The major therapeutic goal for immune thrombocytopenia (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. 80% of patients possess anti-integrin αIIbβ3 (GPIIbIIIa) IgG autoantibodies causing platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in ~50% of patients to recover a normal platelet count after anti-CD20 Rituximab-mediated B cell depletion and splenectomy suggest that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SC) reside in other anatomical compartments. We analyzed >3,300 single IgG-SC from spleen, bone marrow and/or blood of 27 patients with ITP revealing high inter-individual variability in affinity for GPIIbIIIa with variations over 3 logs. IgG-SC dissemination and range of affinities were however similar per patient. Longitudinal analysis of autoreactive IgG-SC upon treatment with anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti-GPIIbIIIa IgG-SC in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.
Pablo Canales-Herrerias, Etienne Crickx, Matteo Broketa, Aurélien Sokal, Guilhem Chenon, Imane Azzaoui, Alexis Vandenberghe, Angga Perima, Bruno Iannascoli, Odile Richard-Le Goff, Carlos Castrillon, Guillaume Mottet, Delphine Sterlin, Ailsa Robbins, Marc Michel, Patrick England, Gael A. Millot, Klaus Eyer, Jean Baudry, Matthieu Mahevas, Pierre Bruhns
Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and available therapies, including immunotherapies, are ineffective for many patients. HCC is characterized by intratumoral hypoxia, and increased expression of hypoxia-inducible factor 1α (HIF-1α) in diagnostic biopsies is associated with patient mortality. Here we report the development of 32-134D, a low-molecular-weight compound that effectively inhibits gene expression mediated by HIF-1 and HIF-2 in HCC cells, and blocks human and mouse HCC tumor growth. In immunocompetent mice bearing Hepa1-6 HCC tumors, addition of 32-134D to anti-PD1 therapy increased the rate of tumor eradication from 25% to 67%. Treated mice showed no changes in appearance, behavior, body weight, hemoglobin, or hematocrit. Compound 32-134D altered the expression of a large battery of genes encoding proteins that mediate angiogenesis, glycolytic metabolism, and responses to innate and adaptive immunity. This altered gene expression led to significant changes in the tumor immune microenvironment, including a decreased percentage of tumor-associated macrophages and myeloid-derived suppressor cells, which mediate immune evasion, and an increased percentage of CD8+ T cells and natural killer cells, which mediate antitumor immunity. Taken together, these preclinical findings suggest that combining 32-134D with immune checkpoint blockade may represent a breakthrough therapy for HCC.
Shaima Salman, David J. Meyers, Elizabeth E. Wicks, Sophia N. Lee, Emmanuel Datan, Aline M. Thomas, Nicole M. Anders, Yousang Hwang, Yajing Lyu, Yongkang Yang, Walter Jackson III, Dominic Dordai, Michelle A. Rudek, Gregg L. Semenza
BACKGROUND. Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy (CPT), remains to be fully elucidated. METHODS. Here, we conducted a proof-of-principle study of CPT based on a phase I trial in thirty hospitalized COVID-19 patients with a median interval between the onset of symptoms and the first transfusion of 9 days (IQR, 7-11.8 days). A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends. RESULTS. In the context of this trial CPT was safe as evidenced by the absence of transfusion related adverse events and a low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (p= 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio (HR)= 3.0 [95% confidence interval (CI) 1.1;8.1], p= 0.026). The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their pre-transfusion endogenous neutralization status recipients benefitted from plasma therapy with high neutralizing antibodies (HR= 3.5 [95% CI 1.1;11], p= 0.034). CONCLUSION. In summary, our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response and more broadly point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT04869072 FUNDING. This study was funded via an “Innovation-Pool” project by the University Hospital Zurich, the “Swiss Red Cross “Glückskette” Corona Funding”, Pandemiefonds of the UZH Foundation and the Clinical Research Priority Program ‘Comprehensive Genomic Pathogen Detection’ of the University of Zurich.
Maddalena Marconato, Irene A. Abela, Anthony Hauser, Magdalena Schwarzmüller, Rheliana Katzensteiner, Dominique L. Braun, Selina Epp, Annette Audigé, Jacqueline Weber, Peter Rusert, Emèry Schindler, Chloé Pasin, Emily West, Jürg Böni, Verena Kufner, Michael Huber, Maryam Zaheri, Stefan Schmutz, Beat M. Frey, Roger D. Kouyos, Huldrych F. Günthard, Markus G. Manz, Alexandra Trkola
Anti-CTLA-4 + anti-PD-1/PD-L1 combination is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAE). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrated myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFNγ–dependent mechanism. Targeting the HIF-1α-PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes (TILs) and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated cancer immunotherapeutic effects of anti-CTLA-4 therapy with efficacy comparable to anti-CTLA-4+anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAE triggered by Ipilimumab, echinomycin protected mice against irAE by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1:PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment (TME) to achieve safer and more effective immunotherapy.
Christopher M. Bailey, Yan Liu, Mingyue Liu, Xuexiang Du, Martin Devenport, Pan Zheng, Yang Liu, Yin Wang
Extracellular proteolysis is frequently dysregulated in disease and can generate proteoforms with unique neoepitopes not found in healthy tissue. Here, we demonstrate that Abs that selectively recognize a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) could enable more effective and safer treatments for solid tumors. CDCP1 is highly overexpressed in RAS-driven cancers, and its ectodomain is cleaved by extracellular proteases. Biochemical, biophysical, and structural characterization revealed that the 2 cleaved fragments of CDCP1 remain tightly associated with minimal proteolysis-induced conformational change. Using differential phage display, we generated recombinant Abs that are exquisitely selective to cleaved CDCP1 with no detectable binding to the uncleaved form. These Abs potently targeted cleaved CDCP1-expressing cancer cells as an Ab-drug conjugate, an Ab-radionuclide conjugate, and a bispecific T cell engager. In a syngeneic pancreatic tumor model, these cleaved-specific Abs showed tumor-specific localization and antitumor activity with superior safety profiles compared with a pan-CDCP1 approach. Targeting proteolytic neoepitopes could provide an orthogonal “AND” gate for improving the therapeutic index.
Shion A. Lim, Jie Zhou, Alexander J. Martinko, Yung-Hua Wang, Ekaterina V. Filippova, Veronica Steri, Donghui Wang, Soumya G. Remesh, Jia Liu, Byron Hann, Anthony A. Kossiakoff, Michael J. Evans, Kevin K. Leung, James A. Wells
Nigel S. Paneth, Michael J. Joyner, Arturo Casadevall
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.
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
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.
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
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.
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
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.
Se Jin Oh, Hyo-Jung Lee, Kwon-Ho Song, Suyeon Kim, Eunho Cho, Jaeyoon Lee, Marcus W. Bosenberg, Tae Woo Kim
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