Analyses of 123 Peripheral Human Immune Cell Subsets: Defining Differences with Age and between Healthy Donors and Cancer Patients not Detected in Analysis of Standard Immune Cell Types

Recent advances in human immunology have led to the identification of novel immune cell subsets and the biological function of many of these subsets has now been identified. The recent US Food and Drug Administration approval of several immunotherapeutics for the treatment of a variety of cancer types and the results of ongoing immunotherapy clinical studies requires a more thorough interrogation of the immune system. We report here the use of flow cytometry-based analyses to identify 123 immune cell subsets of peripheral blood mononuclear cells. The use of these panels defines multiple differences in younger (< 40 years) vs. older (≥ 40 years) individuals and between aged-matched apparently healthy individuals and metastatic cancer patients, aspects not seen in the analysis of the following standard immune cell types: CD8, CD4, natural killer, natural killer-T, regulatory T, myeloid derived suppressor cells, conventional dendritic cells (DCs), plasmacytoid DCs and B cells. The use of these panels identifying 123 immune cell subsets may aid in the identification of patients who may benefit from immunotherapy, either prior to therapy or early in the immunotherapeutic regimen, for the treatment of cancer or other chronic or infectious diseases

The Grizzly, February 6, 1981

Computer Relocation Offers New Services • Breakage and Theft: Wismer Releases Alarming Loss Assessment • Borough Announces Water Alert • Weather Brings Maintenance Headaches • Departmental Focus: Chemistry • News Briefs: Speech exemption examination; Fraternity sponsors foster child; Resident assistant applications • USGA Notes • Union Announces Photo Contest • JDB in Transition • NY Trip A Must • UC Lorelei Tradition • Transplanted Texan • O\u27Neill\u27s First Union Appearance Success • Altered States Weakened • College Placement Office Expecting Busy Semester • NMD Waiting for Windows • Union Snack Shop Receives Needed Improvements • KDK Tops Sorority GPA List • Gymnastics Lookin\u27 Good • Women\u27s B-Ball Seen as Powerhouse • Basketball Still Holding First • W. Maryland Swamped by Swimmershttps://digitalcommons.ursinus.edu/grizzlynews/1051/thumbnail.jp

The Grizzly, September 25, 1981

Greaseband Tonight • Campus Welcome • Fridge Fee Unfrozen • Deutsch und Deutschland Heute: German Professor Co-authors Text • Public Speaking Exemption Exam • Books Sought by Ursinus Friends • Red Cross Bloodmobile at Helfferich Hall • Career Planning and Placement Office • Dessert Held in Union • Fast Food Service Losing Convenience • ProTheatre: Canterbury Tales Presented • Transplanted Texan: Nobody Expects the Moral Majority • School Bands Looking for Musicians • WRUC: Back on the Air? • First Coffeehouse Sparkles With Talent • Late Mail for Off-Campus Houses • [Reprinted Articles About the Greaseband] • Bear\u27s Booters Kick Off Season • Business as Usual for Cross-Country • Bears Drop 10-3 Decision to Western Maryland • Davis Leads Hockey Over Widenerhttps://digitalcommons.ursinus.edu/grizzlynews/1061/thumbnail.jp

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Il foro di Larinum e la nuova dedica per il senatore Gaio Vibio Postumo

The Authors summarize the preliminary results of the project carried on in Larinum (Campobasso, Molise), from the Dipartimento di Scienze dell’Antichità of Sapienza University of Rome under the direction of Enzo Lippolis. The site of Larinum offers various types of evidences, both historical and archaeological, from the archaic to the late Roman period. Larinum can be considered as a case study for better understanding the main phases of the broader urbanization and romanization processes in the middle-late Republican age. During the latest excavation campaigns a new inscription was also found out in the forum area: a new dedication to the senator C. Vibius Postumus, praetor and patron of the municipium, by the urban pleb

Larinum: lo sviluppo dell'area forense e della città

Esame dello sviluppo urbanistico e architettonico di Larino e del suo spazio forense in particolare

Larinum: the development of the forum area

Presentazione dei risultati delle campagne di scavo condotte a Larino dalla misssione archeologica dell'Università 'Sapienza' di Roma. Il lavoro si sofferma sulla ricostruzione culturale dell'insediamento, analizzato attraverso la comprensione dell'impianto urbano e delle sue trasformazioni nel tempo. La ricerca sul terreno concerne in particolare l'area del foro, di cui viene ricostruita per la prima volta la planimetria complessiva e il processo di monumentalizzazione. Di particolare interesse appare il riconoscimento dei forti cambiamenti strutturali, di orientamento e di impianto viario, che segnano in maniera determinante lo sviluppo urbanistico del centro, soprattutto nella fase tardo-repubblicana. Si traccia quindi un profilo della comunità di Larino dagli inizi del processo di costituzione dell'abitato (dalle prime testimonianze dell'età del ferro) sino alle fasi di destrutturazione intervenute verso il VI-VII sec. d.C., quando gran parte dell'area urbanizzata subisce un processo di contrazione e di progressivo abbandono

Anti-PD-L1/TGFI3R2 (M7824) fusion protein induces immunogenic modulation of human urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis

Background: Avelumab has recently been approved by the Food and Drug Administration for the therapy of Merkel cell carcinoma and urothelial carcinoma. M7824 is a novel first-in-class bifunctional fusion protein comprising a monoclonal antibody against programmed death-ligand 1 (PD-L1, avelumab), fused to the extracellular domain of human transforming growth factor beta (TGF beta receptor 2, which functions as a TGF beta "trap." Advanced urothelial tumors have been shown to express TGFO, which possesses immunosuppressive properties that promote cancer progression and metastasis. The rationale for a combined molecule is to block the PD-1/PD-L1 interaction between tumor cells and immune cell infiltrate and simultaneously reduce or eliminate TGF beta from the tumor microenvironment. In this study, we explored the effect of M7824 on invasive urothelial carcinoma cell lines. Methods: Human urothelial (transitional cell) carcinoma cell lines HTB-4, HTB-1, and HTB-5 were treated with M7824, M7824mut (M7824 that is mutated in the anti-PD-Ll portion of the molecule and thus does not bind PD-L1), anti-PD-Ll (avelumab), or IgG1 isotype control monoclonal antibody, and were assessed for gene expression, cell-surface phenotype, and sensitivity to lysis by TRAIL, antigen specific cytotoxic T lymphocytes and natural killer cells. Results: M7824 retains the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti-PD-Ll. However, compared to anti-PD-L1, M7824 increases (A) gene expression of molecules involved in T-cell trafficking in the tumor (e.g., CXCL11), (B) TRAIL-mediated tumor cell lysis, and (C) antigen-specific CD8(+) T-cell mediated lysis of tumor cells. Conclusions: These studies demonstrate the immunomodulatory properties of M7824 on both tumor cell phenotype and immune mediated lysis. Compared to anti-PD-Ll or M7824mut, M7824 induces immunogenic modulation of urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. These findings show the relevance of the dual blockade of PDLl and TGF beta in urothelial carcinoma cell lines and thus support the rationale for future clinical studies of M7824 in patients with urothelial cancer. Published by Elsevier Inc