BCG-resistant and late stage disease. Compared to other solid cancer types, the urinary bladder is an ideal organ to evaluate oncolytic virotherapies due to the urgent medical need for alternative bladder-sparing therapies and its established immunosensitivity to BCG therapy. The current study will determine whether a novel oncolytic Vesicular Stomatitis Virus (VSVd51) containing human immune transgenes can treat NMIBC.MethodsA novel recombinant OV containing a human immune transgene was rescued on the VSVd51 backbone. Features of immunogenic cell death (ICD) on mouse and human bladder cancer cell lines were measured by microscopy, flow cytometry, immunoblot, luminometry, qRT-PCR and ELISA following infection by recombinant VSVd51. The mediating role of immune effector cells was evaluated through pharmacologic in vivo depletion, while combination injection of recombinant VSVd51 following BCG failure was performed in the C57Bl/6-MB49 model. Measurements of ICD was additionally carried out in human BC spheroids and bladder cancer patient tissue following recombinant VSVd51 infection ex vivo.ResultsRecombinant VSVd51 liberated danger signals (calreticulin, HMGB1, ATP) and immunogenic cytokines/chemokines were detected from infected mouse and human BC cell lines. Intravesical instillation of recombinant VSVd51 promoted enhanced activation of systemic and bladder infiltrating natural killer (NK) and cytotoxic CD8+ T cells. The increased functionality of NK and CD8+ T cells was associated with improved survival as determined through depletion studies. Moreover, improved survival and reduced bladder tumor volume was observed in recombinant VSVd51 treated mice who failed BCG therapy. In parallel, VSVd51-induced inflammation of the tumor microenvironment was recapitulated in human BC cell lines, spheroids and patient tissue exposed to recombinant VSVd51 infection.ConclusionsThese translational results suggest that a recombinant VSVd51 is a promising immunotherapy that could provide a bladder-sparing therapeutic benefit in individuals diagnosed with NMIBC each year.Ethics ApprovalThe study was approved by the CIUSSS de l’Estrie CHUS Ethics Board, approval number 2018-2465.

scholarly journals Characterization of the Interaction between the Matrix Protein of Vesicular Stomatitis Virus and the Immunoproteasome Subunit LMP2

2015 ◽  
Vol 89 (21) ◽  
pp. 11019-11029 ◽  
Author(s):  
Frauke Beilstein ◽  
Linda Obiang ◽  
Hélène Raux ◽  
Yves Gaudin
Keyword(s):  
T Cells ◽  
Immune System ◽  
Mhc Class I ◽  
Vesicular Stomatitis Virus ◽  
Cd8 T Cells ◽  
Matrix Protein ◽  
Catalytic Subunit ◽  
The Matrix ◽  
Infected Cells ◽  
Vesicular Stomatitis

ABSTRACTThe matrix protein (M) of vesicular stomatitis virus (VSV) is involved in virus assembly, budding, gene regulation, and cellular pathogenesis. Using a yeast two-hybrid system, the M globular domain was shown to interact with LMP2, a catalytic subunit of the immunoproteasome (which replaces the standard proteasome catalytic subunit PSMB6). The interaction was validated by coimmunoprecipitation of M and LMP2 in VSV-infected cells. The sites of interaction were characterized. A single mutation of M (I96A) which significantly impairs the interaction between M and LMP2 was identified. We also show that M preferentially binds to the inactive precursor of LMP2 (bearing an N-terminal propeptide which is cleaved upon LMP2 maturation). Furthermore, taking advantage of a sequence alignment between LMP2 and its proteasome homolog, PSMB6 (which does not bind to M), we identified a mutation (L45R) in the S1 pocket where the protein substrate binds prior to cleavage and a second one (D17A) of a conserved residue essential for the catalytic activity, resulting in a reduction of the level of binding to M. The combination of both mutations abolishes the interaction. Taken together, our data indicate that M binds to LMP2 before its incorporation into the immunoproteasome. As the immunoproteasome promotes the generation of major histocompatibility complex (MHC) class I-compatible peptides, a feature which favors the recognition and the elimination of infected cells by CD8 T cells, we suggest that M, by interfering with the immunoproteasome assembly, has evolved a mechanism that allows infected cells to escape detection and elimination by the immune system.IMPORTANCEThe immunoproteasome promotes the generation of MHC class I-compatible peptides, a feature which favors the recognition and the elimination of infected cells by CD8 T cells. Here, we report on the association of vesicular stomatitis virus (VSV) matrix protein (M) with LMP2, one of the immunoproteasome-specific catalytic subunits. M preferentially binds to the LMP2 inactive precursor. The M-binding site on LMP2 is facing inwards in the immunoproteasome and is therefore not accessible to M after its assembly. Hence, M binds to LMP2 before its incorporation into the immunoproteasome. We suggest that VSV M, by interfering with the immunoproteasome assembly, has evolved a mechanism that allows infected cells to escape detection and elimination by the immune system. Modulating this M-induced immunoproteasome impairment might be relevant in order to optimize VSV for oncolytic virotherapy.

scholarly journals Dendritic Cells, Infected with Vesicular Stomatitis Virus-Pseudotyped HIV-1, Present Viral Antigens to CD4+and CD8+T Cells from HIV-1-Infected Individuals

2000 ◽  
Vol 165 (11) ◽  
pp. 6620-6626 ◽  
Author(s):  
Angela Granelli-Piperno ◽  
Lei Zhong ◽  
Patrick Haslett ◽  
Jeffrey Jacobson ◽  
Ralph M. Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Vesicular Stomatitis Virus ◽  
Cd8 T Cells ◽  
Viral Antigens ◽  
Vesicular Stomatitis ◽  
Hiv 1

scholarly journals Persistent Antigen Presentation after Acute Vesicular Stomatitis Virus Infection

2006 ◽  
Vol 81 (4) ◽  
pp. 2039-2046 ◽  
Author(s):  
Damian L. Turner ◽  
Linda S. Cauley ◽  
Kamal M. Khanna ◽  
Leo Lefrançois
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Antigen Presentation ◽  
Vesicular Stomatitis Virus ◽  
Cd8 T Cells ◽  
Antigen Expression ◽  
T Cell Response ◽  
Antiviral Immune Response ◽  
Vesicular Stomatitis

ABSTRACT Long-term antigen expression is believed to play an important role in modulation of T-cell responses to chronic virus infections. However, recent studies suggest that immune responses may occur late after apparently acute infections. We have now analyzed the CD8 T-cell response to vesicular stomatitis virus (VSV), which is thought to cause to an infection characterized by rapid virus clearance by innate and adaptive immune system components. Unexpectedly, virus-encoded antigen was detectable more than 6 weeks after intranasal VSV infection in both draining and nondraining lymph nodes by adoptively transferred CD8 T cells. Infection with Listeria monocytogenes expressing the same antigen did not result in prolonged antigen presentation. Weeks after VSV infection, discrete T-cell clustering with dendritic cells within the lymph node was observed after transfer of antigen-specific CD8 T cells. Moreover, memory CD8 T cells as defined by phenotype and function were generated from naïve CD8 T cells entering the response late after infection. These findings suggested that protracted antigen presentation after an apparently acute virus infection may contribute to an ongoing antiviral immune response.

626: Initial Experience with Vesicular Stomatitis Virus as a Treatment for Bladder Cancer

2006 ◽  
Vol 175 (4S) ◽  
pp. 202-202
Author(s):  
Sherwin Zargaroff ◽  
Yuancheng Wang ◽  
Xiayong Zheng ◽  
Jian Pu ◽  
Savio L. Woo ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Vesicular Stomatitis Virus ◽  
Initial Experience ◽  
Vesicular Stomatitis

scholarly journals Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study

2021 ◽  
Vol 9 (3) ◽  
pp. e001941
Author(s):  
Niannian Ji ◽  
Neelam Mukherjee ◽  
Ryan M Reyes ◽  
Jonathan Gelfond ◽  
Martin Javors ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Γδ T Cells ◽  
Percentage Change ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Double Blind ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Muscle Invasive

BackgroundAlthough intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG’s antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.MethodsA randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.ResultsThirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1–2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: −26% (−51% to 24%) for placebo, 9.6% (−59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (−31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02).ConclusionsFour weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.

scholarly journals Mechanisms that allow vaccination against an oncolytic vesicular stomatitis virus-encoded transgene to enhance safety without abrogating oncolysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amanda W. K. AuYeung ◽  
Robert C. Mould ◽  
Ashley A. Stegelmeier ◽  
Jacob P. van Vloten ◽  
Khalil Karimi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vesicular Stomatitis Virus ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Response ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Cell Immunity ◽  
Vesicular Stomatitis

AbstractVaccination can prevent viral infections via virus-specific T cells, among other mechanisms. A goal of oncolytic virotherapy is replication of oncolytic viruses (OVs) in tumors, so pre-existing T cell immunity against an OV-encoded transgene would seem counterproductive. We developed a treatment for melanomas by pre-vaccinating against an oncolytic vesicular stomatitis virus (VSV)-encoded tumor antigen. Surprisingly, when the VSV-vectored booster vaccine was administered at the peak of the primary effector T cell response, oncolysis was not abrogated. We sought to determine how oncolysis was retained during a robust T cell response against the VSV-encoded transgene product. A murine melanoma model was used to identify two mechanisms that enable this phenomenon. First, tumor-infiltrating T cells had reduced cytopathic potential due to immunosuppression. Second, virus-induced lymphopenia acutely removed virus-specific T cells from tumors. These mechanisms provide a window of opportunity for replication of oncolytic VSV and rationale for a paradigm change in oncolytic virotherapy, whereby immune responses could be intentionally induced against a VSV-encoded melanoma-associated antigen to improve safety without abrogating oncolysis.

scholarly journals The chromatin accessibility signature of human immune aging stems from CD8+ T cells

2017 ◽  
Vol 214 (10) ◽  
pp. 3123-3144 ◽  
Author(s):  
Duygu Ucar ◽  
Eladio J. Márquez ◽  
Cheng-Han Chung ◽  
Radu Marches ◽  
Robert J. Rossi ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Chromatin Accessibility ◽  
T Cell Signaling ◽  
Memory Cd8 T Cells ◽  
Systems Immunology ◽  
Human Immune ◽  
Chromatin Opening ◽  
Il7r Gene

Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programs behind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptome in PBMCs and purified monocytes, B cells, and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging and identified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8+ T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study provides a unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associated immunodeficiency.

scholarly journals An Isolated TCR αβ Restricted by HLA-A*02:01/CT37 Peptide Redirecting CD8+T Cells To Kill and Secrete IFN-γ in Response to Lung Adenocarcinoma Cell Lines

2018 ◽  
Vol 200 (8) ◽  
pp. 2965-2977
Author(s):  
Pedro O. Flores-Villanueva ◽  
Malathesha Ganachari ◽  
Heinner Guio ◽  
Jaime A. Mejia ◽  
Julio Granados
Keyword(s):  
T Cells ◽  
Lung Adenocarcinoma ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Adenocarcinoma Cell ◽  
Ifn Γ
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