bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, tolerability, pharmacokinetics and pharmacodynamics of VTP-43742, a RORγt inhibitor, in normal healthy volunteers
Authors: McGeehan Gerard M , Palmer Sally A , Bryson Catherine C , Zhao Yi , Shi Meng , Lipinski Kerri K , Bukhtiyarov Yuri , Guo Joan , Claremon David A , Lala Deepak S , Gregg Richard E 
Published: January 2023

Abstract
VTP-43742 is an orally active RORγt inhibitor being developed for the treatment of autoimmune disorders, including psoriasis, through inhibition of IL-17A production and down regulation of the IL-23 receptor. Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of VTP-43742 were assessed in two, randomized, double-blind, placebo-controlled studies in which VTP-43742 was administered to normal healthy volunteers. The first study was a single ascending dose (SAD) study (N = 53) in which participants were randomized to a one-time administration of VTP-43742 (7 dose levels, 30–2000 mg) or placebo. The second study (NCT02555709) was a multiple ascending dose (MAD) study in which participants (N = 40) received VTP-43742 (5 dose levels, 100–1400 mg/d) or placebo once daily for 10 days. VTP-43742 was shown to be safe and generally well tolerated at all dose levels in both studies. No serious adverse events were reported, and all study subjects completed dosing. No clinically significant clinical chemistry, hematologic or ECG abnormalities were observed, and dose proportionality was demonstrated across all dose levels. In the SAD study, VTP-43742 had a terminal plasma half-life of ~30 hours. In an ex vivo whole blood assay (WBA) of IL-17A secretion, VTP-43742 suppressed RORγt dependent secretion of IL-17A in a dose-responsive manner; &gt;90% inhibition was observed at the higher doses which was mostly maintained over 24 hours. In the MAD study, those receiving VTP-43742 showed &gt;90% inhibition of RORγt dependent IL-17A secretion in the WBA for a full 24hrs in all but the lowest dose cohort. These data support the further development of VTP-43742 for the treatment of autoimmune disorders.
Disruption of tumor subline cooperation may be a new way to understand EMT, dormancy and metastasis
Authors: Cohen Stefan A. , Everson Paul , Kim Untae 
Published: January 2023

Abstract
Tumors are heterogeneous since they contain sublines. Immunodeficient mice can function as an in vivo cell sorter (USP#7989001) to separate SW480 parental tumor cells (PTC) into 2 distinct sublines. Subline 1 TC (S1TC) are lymphotropic, hybrid non-EMT TC and are sensitive to cytostatic NK cells (cNK). S2TC are hematotropic, EMT TC and are resistant to cNK. Mice have a mechanism to distinguish non-EMT from EMT TC. PTC injected SC into SCID mice form local tumors and colonize lymph nodes (LN) and lungs (LU). In contrast, S1TC colonize the LN but do not form local tumors or colonize the LU. cNK suppress local S1TC growth and induce dormancy. Ablation of cNK by anti-NK leads to local S1TC growth while suppressing LN invasion. Stoppage of cNK ablation leads to an intense local anti-tumor response of S1TC. S2TC form local tumors that grow faster than PTC but do not colonize the LU or LN. S1TC cooperate with S2TC to colonize the LU. Some biomarkers (ZAP70, CXCR4) are expressed only on PTC and S1TC while others (SRC, CD21) are only on PTC and S2TC. CD26 has been linked to decreased invasiveness of some TC. Only S2TC expressed CD26 and not PTC or S1TC. S1TC may have suppressive effects on S2TC surface proteins. CD26 on S2TC may result in reduced invasion by peptidase action on SDF1 (CXCR4 ligand). S1TC may inhibit CD26 expression on S2TC resulting in SDF1/CXCR4 signaling and LU invasion. Disruption of tumor subline cooperation may be a new way to control metastasis.
Processed Aloe vera gel inhibits colitis-related colon carcinogenesis by inhibiting both chronic inflammation and cell cycle progression in the colon
Authors: Im Sun-A , Kim Heesuk , Kim Jiwhan , Shin Eunju , Do Seon-Gil , Kim Kyungjae , Lee Chong-Kil 
Published: January 2023

Abstract
The processed Aloe vera gel (PAG) contains immunomodulatory polysaccharides, which consists of a mixture of polymer chains of b-(1,4)-linked acetylated galactomannan with different lengths. PAG was shown to inhibit azoxymethane(AOM)-initiated and dextran sodium sulfate(DSS)-promoted colon carcinogenesis model in mice. In the present study, we examined the molecular mechanisms for the inhibition of colitis-associated colon carcinogenesis by PAG. PAG administration significantly inhibited the production of pro-inflammatory cytokines and mediators in the colon. Western blot analysis using the colon extracts showed that PAG administration reduced the activation of NF-kB resulting in the inhibition of iNOS and COX-2 expression. PAG appeared to inhibit NF-kB activation through the PPARγ activation. PAG administration also inhibited the expression and phosphorylation of STAT3, which was known to connect inflammation and cancer. PAG administration also inhibited cell cycle progression-related transcription factors such as the proliferating cell nuclear antigen (PCNA), ERK, cyclin-dependent kinase (CDK) 4 and cyclin D1. In contrast, PAG administration increased the expression of CDX2, which was known to be a tumor suppressor in colorectal cancers. These findings show that PAG suppresses colitis-related colon carcinogenesis by inhibiting both chronic inflammation and cell cycle progression in the colon.
Modulation of the myeloid tumor microenvironment in chronic lymphocytic leukemia by targeting CSF-1R
Authors: Yazdanparast Haniyeh , Hanna Bola , Rößner Philipp , Haderk Franziska , Haegel Helene , Lichter Peter , Seiffert Martina 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL) is highly dependent on the tumor microenvironment, which comprises monocyte-derived nurse-like cells (NLCs) as key players that possess tumor-supportive properties and resemble tumor-associated macrophages. Our main goal is to understand and target the tumor supportive properties of myeloid cells in CLL.
CSF-1R is known to be important for proliferation, differentiation, and survival of myeloid cells. Targeting CSF-1R has revealed clinical relevance in solid tumors. However, its role in hematological malignancies has not been assessed so far. Therefore, we tested a unique novel monoclonal antibody, TG3003 (Transgene S.A.), against this receptor in cocultures of primary CLL cells and NLCs and observed a significant decrease in CLL cell survival as well as a change in the concentration of inflammatory factors such as CCL2 and IL-6 in the cell culture supernatant. Moreover, we found that these changes were connected to a decrease in NLC numbers. Therefore, we aimed at exploring the in vivo activity of TG3003 in a well-established mouse model of CLL, that is the adoptive transfer of malignant splenocytes from leukemic Eμ-TCL1 mice into syngeneic recipient animals. Targeting CSF-1R in these mice resulted in a significant decrease of splenic monocytes but not macrophages and dendritic cells, indicating that monocytes are the main target of the antibody. More detailed investigations of monocyte subsets revealed that the previously described CLL-associated enrichment of patrolling monocytes was significantly but incompletely reversed. As TG3003 treatment had no effect on tumor development in this model, our future work will focus on combination approaches including other immunomodulatory drugs.
Microencapulated rapamycin prevents carcinogen and inflammation driven colon cancer through immune mechanisms
Authors: chen wanjiao , Dao Vinh A , Cardenas Kim , Lao Shunhua , Padrón Álvaro , Hasty Edward P. , Sharp Zelton Dave , Hurez Vincent , Curiel Tyler J. 
Published: January 2023

Abstract
We tested microencapsulated rapamycin (eRapa, ~2.2 mg/kg rapamycin/mouse/day) in carcinogen (azoxymethane, AOM) + inflammatory agent (dextran sodium sulfate, DSS) colon cancer. WT BL6 mice fed eRapa before, and during AOM/DSS had significantly fewer colon tumors and tumor burden than control fed mice (empty microcapsules). eRapa prevented colon cancer in δ TCR KO mice lacking γδ T cells but not in IFN-γ KO mice. In carcinogen (DMBA) + inflammatory agent (TPA) skin cancer, IFN-γ and γδ T cells were both needed for eRapa cancer prevention, showing tumor-specific and common immune requirements for eRapa-mediated cancer prevention. In βδ TCR KO mice lacking all T cells, AOM/DSS induced no cancer or only few tumors, suggesting αβ T cells are required for colon neoplasia and cancer in the AOM/DSS model. Protection from acute colitis in this model usually predicts colon cancer protection. Strikingly, however, eRapa did not prevent acute clinical or histologic colitis induced by DSS, despite cancer protection, suggesting effects on chronic colitis, or induction of cancer-protective but not acute colitis-protective mechanisms. In acute colitis, eRapa significantly decreased spleen and colon weights and CD3+CD4+ T cells, and increased mesenteric lymph node γδ T cells (with decreased Vγ1.1+ and increased Vγ2+ subsets) consistent with altered inflammation and reduced CD4-CXCR3+ and CD4-α4β7 T cells (likely γδ T cells) consistent with altered trafficking but did not affect CCR9+ T cells. In chronic colitis, eRapa significantly increased γδ T cells (with no changes in Vγ1.1+ or Vγ2+ subsets) that could mediate cancer protection. These novel immune effects of rapamycin help define its cancer prevention mechanisms and define novel clinical uses.
Conditioned media from the renal cell carcinoma cell line 786.O drives human blood monocytes to a monocytic myeloid-derived suppressor cell phenotype
Authors: Okada Shannon , Simmons Randi , Franke-Welch Secil , Gilbertson Deb 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that can be found in high numbers in the tumor microenvironment and are critical in mediating immune suppression in cancer patients. To develop an in vitro assay system that functionally mimics the tumor microenvironment, we cultured human blood monocytes with conditioned media from several cancer cell lines. Conditioned media from 4 out of 8 tumor cell lines tested induced survival and differentiation of monocytes into cells with characteristics similar to macrophages and MDSCs. Media from one cell line in particular, 786.O (a renal cell carcinoma line), induced the monocytes to acquire a monocytic MDSC phenotype characterized by a decrease in cell surface expression of HLA-DR, an increase in nitric oxide (NO) production, and changes in morphology similar to an immature myeloid cell. Additionally, these in vitro generated MDSCs suppressed autologous CD3+ T cell proliferation. The tumor conditioned MDSCs were compared, functionally and phenotypically, to MDSCs derived using GM-CSF and IL-6 and to M1 and M2 differentiated and polarized macrophages. We further demonstrated that the in vitro MDSCs are phenotypically and functionally similar to patient-derived MDSCs. MDSCs differentiated in vitro from 786.O tumor conditioned media represent a platform to identify potential therapeutics that inhibit MDSC activities.
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is necessary for human melanoma MDSC differentiation and function
Authors: Grewal Jaspreet , Ricthie Jamaal , Al Rayyan Numan , Telang Sucheta , Yaddanapudi Kavitha , Chesney Jason 
Published: January 2023

Abstract
Myeloid derived suppressor cells (MDSCs) inhibit the expansion of tumor antigen-specific effector CD8+ T cells via arginase, transforming growth factor – β (TGF – β) and indoleamine 2,3-dioxygenase (IDO). Recently, MDSCs were found to over-express hypoxia inducible factor 1 alpha (HIF-1α) which is required for their differentiation. An essential transcriptional target of HIF-1α is 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) which synthesizes fructose 2,6-bisphosphate, an allosteric stimulator of glycolysis and of proliferation via stimulation of cyclin dependent kinase-1 (CDK1). We hypothesized that MDSCs might over-express PFKFB3 which in turn might be required for their function as T cell suppressors. We demonstrate that monocytic MDSCs (M-MDSCs) induced by co-culture with A375 melanoma cells express increased PFKFB3 and that exposure to the PFKFB3 inhibitor, PFK-158, blocks the suppressive function of these M-MDSCs on T cell activation. Furthermore, we analyzed three advanced cancer patients for circulating MDSCs before and after PFK-158 administration as part of a multi-center phase 1 clinical trial. And, we found that the MDSCs were markedly reduced in each patient. Taken together, these data indicate that selective inhibition of PFKFB3 may be a novel approach to target MDSCs and combinations of PFKFB3 inhibitors with immunotherapies may be a rational strategy to promote durable immune-mediated remissions in cancer patients.
CITN11-02 phase I trial of subcutaneous recombinant human IL-15 (rhIL-15) is associated with expansion of circulating CD56+ NK cells and CD8+ T cells
Authors: Morishima Chihiro , McNeel Douglas G , Patel Manish R , Kohrt Holbrook E.K. , Waldmann Thomas A , Thompson John A , Conlon Kevin C , Sondel Paul M , Wakelee Heather A , Apodaca Minjun C , Fling Steven P , Disis Mary L , Creekmore Steven P , Miller Jeffrey S 
Published: January 2023

Abstract

Background
IL-15 is a high priority for clinical development because of its homeostatic effects on both NK cells and CD8+ T cells, and minimal effect on regulatory T cells. The Cancer Immunotherapy Trials Network is conducting a phase I dose-escalation study of subcutaneous (SQ) rhIL-15 in advanced melanoma, renal cell, non-small cell lung and squamous cell head and neck carcinoma patients.

Methods
A cycle consists of 5 daily SQ injections of rhIL-15 (E.coli-derived, NCI) given Monday-Friday for two weeks, then 2 weeks observation. The absolute lymphocyte count is tested every injection day, and whole blood flow cytometric analyses are conducted on Days 1, 11 and 15 of each cycle.

Results
Three patients each were treated at the 0.25, 0.5, 1.0 and 3.0 mcg/kg dose levels and six patients at 2.0 mcg/kg/dose (N=18). Seventeen patients completed ≥1 cycle, with one dose limiting toxicity (DLT) at 3.0 mcg/kg and one serious adverse event at 2.0 mcg/kg. Flow cytometric data indicate a consistent increase in the frequency of CD56+CD3− NK cell frequencies peaking at Day 15 of Cycle 1 (Day 12=last dose), with lesser increases in subsequent cycles. The median fold-increase in circulating NK cells during Cycle 1 demonstrated dose responsiveness and peaked at 11.5-fold with 3.0 mcg/kg. By contrast, the maximum fold-increase in circulating CD8+ T cells was 2.6-fold.

Conclusion
SQ rhIL-15 has been well tolerated and the 3.0 mcg/kg dose cohort is being expanded. Higher doses of rhIL-15 were associated with profound increases in circulating NK cells with significant but smaller increases in CD8+ T cells. Outpatient use of SQ rhIL-15 is safe and will be combined with other cancer immunotherapies.
Study support: NIH 1U01 CA154967-01 (Clinical Trials.gov NCT01727076).
Immunogenicity and biodistribution of nanoparticles in vivo
Authors: Tsirikis Peter , Wilson Kirsty , Xiang Sue , Wei Wei , Ma Guanghui , Selomulya Cordelia , Plebanski Magdalena 
Published: January 2023

Abstract
Nanoparticles have been widely used in vaccine design as both adjuvants and antigen delivery vehicles. In a seminal study, 40–50 nm nanoparticles with conjugated antigen were shown to induce high antibody titers and IFN-γ production in mice but with no added inflammatory stimuli. Subsequent research has shown that similar levels of immunogenicity can be achieved via the co-injection of naked 40–50 nm nanoparticles adjuvants and larger 500 nm nanoparticles with conjugated antigen. Furthermore, recent works indicate that particle shape can also influence the immune response. As such, we investigate the influence of surface morphology using 40–50 nm smooth and rough surfaced nanoparticle adjuvants and report their differential immunogenicity via ELISA, ELISpot and flow cytometry. Further, we determine the biodistribution of fluorescent 40–50 nm nanoparticle adjuvants with smooth and rough surfaces and larger 500 nm nanoparticles. Nanoparticle size is shown to be a discriminating factor in lymph node drainage, using a Carestream FX PRO in vivo imaging system and fluorescence microscopy of lymph nodes sectioned ex vivo. To elucidate the safety profile of this vaccine construct, we also investigate the biodistribution of nanoparticles within the major organs. The outcomes from this study provide key design criteria in the development of novel nanoparticle immunotherapeutics for the treatment of disease.
Small molecule agonists of IRF3 activation function as influenza vaccine adjuvants by modulating the humoral and cellular anti-viral immune response
Authors: Probst Peter , Grigg John B , Hemann Emily A , Loo Yueh-Ming , Knoll Megan L , Ireton Renee , Gale Michael J , Iadonato Shawn P , Bedard Kristin M 
Published: January 2023

Abstract
We have identified a panel of small molecule immunomodulators that activate IRF3 and induce innate immune signaling to drive an antigen-specific protective immune response against viral infections. Our lead adjuvant candidate, KIN1148, binds to retinoic acid inducible gene-I (RIG-I) and induces RIG-I signaling to drive IRF3 activation. Studies using the H1N1 influenza virus challenge model demonstrate that immunization with monovalent influenza split vaccine (SV) and KIN1148 is dose sparing and protects mice against a lethal H1N1 A/California/04/2009 challenge. The SV-H1N1/KIN1148 adjuvant system induces functional antibodies neutralizing viral infectivity and inhibiting influenza hemagglutinin-mediated blood agglutination. SV-H1N1/KIN1148 prime/boost immunizations mediate a strong influenza-specific Th2 response and enhance the production of the immunoregulatory cytokine IL-10 by lung and draining lymph-node-derived T cells from challenged mice. In addition, prime immunization with SV-H1N1/KIN1148 alone provides protection against a 10xLD50 H1N1 challenge by reducing the viral load in the lungs of infected mice. Passive transfer experiments suggest that the protection after prime immunization is at least partially mediated by a cellular immune component. In summary, the KIN1148 split vaccine adjuvant system controls influenza virus infection by boosting the production of functional antibodies, reducing viral load, and inducing a Th2-type immune response. The induction of Th2 and immunoregulatory cytokines by KIN1148-adjuvanted SV might be beneficial to ameliorate the immunopathogenesis of an immune response to highly pathogenic avian influenza virus in infected individuals.
Intrapulmonary delivery of TLR agonists to treat metastatic cancer
Authors: Goguet Emilie , Tross Debra , Klinman Dennis M 
Published: January 2023

Abstract
The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that intra-tumoral delivery of this agonist combination was synergistic and led to the eradication of large primary tumors and the establishment of long-term protective immunity in murine tumor models. We explored the effect of delivering 3M-052 plus CpG ODN to the lungs of mice bearing breast-derived lung metastases. 66Cl4-Luc cells (a luciferase-expressing variant of the 4T1 murine mammary carcinoma) were orthotopically implanted in the fourth mammary fat pad of Balb/c mice. Progression of the primary tumor and lung metastases was monitored by bioluminescence. TLR agonist treatment by intratracheal instillation was initiated after mets were detected in the lungs. Results show that intra-pulmonary treatment with the combination of TLR7/8 and TLR9 agonists slowed the growth of the lung metastases compared to either agonist alone. This treatment decreased pulmonary tumor burden and significantly prolonged survival when compared to control (untreated) animals. In contrast, pulmonary therapy had no significant effect on the primary tumor. Results from ongoing studies examining the effect of higher/more frequent lung delivery combined with direct treatment of the primary tumor will be presented.
Enterobactin, a metallophore, mitigates the immune responses of macrophages
Authors: Yeoh Beng San , Saha Piu , Xiao Xia , Singh Vishal , Vijay-Kumar Matam 
Published: January 2023

Abstract
Iron is required to facilitate the redox activity of heme proteins expressed in both immune and non-immune cells. In this study, we investigated whether the chelation of iron by enterobactin (Ent; a prototypical bacterial siderophore) can affect the immune and nitrosative responses of RAW 264.7 and bone marrow-derived macrophages. We observed that Ent dose-dependently inhibited the LPS-induced secretion of cytokines (i.e., serum amyloid A, IL-6, lipocalin 2) and nitrite in the macrophages. The LPS-induced expression of inducible nitric oxide synthase (iNOS; a heme protein) was also inhibited by Ent at both the mRNA and protein levels. To demonstrate the physiological relevance of these findings, we next investigated whether Ent could protect the intracellular pathogen Salmonella enterica serovars typhimurium in the gentamycin protection assay. Ent reduced the nitrite levels in Salmonella-infected macrophages, but upregulated the expression of iNOS (mRNA, protein) and Arginase-1 (mRNA). More importantly, Ent-treated macrophages were impaired in mediating the killing of Salmonella. Ent-sufficient Salmonella also survived better compared with their isogenic Ent-deficient strains, whereas the addition of exogenous Ent substantially improved the survival of both strains. The inhibitory effects of Ent, however, were abrogated when saturated with iron (1:1 ratio), thus indicating that Ent is required to be in its iron-free form to mediate efficient inhibition on the macrophages. Taken together, our findings advance the concept that Ent not only facilitate bacterial iron uptake, but also serve to safeguard bacteria against macrophage immune responses.
The role of LPC and lipid transporter MFSD2A in CD8 T cells
Authors: Piccirillo Ann , Hawse William F , Menk Ashley V , Wallace Callen T , Buechel Heather M , Watkins Simon C , Wendell Stacy G , Delgoffe Greg M , Silver David L , D’Cruz Louise M 
Published: January 2023

Abstract
Little is known about how effector CD8 T cells obtain exogenous long chain fatty acids (LCFAs) during T cell activation. LCFAs assist with membrane biogenesis and are required for rapid proliferation as well as effector molecule generation. One potential mechanism of fatty acid import is in the form of lysophophatidylcholine (LPC) by lipid carrier major facilitator superfamily domain containing 2a (MFSD2A). Here, we show that MFSD2A is highly expressed in activated CD8 T cells. Conditional loss of MFSD2A caused an altered effector response and resulted in defective memory cell formation. Taken together, these data show MFSD2A and LPC play a role in CD8 T cell metabolomics. Our future studies will use mass spectrometry lipidomics and gene expression analysis to identify the mechanisms by which CD8 T cells use LCFAs to mount a robust immune response to infection.