A Phase II Study of the Purine Nucleoside Phosphorylase (PNP) Inhibitor RO5092888 (BCX-4208) in Patients with Moderate to Severe Chronic Plaque Psoriasis: Safety, Tolerability and Lymphocyte Effects

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2583-2583
Author(s):  
Joseph P Gomes ◽  
Angela Georgy ◽  
Sharon Passe ◽  
Adrienne Farid ◽  
Shanta Bantia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plaque Psoriasis ◽  
Apoptotic Cell ◽  
Study Drug ◽  
T Cell Subsets ◽  
Upper Respiratory Tract ◽  
Chronic Plaque Psoriasis ◽  
Double Blind ◽  
Tract Infections

Abstract Introduction: PNP is a purine-metabolizing enzyme that catalyzes the phosphorolysis of 2′-deoxyguanosine [dGuo] to guanine and deoxyribose-1-phosphate. In T-cells, PNP inhibition leads to accumulation of deoxyguanosine triphosphate (dGTP), triggering apoptotic cell death. Chronic-plaque type psoriasis (psoriasis) is an autoimmune disorder, in which T-cells contribute, at least in part, to the manifestations and maintenance of the disease. Therefore, targeting T-cells may be a beneficial treatment strategy. Since for chronic inflammatory diseases the safety of potential immunosuppressive drugs is a major consideration, we conducted this study to investigate safety and tolerability of oral RO5092888 (BCX-4208) in patients with moderate to severe chronic plaque psoriasis. Methods: This was a randomized, double-blind, placebo-controlled, dose-ranging study. Sixty-six patients 18 to 70 years old were randomized into one of three groups: placebo, 20mg/d or 120mg/d. The study was conducted from August 2007 to June 2008. Patients received study drug over six weeks and were observed over an additional 4 weeks. Assessments for safety included tracking of adverse events (AEs) including infections; vital signs; ECGs; chemistry panel; LFTs; hematologic parameters including peripheral blood (PB) lymphocyte subsets CD3+, CD4+, CD8+, CD56+, CD20+; and urinalysis. Results: 65 of the 66 enrolled patients were analyzed. One serious AE was observed in the 20mg/d group, a deep vein thrombosis (DVT) in a patient with a history of DVTs, and was considered unrelated to study drug. The percentage of patients experiencing at least one adverse event (AE) of any grade was placebo: 33% (7/21), 20mg: 41% (9/22), and 120mg: 59% (13/22). During treatment, two infections occurred in the placebo group (influenza and sinusitis), one in the 20mg group (nasopharyngitis), and 4 in the 120mg group (2-upper respiratory tract infections, 1 bronchitis, and 1 otitis externa). Reductions in PB lymphocytes and subsets were observed (Table 1). Nine patients showed decreased levels of CD4+ lymphocytes, below 350 cells/μL (20mg/d, 3; 120mg/d, 6). Conclusion: Daily oral administration of 20 mg or 120 mg of RO5092888 for up to 6 weeks demonstrated adequate safety and tolerability. Reductions in PB T cells, T cell subsets and B cells were observed. Further investigation of RO5092888 is warranted in both T-cell and B-cell diseases. Lymphocyte subpopulation Mean Nadir (% change from baseline) Placebo (n=21) 20 mg (n=22) 120 mg (n=22) CD3+ 24.0 30.6 47.5 CD4+ 23.6 28.9 44.9 CD8+ 26.1 31.8 53.9 CD20+ 37.5 42.6 64.2 CD56+ 40.1 47.7 72.6 Table 1

696 Brentuximab vedotin, a CD30-directed antibody-drug conjugate, selectively depletes activated Tregs in vitro and in vivo

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A738-A738
Author(s):  
Bryan Grogan ◽  
Reice James ◽  
Michelle Ulrich ◽  
Shyra Gardai ◽  
Ryan Heiser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Efflux Pump ◽  
Apoptotic Cell ◽  
T Cell Subsets ◽  
Memory Cells ◽  
Antibody Drug Conjugate ◽  
Selective Depletion

BackgroundRegulatory T cells (Tregs) play an important role in maintaining immune homeostasis, preventing excessive inflammation in normal tissues. In cancer, Tregs hamper anti-tumor immunosurveillance and facilitate immune evasion. Selective targeting of intratumoral Tregs is a potentially promising treatment approach. Orthogonal evaluation of tumor-infiltrating lymphocytes (TILs) in solid tumors in mice and humans have identified CCR8, and several tumor necrosis family receptors (TNFRs), including TNFSFR8 (CD30), as receptors differentially upregulated on intratumoral Tregs compared to normal tissue Tregs and other intratumoral T cells, making these intriguing therapeutic targets.Brentuximab vedotin (BV) is approved for classical Hodgkin lymphoma (cHL) across multiple lines of therapy including frontline use in stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine. BV is also approved for certain CD30-expressing T-cell lymphomas. BV is comprised of a CD30-directed monoclonal antibody conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE).The activity of BV in lymphomas is thought to primarily result from tumor directed intracellular MMAE release, leading to mitotic arrest and apoptotic cell death.The role CD30 plays in normal immune function is unclear, with both costimulatory and proapoptotic roles described. CD30 is transiently upregulated following activation of memory T cells and expression has been linked to highly activated/suppressive IRF4+ effector Tregs.MethodsHere we evaluated the activity of BV on CD30-expressing T cell subsets in vitro and in vivo.ResultsTreatment of enriched T cell subsets with clinically relevant concentrations of BV drove selective depletion of CD30-expressing Tregs > CD30-expressingCD4+ T memory cells, with minimal effects on CD30-expressing CD8+ T memory cells. In a humanized xeno-GVHD model, treatment with BV selectively depleted Tregs resulting in accelerated wasting and robust T cell expansion. The observed differential activity on Tregs is likely attributable to significant increases in CD30 expression and reduced efflux pump activity relative to other T cell subsets. Interestingly, blockade of CD25 signaling prevents CD30 expression on T cell subsets without impacting proliferation, suggesting a link between CD25, the high affinity IL-2 receptor, and CD30 expression.ConclusionsTogether, these data suggest that BV may have an immunomodulatory effect through selective depletion of highly suppressive CD30-expressing Tregs.AcknowledgementsThe authors would like to thank Michael Harrison, PharmD for their assistance in abstract preparation.Ethics ApprovalAnimals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-024.

scholarly journals Rapid Generation of Multivirus-Specific T Lymphocytes for the Prevention and Treatment of Respiratory Viral Infections

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3332-3332
Author(s):  
Spyridoula Vasileiou ◽  
Annie Turney ◽  
Manik Kuvalekar ◽  
Shivani Mukhi ◽  
Ayumi Watanabe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Antigen ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Cell Transplant ◽  
Activation Markers ◽  
Hematopoietic Stem ◽  
Equity Ownership ◽  
Tract Infections

Abstract Acute upper and lower respiratory tract infections (RTIs) due to community-acquired respiratory viruses (CARVs) including respiratory syncytial virus (RSV), influenza, parainfluenza virus (PIV) and human metapneumovirus (hMPV) are a leading cause of morbidity and mortality worldwide, with individuals whose immune systems are naïve (e.g. children) or compromised being most vulnerable. In allogeneic hematopoietic stem cell transplant (HSCT) recipients, the incidence of CARV-related respiratory viral infection reaches 29%. Most patients initially present with mild symptoms of upper RTI and in 50% of cases the infection progresses to a lower RTI with severe symptoms including bronchiolitis and pneumonia and mortality rates as high as 50%. Currently there are no approved vaccines nor antiviral drugs for hMPV and PIV, while the preventative vaccine for Influenza is not indicated earlier than 6 months post-HSCT. Aerosolized ribavirin is FDA-approved for the treatment of RSV infections, but it is logistically difficult to administer and comes at a considerable cost. Thus, the lack of approved antiviral agents combined with the high cost of antiviral therapy emphasize the need for alternative treatment strategies for CARVs. Our group has previously demonstrated the safety and clinical efficacy of using adoptive T-cell transfer for the treatment of both latent [Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK virus (BKV), human herpesvirus 6 (HHV6)] and lytic [adenovirus (AdV)] viruses in recipients of allo-HSCT by generation of multivirus-specific T cell (VST) lines. Given that susceptibility to CARVs is highly associated with underlying immune deficiency, we wanted to explore the potential for extending this approach to Influenza, RSV, hMPV and PIV3 infections. In order to do so, we exposed PBMCs from healthy donors to a cocktail of pepmixes (overlapping peptide libraries) spanning immunogenic antigens derived from our target viruses [Influenza - NP1 and MP1; RSV - N and F; hMPV - F, N, M2-1 and M; PIV3 - M, HN, N and F] followed by expansion in the presence of activating cytokines in a G-Rex device. Over 10-13 days we achieved an average 8.5 fold expansion [increase from 0.25x107 PBMCs/cm2 to mean 1.9±0.2x107 cells/cm2; n=12). Cells were comprised almost exclusively of CD3+ T cells (96.2±0.6%; mean±SEM), with a mixture of cytotoxic (CD8+) and helper (CD4+) T cells and a phenotype consistent with immediate effector function and long term memory, as evidenced by upregulation of the activation markers CD25, CD69, and CD28 as well as expression of central (CD45RO+/CD62L+) and effector memory markers (CD45RO+/CD62L−), with minimal PD1 or Tim3 expression. Anti-viral specificity of multi-R-VSTs was tested in an IFNγ Elispot assay using each of the individual stimulating antigens as an immunogen and all 12 lines screened proved to be reactive against all 4 of the target viruses [Influenza: mean 735±75.6 SFC/2x105, RSV: 758±69.8, hMPV: 526±100.8, PIV3: 391±93.7]. As demonstrated by intracellular cytokine staining, the immune response was mediated by both CD4+ and CD8+ T cell subsets, and the majority of IFNγ-producing cells also produced TNFα. In addition, the cells secreted GM-CSF as measured by Luminex array, with baseline levels of Th2/suppressive cytokines. Furthermore, upon antigenic stimulation our VSTs produced the effector molecule Granzyme B suggesting the cytolytic potential of these expanded cells, which was confirmed in a standard Cr51-release assay against viral pepmix-loaded autologous PHA blasts. Viral antigen-loaded targets were specifically recognized and lysed by our VSTs, while there was no evidence of activity against non-infected autologous or allogeneic targets. In conclusion, we have shown that it is feasible to rapidly generate a single preparation of polyclonal multi-respiratory (multi-R)-VSTs with specificities directed to Influenza, RSV, hMPV and PIV3 and a total of 12 encoded antigens using GMP-compliant manufacturing methodologies. The expanded cells are Th1-polarized, polyfunctional and selectively able to react to and kill viral antigen-expressing targets with no auto- or alloreactivity, attesting to both their selectivity and their safety for clinical use in HSCT recipients. We anticipate such multi-R-VSTs will provide clinical benefit in preventing or treating CARV infections in the immunocompromised. Disclosures Vera: Viracyte: Equity Ownership. Tzannou:Viracyte: Consultancy, Equity Ownership. Leen:Viracyte: Equity Ownership.

scholarly journals Transcriptomic profiling of plaque psoriasis and cutaneous T cell subsets during treatment with secukinumab

2019 ◽  
Author(s):  
Jared Liu ◽  
Hsin-Wen Chang ◽  
Kristen M. Beck ◽  
Sahil Sekhon ◽  
Timothy H. Schmidt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plaque Psoriasis ◽  
Immune Cell ◽  
T Cell Subsets ◽  
Skin Tissue ◽  
Rapid Reduction ◽  
Effector Cells ◽  
Lesional Skin ◽  
T Effector Cells

AbstractThe IL17A inhibitor secukinumab is efficacious for the treatment of psoriasis. In order to define its mechanism of action, it is important to understand its impact on psoriatic whole skin tissue as well as specific skin-resident immune cell populations such as T lymphocytes. In this study, we treated 15 moderate-to-severe plaque psoriasis patients with secukinumab and characterized the longitudinal transcriptomic changes of whole lesional skin tissue and cutaneous CD4+ T effector cells (Teffs), CD4+ T regulatory cells (Tregs), and CD8+ T effector cells during 12 weeks of treatment. Secukinumab was clinically effective, with 100%, 47%, and 27% of patients in the study achieving PASI75, PASI90, and PASI100 by week 12, respectively. At baseline prior to treatment, we observed that IL17A overexpression predominates in psoriatic CD8+ T cells rather than Teffs, supporting the importance of IL-17-secreting CD8+ T cells (Tc17) compared to IL-17-secreting CD4+ T cells (Th17) cells in the pathogenesis of psoriasis. Although secukinumab targets only IL17A, we observed rapid reduction of IL17A, IL17F, IL23A, IL23R, and IFNG expression in lesional skin as soon as 2 weeks after initiation of treatment and normalization of expression by week 12. Secukinumab treatment resulted in resolution of 89-97% of psoriasis-associated expression differences in both bulk tissue and T cell subsets by week 12 of treatment. Overall, secukinumab appears to rapidly reverse many of the molecular hallmarks of psoriasis.

scholarly journals Traditional Thai Massage Promoted Immunity in the Elderly via Attenuation of Senescent CD4+ T Cell Subsets: A Randomized Crossover Study

2021 ◽  
Vol 18 (6) ◽  
pp. 3210
Author(s):  
Kanda Sornkayasit ◽  
Amonrat Jumnainsong ◽  
Wisitsak Phoksawat ◽  
Wichai Eungpinichpong ◽  
Chanvit Leelayuwat
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crossover Study ◽  
Intracellular Cytokine Staining ◽  
The Elderly ◽  
Complementary Therapy ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
T Subsets ◽  
Randomized Crossover Study

The beneficial physiological effects of traditional Thai massage (TTM) have been previously documented. However, its effect on immune status, particularly in the elderly, has not been explored. This study aimed to investigate the effects of multiple rounds of TTM on senescent CD4+ T cell subsets in the elderly. The study recruited 12 volunteers (61–75 years), with senescent CD4+ T cell subsets, who received six weekly 1-h TTM sessions or rest, using a randomized controlled crossover study with a 30-day washout period. Flow cytometry analysis of surface markers and intracellular cytokine staining was performed. TTM could attenuate the senescent CD4+ T cell subsets, especially in CD4+28null NKG2D+ T cells (n = 12; p < 0.001). The participants were allocated into two groups (low < 2.75% or high ≥ 2.75%) depending on the number of CD4+28null NKG2D+ T cells. After receiving TTM over 6 sessions, the cell population of the high group had significantly decreased (p < 0.001), but the low group had no significant changes. In conclusion, multiple rounds of TTM may promote immunity through the attenuation of aberrant CD4+ T subsets. TTM may be provided as a complementary therapy to improve the immune system in elderly populations.

scholarly journals 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A438-A438
Author(s):  
Mara Shainheit ◽  
Devin Champagne ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
Ece Bicak ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

scholarly journals The role of unconventional T cells in COVID-19

2021 ◽  
Author(s):  
Kristen Orumaa ◽  
Margaret R. Dunne
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Treatment Strategies ◽  
Γδ T Cells ◽  
Protective Role ◽  
T Cell Subsets ◽  
Viral Immunity ◽  
Mait Cells

AbstractCOVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.

scholarly journals Single-cell analysis reveals cell communication triggered by macrophages associated with the reduction and exhaustion of CD8+ T cells in COVID-19

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lei He ◽  
Quan Zhang ◽  
Yue Zhang ◽  
Yixian Fan ◽  
Fahu Yuan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cell Communication ◽  
Cell Types ◽  
Trial Registration ◽  
T Cell Subsets ◽  
Disease Group ◽  
Communication Analysis ◽  
Receptor Interactions

Abstract Background The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand–receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures. Methods A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand–receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1β, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured. Results Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand–receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis. Conclusions Our study showed that macrophages driving ligand–receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1β, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy. Trial registration: This is a retrospective observational study without a trial registration number.

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