Therapeutics
Abstract
Authors
Nigel S. Paneth, Michael J. Joyner, Arturo Casadevall
Abstract
Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T cells (Tconv, CD45RChigh), their precursors and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs, CD45RClow/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation but its potential has not been examined in autoimmune diseases. APECED is a rare genetic syndrome caused by loss-of-function mutations of the key central tolerance mediator, autoimmune regulator (AIRE) leading to abnormal auto-reactive T cell responses and autoantibodies production. Herein, we showed that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective both as prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChigh T cells, inhibited CD45RChigh B cells, and restored the Treg/Tconv ratio and the altered Tregs transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells and lesioned organs from APECED patients were infiltrated by CD45RChigh cells. Our observations highlight the potential role for CD45RChigh cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.
Authors
Marine Besnard, Céline Sérazin, Jason Ossart, Anne Moreau, Nadège Vimond, Léa Flippe, Hanna Sein, Grace A. Smith, Stefania Pittaluga, Elise M.N. Ferré, Claire Usal, Ignacio Anegon, Annamari Ranki, Michail S. Lionakis, Pärt Peterson, Carole Guillonneau
Abstract
BACKGROUND. Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies have shown that excessive TGF-β signaling is a driver of pathogenesis in OI. Here, we evaluated TGF-β signaling in children with OI and translated this discovery by conducting a phase 1 clinical trial of TGF-β inhibition in adults with OI. METHODS. Histology and RNASeq were performed on bones obtained from children affected (n=10) and unaffected (n=4) by OI. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify key dysregulated pathways. Reverse-phase protein array (RPPA), Western blot (WB), and Immunohistochemistry (IHC) were performed to evaluate changes at the protein level. A phase 1 study with a single administration of fresolimumab, a pan-anti-TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects of fresolimumab on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed. RESULTS. OI bone demonstrated woven structure, increased osteocyte density, high turnover, and reduced bone maturation. SMAD phosphorylation was the most significantly up-regulated GO molecular event. GSEA identified TGF-β pathway as top activated signaling pathway in OI. IPA showed that TGF-β was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increase in LS aBMD in participants with OI type IV, while those with more severe OI type III and VIII had unchanged or decreased LS aBMD. CONCLUSIONS. Our data confirm that TGF-β signaling is a driver pathogenic mechanism in OI bone and that anti-TGF-β therapy could be a potential disease-specific therapy with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION. NCT03064074 FUNDING. This work was supported by the Brittle Bone Disorders Consortium (BBDC) (U54AR068069). The BBDC is a part of the National Center for Advancing Translational Science’s (NCATS’) RDCRN. The BBDC is funded through a collaboration between the Office of Rare Disease Research (ORDR) of NCATS, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The BBDC was also supported by the OI Foundation. The work was supported by The Clinical Translational Core of BCM IDDRC (P50HD103555) from the Eunice Kennedy Shriver NICHD. Funding from the USDA/ARS under Cooperative Agreement No. 58-6250-6-001 also facilitated analysis for the study procedures. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The study was supported by a research agreement with Sanofi Genzyme.
Authors
I-Wen Song, Sandesh C.S. Nagamani, Dianne Nguyen, Ingo Grafe, Vernon Reid Sutton, Francis H. Gannon, Elda Munivez, Ming-Ming Jiang, Alyssa Tran, Maegen Wallace, Paul Esposito, Salma Musaad, Elizabeth Strudthoff, Sharon McGuire, Michele Thornton, Vinitha Shenava, Scott Rosenfeld, Roman Shypailo, Eric Orwoll, Brendan Lee
Abstract
New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine depleting agent ADI-PEG20 in a non-arginine auxotrophic cellular background (Arginine Succinate Synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response with extended disease-free survival in an orthotopic immune competent model of GBM with no significant toxicity. ADI-PEG20 not only enhances the cellular sensitivity of Arginine succinate synthetase 1 positive GBM to ionising radiation by elevated production of nitric oxide (NO) and hence generation of cytotoxic peroxynitrites, but also promotes glioma-associated macrophages/microglia infiltration into tumors and turns their classical anti-inflammatory (pro-tumor) phenotype into a pro-inflammatory (anti-tumor) phenotype. Our results provide an effective, well-tolerated and simple strategy to improve GBM treatment which merits consideration for early evaluation in clinical trials.
Authors
Nabil Hajji, Juan Garcia-Revilla, Manuel Sarmiento Soto, Richard Perryman, Jake J. Symington, Chad C. Quarles, Deborah R. Healey, Yijie Guo, Manuel Luis Orta-Vázquez, Santiago Mateos-Cordero, Khalid Shah, John Bomalaski, Giulio Anichini, Andreas G. Tzakos, Timothy Crook, Kevin O'Neill, Adrienne C. Scheck, Jose Luis Venero, Nelofer Syed
Abstract
Immune checkpoint blockade (ICB) therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to the emergence of immune-refractory tumors that disrupt the amplification of anti-tumor immunity. Therefore, identifying clinically available targets that restrict anti-tumor immunity is required to develop potential combination strategies. Here, using the transcriptome data of cancer patients treated with programmed cell death protein-1 (PD-1) therapy, and newly-established mouse preclinical anti-PD-1 therapy-refractory models, we identified NANOG as a novel factor restricting the amplification of anti-tumor immunity cycle, thereby contributing to the immune-refractory feature of the tumor microenvironment (TME). Mechanistically, NANOG induced insufficient T cell infiltration and resistance to CTL-mediated killing via the HDAC1-dependent regulation of CXCL10 and MCL1, respectively. Importantly, HDAC1 inhibition using an actionable agent sensitized NANOGhigh immune-refractory tumors to PD-1 blockade by reinvigorating the anti-tumor immunity cycle. Thus, our findings implicate the NANOG/HDAC1 axis as a central molecular target for controlling immune-refractory tumors and provide a rationale for combining HDAC inhibitors to reverse the refractoriness of tumors to ICB therapy.
Authors
Se Jin Oh, Hyo-Jung Lee, Kwon-Ho Song, Suyeon Kim, Eunho Cho, Jaeyoon Lee, Marcus W. Bosenberg, Tae Woo Kim
Abstract
BACKGROUND. Neoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TILs). Yet, how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined. METHODS. Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic mela-noma patients who received ACT. RESULTS. We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product. CONCLUSIONS. These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma, and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells. FUNDING. NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.
Authors
Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup
Abstract
The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine–regulated transfer RNA–derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.
Authors
Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng
Abstract
Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitors (SSRIs) antidepressants correlates with body weight gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased body weight by enhancing food intake in healthy mice at two different time points and through two distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through the Htr1a receptor. Upon longer treatment Flx blunted Htr2c expression/signaling, decreased the phosphorylation of Creb and Stat3 and dampened the production of POMC/α-MSH in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (MC4R) by co-treating mice with Flx and lipocalin-2, an anorexigenic hormone signaling through this receptor, normalized feeding and body weight. Flx and other SSRIs also inhibit CREB/STAT3 phosphorylation in a human neuronal cell line suggesting that these non-canonical effects could also occur in long-term users of SSRIs. By defining the molecular basis of the long-term SSRIs-associated weight gain this study proposes a therapeutic strategy to counter it.
Authors
Maria Jose Ortuno, Marc Schneeberger, Anoj Ilanges, François Marchildon, Kyle Pellegrino, Jeffrey M. Friedman, Patricia Ducy
Abstract
Human monoclonal antibodies were used here to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate them as a safe preventive and therapeutic substitute of hyperimmune sera for tetanus in mice. By screening memory B cells of immune donors, we selected two monoclonal antibodies specific for tetanus neurotoxin with exceptionally high neutralizing activities, which were extensively characterized both structurally and functionally. We found that these antibodies interfere with the binding and translocation of the neurotoxin into neurons by interacting with two epitopes, whose definition pinpoints crucial events in the cellular pathogenesis of tetanus. This information explains the unprecedented neutralization ability of these antibodies, which were found to be exceptionally potent in preventing experimental tetanus when injected in mice long before the neurotoxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential therapeutic use via intrathecal injection. As such, these human monoclonal antibodies, as well as their Fab derivatives, meet all requirements for being considered for prophylaxis and therapy of human tetanus and are ready for clinical trials.
Authors
Marco Pirazzini, Alessandro Grinzato, Davide Corti, Sonia Barbieri, Oneda Leka, Francesca Vallese, Marika Tonellato, Chiara Silacci-Fregni, Luca Piccoli, Eaazhisai Kandiah, Giampietro Schiavo, Giuseppe Zanotti, Antonio Lanzavecchia, Cesare Montecucco
Abstract
NKTR-255 is a novel polyethylene glycol (PEG)-conjugate of recombinant human IL-15 (rhIL-15) being examined as a potential cancer immunotherapeutic. Since IL-15 responses can be mediated by trans- or cis-presentation via IL-15Rα or soluble IL-15/IL-15Rα complexes, we investigated the role of IL-15Rα in driving NKTR-255 responses using defined naïve and memory ovalbumin-specific CD8 T cells (OT-I) CD8 T and NK cells in mice. NKTR-255 induced a 2.5 and 2.0-fold expansion of CD8 T and NK cells, respectively in WT mice. In adoptive transfer studies, proliferation of naïve and memory Wt OT-I T cells in response to NKTR-255 was not impaired in IL-15Rα−/− mice, suggesting trans-presentation was not utilized by NKTR-255. Interestingly, naïve IL-15Rα−/− OT-I cells had deficient responses to NKTR-255 while memory IL-15Rα−/− OT-I cell responses were partially impaired, suggesting that naive CD8 T cells are more dependent on cis-presentation of NKTR-255 than memory CD8 T cells. In bone marrow chimeras studies, IL-15Rα−/− and WT NK cells present in WT recipients had similar responses to NKTR-255, suggesting that cis-presentation is not utilized by NK cells. NKTR-255 could form soluble complexes with IL-15Rα; binding to murine IL-15Rα generated superagonists that preferentially stimulated NK cells showing that conversion to IL-15Rβ agonist biases the response towards NK cells. These findings highlight the ability of NKTR-255 to utilize IL-15Rα for cis-presentation and act as an IL-15Rαβ agonist on CD8 T cells.
Authors
Tanya O. Robinson, Shweta M. Hegde, Allison J. Chang, Achintyan Gangadharan, Sarai Rivas, Loui Madakamutil, Jonathan Zalevsky, Takahiro Miyazaki, Kimberly S. Schluns
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ISSN: 0021-9738 (print), 1558-8238 (online)