scholarly journals Computational verification of large logical models – application to the prediction of T cell response to checkpoint inhibitors

2020 ◽  
Author(s):  
Céline Hernandez ◽  
Morgane Thomas-Chollier ◽  
Aurélien Naldi ◽  
Denis Thieffry
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
T Cell Response ◽  
Model Verification ◽  
Dynamical Analysis ◽  
Computational Systems Biology ◽  
Analysis Methods ◽  
The Impact

ABSTRACTAt the crossroad between biology and mathematical modelling, computational systems biology can contribute to a mechanistic understanding of high-level biological phenomenon. But as knowledge accumulates, the size and complexity of mathematical models increase, calling for the development of efficient dynamical analysis methods. Here, we propose the use of two approaches for the development and analysis of complex cellular network models.A first approach, called “model verification” and inspired by unitary testing in software development, enables the formalisation and automated verification of validation criteria for whole models or selected sub-parts. When combined with efficient analysis methods, this approach is suitable for continuous testing, thereby greatly facilitating model development.A second approach, called “value propagation”, enables efficient analytical computation of the impact of specific environmental or genetic conditions on the dynamical behaviour of some models.We apply these two approaches to the delineation and the analysis of a comprehensive model for T cell activation, taking into account CTLA4 and PD-1 checkpoint inhibitory pathways. While model verification greatly eases the delineation of logical rules complying with a set of dynamical specifications, propagation provides interesting insights into the different potential of CTLA4 and PD-1 immunotherapies.Both methods are implemented and made available in the all-inclusive CoLoMoTo Docker image, while the different steps of the model analysis are fully reported in two companion interactive jupyter notebooks, thereby ensuring the reproduction of our results.

scholarly journals 268 KVA 12.1 a novel fully human anti-VISTA antibody: clinical trial design in monotherapy and in combination with an anti-PD1 antibody

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A291-A291
Author(s):  
Thierry Guillaudeux ◽  
Shawn Iadonato ◽  
Eric Tarcha ◽  
Craig Philips
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Clinical Chemistry ◽  
T Cell Response ◽  
Fixed Dose ◽  
List Type ◽  
Cytokine Levels

BackgroundV-domain Ig Suppressor of T cell Activation (VISTA) is an immune-suppressive checkpoint inhibitor of T cell response. VISTA is expressed in the immuno-suppressive tumor microenvironment, mostly by cells of the myeloid lineage, and its blockade can restore an efficient antitumor immune response especially in hard-to-treat tumors.1 In addition, an increase in VISTA expression has been described after treatment by the current immune checkpoint inhibitors, anti-CTLA-4 or anti-PD1-(L),1 especially in patients refractory to these treatments.2 3 Therefore, VISTA may be involved in a compensatory resistance mechanism to checkpoint inhibitors.MethodsKineta has selected a lead candidate anti-VISTA monoclonal antibody, KVA12.1, after a deep screen of 107 fully human and highly diverse antibodies directed against the extracellular domain of VISTA.ResultsKVA12.1 exhibits high potency and binds to a unique epitope. It restores T cell activation and induces a pro-inflammatory response in in vitro assays. In vivo, in human VISTA knock-in mice, KVA12.1 treatment mediates strong single-agent antitumor activity in multiple syngeneic tumor models and shows enhanced efficacy in combination with either anti-PD-(L)1 or anti-CTLA-4 treatment. Finally, our anti-VISTA antibody was well-tolerated in exploratory toxicology studies in cynomolgus monkey, where hematology and clinical chemistry evaluations as well as clinical observations including monitoring of body weight revealed no indicators of toxicity. Safety endpoints, including the monitoring of cytokine levels related to cytokine release syndrome (CRS), clinical pathology and immunogenicity were evaluated. Cytokine levels associated with CRS (e.g., TNF-alpha, IL-6, IL-1β) were assessed, and none were elevated to levels associated with CRS. These studies provided drug exposures (AUC) well over the expected exposures required for clinical efficacy, and KVA12.1 exhibits a good half-life consistent with other monoclonal check-point inhibitors. We are currently engaged in pre-IND studies and manufacturing of KVA12.1.ConclusionsHere we are presenting the design of a phase 1/2 multicenter, open label, dose escalation and dose expansion study of intravenous infusion of KVA12.1 as a monotherapy and in combination with a fixed dose of an anti-PD1 antibody in patients with advanced refractory or metastatic solid tumors.ReferencesElTanbouly MA, Schaafsma E, Noelle RJ, Lines JL. VISTA: Coming of age as a multi-lineage immune checkpoint. Clin Exp Immunol 2020;200(2):120–130.Kuklinski LF, Yan S, Li Z, Fisher JL, Cheng C, Noelle RJ, Angeles CV, Turk MJ, Ernstoff MS. VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol Immunother 2018 July;67(7):1113–1121.Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM, Thompson JF, Wilmott JS, Long GV, Scolyer RA. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol 2017 December;30(12):1666–1676.

scholarly journals Role of Bladder Cancer Metabolic Reprogramming in the Effectiveness of Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 288
Author(s):  
Mathijs P. Scholtes ◽  
Florus C. de Jong ◽  
Tahlita C. M. Zuiverloon ◽  
Dan Theodorescu
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
T Cell Therapy ◽  
Literature Searches ◽  
The Impact

Metabolic reprogramming (MR) is an upregulation of biosynthetic and bioenergetic pathways to satisfy increased energy and metabolic building block demands of tumors. This includes glycolytic activity, which deprives the tumor microenvironment (TME) of nutrients while increasing extracellular lactic acid. This inhibits cytotoxic immune activity either via direct metabolic competition between cancer cells and cytotoxic host cells or by the production of immune-suppressive metabolites such as lactate or kynurenine. Since immunotherapy is a major treatment option in patients with metastatic urothelial carcinoma (UC), MR may have profound implications for the success of such therapy. Here, we review how MR impacts host immune response to UC and the impact on immunotherapy response (including checkpoint inhibitors, adaptive T cell therapy, T cell activation, antigen presentation, and changes in the tumor microenvironment). Articles were identified by literature searches on the keywords or references to “UC” and “MR”. We found several promising therapeutic approaches emerging from preclinical models that can circumvent suppressive MR effects on the immune system. A select summary of active clinical trials is provided with examples of possible options to enhance the effectiveness of immunotherapy. In conclusion, the literature suggests manipulating the MR is feasible and may improve immunotherapy effectiveness in UC.

scholarly journals DDIS-23. CMV-BASED PLASMID DNA VACCINE FOR GBM USING THE UNITE PLATFORM

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi68-vi68
Author(s):  
Amit Adhikari ◽  
Barb Toll ◽  
Yoshimi Johnson ◽  
Anthony Marketon ◽  
Greg Wilson ◽  
...  
Keyword(s):  
T Cell ◽  
Dna Vaccine ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
T Cell Response ◽  
Great Opportunity ◽  
Expression Platform

Abstract Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months, remaining unchanged in spite of technological advances in the standard of care. The presence of the partial CMV genome, specifically in GBM cells, provides a great opportunity for a targeted therapy. We have utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to build a polyvalent DNA vaccine which includes HCMV proteins, pp65, gB and IE-1. The UNITE platform is based, in part, on a lysosomal targeting technology which can result in increased antigen presentation, a balanced T cell response, and subsequent immunologic benefit. Using an orthotopic GBM mouse model expressing CMV proteins in the CT2A cell line, we have shown up to 45% survival when treated therapeutically with the pp65-IE-1 vaccine. In order to further improve the vaccine’s efficacy, and also to understand the mechanism of action, we are evaluating the post-vaccination tumor microenvironment and testing combination therapies with immune checkpoint inhibitors. Preliminary data on treated tumors suggest an increase in the PD-1 immune checkpoint regulator and a higher number of regulatory T cells. Our immune response evaluation of the polyvalent vaccine in naïve mice showed generation of robust antigen specific T cell activation. The use of multiple antigens in this vaccine makes it better suited to prevent antigen escape by tumor cells. Encouraged by our non-clinical data and the promising outcomes from our collaborators’ clinical trials using pp65 mRNA transfected autologous dendritic cells (ATTAC and ATTAC-II), we are moving forward with a phase I trial. We believe that the immune boost from our UNITE platform combined with deactivation of the immunosuppressive microenvironment by checkpoint inhibition holds a promising treatment against GBM.

scholarly journals Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 409
Author(s):  
Enrique Gómez Alcaide ◽  
Sinduya Krishnarajah ◽  
Fabian Junker
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Lessons Learned ◽  
Antigen Delivery ◽  
Tumor Vaccination ◽  
Translational Studies

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

scholarly journals Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

2009 ◽  
Vol 22 (4) ◽  
pp. 651-663 ◽  
Author(s):  
Patricia Price ◽  
David M. Murdoch ◽  
Upasna Agarwal ◽  
Sharon R. Lewin ◽  
Julian H. Elliott ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Granulomatous Inflammation ◽  
T Cell Response ◽  
Immune Restoration ◽  
Immunological Parameters ◽  
Varicella Zoster

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

scholarly journals The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy

AIDS ◽  
2013 ◽  
Vol 27 (13) ◽  
pp. 2101-2110 ◽  
Author(s):  
Judith J. Lok ◽  
Peter W. Hunt ◽  
Ann C. Collier ◽  
Constance A. Benson ◽  
Mallory D. Witt ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
The Impact

Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
Amit Adhikari ◽  
Juliete Macauley ◽  
Yoshimi Johnson ◽  
Mike Connolly ◽  
Tim Coleman ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Response

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.

scholarly journals Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes

2020 ◽  
Vol 8 (2) ◽  
pp. e001521
Author(s):  
Javier Arranz-Nicolás ◽  
Miguel Martin-Salgado ◽  
Cristina Rodríguez-Rodríguez ◽  
Rosa Liébana ◽  
Maria C Moreno-Ortiz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Tumor Rejection ◽  
Cytotoxic T Cell ◽  
Adenocarcinoma Cells ◽  
The Impact

BackgroundThe inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving hyporesponsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase ζ (DGKζ) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKζ deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKζ function in human T cells, and no known inhibitors target this isoform.MethodsWe used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells.ResultsWe demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGKζ-deficient mice.ConclusionsOur results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8+ T cell dysfunctional states.

scholarly journals DNAM1 and TIGIT balance the T cell response, with low T cell TIGIT expression corresponding to inflammation in psoriatic disease

2020 ◽  
Author(s):  
M E Jacobs ◽  
J N Pouw ◽  
M A Olde Nordkamp ◽  
T R D J Radstake ◽  
E F A Leijten ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Inverse Correlation ◽  
T Cell Response ◽  
Peripheral Blood Mononuclear ◽  
Psoriatic Disease

Abstract Background Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods By flow cytometry we analyzed peripheral blood mononuclear cells of patients with psoriasis (n=20) or psoriatic arthritis (n=21), and healthy individuals (n=7). We measured CD155, TIGIT and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and -negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results High CD155 expression associates with TNF production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells - but not CD4 T cells - express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.

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