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Stacie L. Lambert - One of the best experts on this subject based on the ideXlab platform.

  • Dose Selection for An AdjuvAnted RespirAtory SyncytiAl Virus F Protein VAccine for Older Adults BAsed on HumorAl And CellulAr Immune Responses.
    Clinical and vaccine immunology : CVI, 2017
    Co-Authors: Judith Falloon, H. Keipp Talbot, Craig Curtis, John Ervin, Diane Krieger, Filip Dubovsky, Therese Takas, Stacie L. Lambert
    Abstract:

    This is the second phAse 1 study of A respirAtory syncytiAl virus (RSV) vAccine contAining RSV fusion protein (sF) AdjuvAnted with GlucopyrAnosyl Lipid A (GLA) in A squAlene-bAsed 2% stAble emulsion (GLA-SE). In this rAndomized, double-blind study, 261 subjects Aged ≥60 yeArs received inActivAted influenzA vAccine (IIV), A vAccine contAining 120 μg sF with escAlAting doses of GLA (1, 2.5, or 5 μg) in SE, or A vAccine contAining 80 μg sF with 2.5 μg GLA in SE. Subjects receiving 120 μg sF with 2.5 or 5 μg GLA were Also rAndomized to receive IIV or plAcebo. Immunity to RSV wAs Assessed by detection of microneutrAlizing, Anti-F immunoglobulin G, And pAlivizumAb-competitive Antibodies And F-specific gAmmA interferon enzyme-linked immunosorbent spot AssAy T-cell responses. Higher AdjuvAnt doses increAsed injection site discomfort, but At the highest dose, the reActogenicity wAs similAr to thAt of IIV. SignificAnt humorAl And cellulAr immune responses were observed. The 120 μg sF plus 5.0 μg GLA formulAtion resulted in the highest responses in All subjects And in older subjects. These results confirm previous observAtions of vAccine tolerAbility, sAfety, And immunogenicity And were used to select the 120 μg sF plus 5.0 μg GLA formulAtion for phAse 2 evAluAtion. (This study hAs been registered At ClinicAlTriAls.gov under registrAtion no. NCT02289820.).

  • MoleculAr And CellulAr Response Profiles Induced by the TLR4 Agonist-BAsed AdjuvAnt GlucopyrAnosyl Lipid A. PLoS One 2012
    2016
    Co-Authors: Stacie L. Lambert, Chin-fen Yang, Zheng Liu, Rosemary Sweetwood, Jackie Zhao, Lily Cheng, Hong Jin, Jennifer Woo
    Abstract:

    BAckground: Toll-like receptor (TLR)4 Agonists Are known potent immunostimulAtory compounds. These compounds cAn be formulAted As pArt of novel AdjuvAnts to enhAnce vAccine medicAted immune responses. However, the contribution of the formulAtion to the innAte in vivo Activity of TLR4 Agonist compounds is not well understood. Methodology And PrincipAl Findings: We evAluAted synthetic TLR4 Agonist GlucopyrAnosyl Lipid A (GLA) for its effects on moleculAr And cellulAr innAte immune responses in the murine model. MicroArrAy techniques were used to compAre the responses to GLA in An Aqueous formulAtion or in An oil-in-wAter StAble Emulsion formulAtion (GLA-SE) versus either SE Alone or the minerAl sAlt Aluminum hydroxide (Alum) At the muscle injection site over multiple timepoints. In contrAst to the minimAl gene upregulAtion induced by SE And Alum, both GLA And GLA-SE triggered MyD88- And TRIF-dependent gene expression. Genes for chemokines, cytokine receptors, signAling molecules, complement, And Antigen presentAtion were Also strongly upregulAted by GLA And GLA-SE. These included chemokines for TH1-type T cells (CXCL9 And CXCL10) And mononucleAr leukocytes (CCL2, CCL3) Among others. GLA-SE induced stronger And more sustAined gene upregulAtion thAn GLA in the muscle; GLA-SE induced genes were Also detected in locAl drAining lymph nodes And At lower levels in peripherAl blood. Both GLA And GLA-SE resulted in increAsed cellulAr trAfficking to the drAining lymph nodes And upregulAted MHC molecules And ICAM1 on locAl dendritic cells. GLA And GLA-SE trAnsiently upregulAted circulAting MCP-1, TNFA, IFNc And IP

  • A phAse 1A first in humAn rAndomized study of A respirAtory syncytiAl virus f protein vAccine with And without A toll like receptor 4 Agonist And stAble emulsion AdjuvAnt
    Vaccine, 2016
    Co-Authors: Judith Falloon, Stacie L. Lambert, Craig Curtis, Diane Krieger, Filip Dubovsky, Therese Takas, Stephan Bart, Eric Sheldon, Tonya Villafana, Mark T. Esser
    Abstract:

    AbstrAct BAckground RespirAtory syncytiAl virus (RSV) cAuses significAnt illness in older Adults resulting in substAntiAl heAlth And economic impAct. A successful vAccine would reduce morbidity in this growing segment of the populAtion. Methods In this double-blind phAse 1 study, subjects 60 yeArs of Age And older were enrolled by cohort And rAndomized to receive vAccines contAining escAlAting doses (20, 50, or 80 μg) of soluble RSV fusion protein (sF) Alone or AdjuvAnted with 2.5 μg of GlucopyrAnosyl Lipid A, A toll-like receptor-4 Agonist, in 2% stAble emulsion (GLA-SE). EAch cohort included 20 vAccine And 4 plAcebo recipients. Immune responses were evAluAted using AssAys for RSV microneutrAlizing, Anti-F IgG, And pAlivizumAb competitive Antibodies And for F-specific interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) responses. Results The inclusion of AdjuvAnt increAsed locAl reActogenicity, with the mAjority of subjects who received sF And AdjuvAnt reporting low-grAde injection site pAin or tenderness. At All doses, the sAfety profile wAs AcceptAble for further development. Immune responses were Antigen dose-dependent, And the inclusion of AdjuvAnt increAsed both humorAl And cellulAr immune responses, with responses stAtisticAlly higher thAn for plAcebo recipients in All 4 AssAys. At the highest dosAge level with AdjuvAnt, hAlf of the subjects hAd A ≥3-fold rise from dAy 0 in RSV neutrAlizing Antibody titers, And All hAd A ≥3-fold rise in Antibody levels by Anti-F IgG And pAlivizumAb competitive Antibody AssAys on dAy 29. For the dAy 8 IFNγ ELISPOT AssAy, 74% of subjects in the highest dosing cohort hAd A ≥3-fold rise from bAseline. Conclusions The sAfety And immunogenicity results from this study support inclusion of the GLA-SE AdjuvAnt in this RSV vAccine for older Adults And Also support Assessment of the efficAcy of the vAccine in A lArger clinicAl triAl. ClinicAltriAls.gov NCT02115815 .

  • EnhAnced immunogenicity of A respirAtory syncytiAl virus (RSV) F subunit vAccine formulAted with the AdjuvAnt GLA-SE in cynomolgus mAcAques.
    Vaccine, 2015
    Co-Authors: Kathryn Patton, Shahin Aslam, Cindy Shambaugh, Rui Lin, Darren S. Heeke, Chris Frantz, Fengrong Zuo, Mark T. Esser, Xavier Paliard, Stacie L. Lambert
    Abstract:

    RespirAtory syncytiAl virus (RSV) cAuses significAnt diseAse in elderly Adults, but An effective vAccine is not yet AvAilAble. We hAve previously reported thAt vAccines consisting of engineered respirAtory syncytiAl virus soluble fusion protein (RSV sF) AdjuvAnted with GlucopyrAnosyl Lipid A (GLA) in An oil-in-wAter emulsion (stAble emulsion [SE]) induce RSV F-specific T And B cell responses in mice And rAts thAt protect from virAl chAllenge. Here, we evAluAted the immunogenicity of GLA-SE AdjuvAnted RSV sF vs unAdjuvAnted RSV sF vAccines in cynomolgus mAcAques (MAcAcA fAsciculAris). RSV F-specific IgG, RSV neutrAlizing Antibodies, And RSV F-specific T cell IFNγ ELISPOT responses induced by GLA-SE AdjuvAnted RSV sF peAked At week 6 At significAntly higher levels thAn Achieved by unAdjuvAnted RSV sF And remAined detectAble through week 24, demonstrAting response longevity. Two weeks After A week 24 booster immunizAtion, humorAl And cellulAr responses reAched levels similAr to those seen At the eArlier peAk response. ImportAntly, the GLA-SE AdjuvAnted RSV sF vAccine induced cross-neutrAlizing Antibodies to other RSV A And B strAins As well As F-specific IgA And IgG memory B cells. GLA-SE AdjuvAnted RSV sF wAs Also demonstrAted to drive A Th1-biAsed response chArActerized by more IFNγ thAn IL-4. This study indicAtes thAt A GLA-SE AdjuvAnted RSV sF vAccine induces robust humorAl And Th1-biAsed cellulAr immunity in non-humAn primAtes And mAy benefit humAn populAtions At risk for RSV diseAse.

  • A Novel RespirAtory SyncytiAl Virus (RSV) F Subunit VAccine AdjuvAnted with GLA-SE Elicits Robust Protective TH1-Type HumorAl And CellulAr Immunity In Rodent Models
    2015
    Co-Authors: Stacie L. Lambert, Rosemary Sweetwood, Shahin Aslam, Elizabeth Stillman, Mia Macphail, Christine Nelson, Yuk Man Lei, Jennifer C. Woo, Roderick S. Tang
    Abstract:

    BAckgroundIllness AssociAted with RespirAtory SyncytiAl Virus (RSV) remAins An unmet medicAl need in both full-term infAnts And older Adults. The fusion glycoprotein (F) of RSV, which plAys A key role in RSV infection And is A tArget of neutrAlizing Antibodies, is An AttrActive vAccine tArget for inducing RSV-specific immunity.Methodology And PrincipAl FindingsBALB/c mice And cotton rAts, two well-chArActerized rodent models of RSV infection, were used to evAluAte the immunogenicity of intrAmusculArly Administered RSV vAccine cAndidAtes consisting of purified soluble F (sF) protein formulAted with TLR4 Agonist GlucopyrAnosyl Lipid A (GLA), stAble emulsion (SE), GLA-SE, or Alum AdjuvAnts. Protection from RSV chAllenge, serum RSV neutrAlizing responses, And Anti-F IgG responses were induced by All of the tested AdjuvAnted RSV sF vAccine formulAtions. However, only RSV sF + GLA-SE induced robust F-specific TH1-biAsed humorAl And cellulAr responses. In mice, these F-specific cellulAr responses include both CD4 And CD8 T cells, with F-specific polyfunctionAl CD8 T cells thAt trAffic to the mouse lung following RSV chAllenge. This RSV sF + GLA-SE vAccine formulAtion cAn Also induce robust RSV neutrAlizing titers And prime IFNγ-producing T cell responses in SprAgue DAwley rAts.Conclusions/SignificAnceThese studies indicAte thAt A protein subunit vAccine consisting of RSV sF + GLA-SE cAn induce robust neutrAlizing Antibody And T cell responses to RSV, enhAncing virAl cleArAnce viA A TH1 immune-mediAted mechAnism. This vAccine mAy benefit older populAtions At risk for RSV diseAse.

Steven G Reed - One of the best experts on this subject based on the ideXlab platform.

  • Heterologous ImmunizAtion With Defined RNA And Subunit VAccines EnhAnces T Cell Responses ThAt Protect AgAinst LeishmAniA donovAni.
    Frontiers in Immunology, 2018
    Co-Authors: Malcolm S. Duthie, Neal Van Hoeven, Zachary Macmillen, Alessandro Picone, Raodoh Mohamath, Jason H Erasmus, Dan T Stinchcomb, Steven G Reed
    Abstract:

    The rApid generAtion of strong T cell responses is Also highly desirAble And virAl vectors cAn hAve potent CD8+ T cell-inducing Activity. Immunity to leishmAniAsis requires selective T cell responses, with immunizAtion schemes thAt rAise either CD4 or CD8 T cell responses being protective in smAll AnimAl models. We hAve defined the leishmAniAsis vAccine cAndidAte recombinAnt fusion Antigens, LEISH-F2 And LEISH-F3+, thAt when formulAted in A stAble emulsion with A Toll-like receptor (TLR) 4 Agonist induce protective CD4+ T cell responses in AnimAl models, As well As providing therApeutic efficAcy in cAnine leishmAniAsis And in clinicAl triAls in leishmAniAsis pAtients. We used the genetic sequences of these vAlidAted vAccine Antigens to design RNA vAccine constructs. ImmunizAtion of mice with the RNA replicons induced potent, locAl innAte responses thAt were surprisingly independent of TLR7 And ActivAted Antigen-presenting cells (APC) to prime for extremely potent Antigen-specific T helper 1 type responses upon heterologous boosting with either of the subunit vAccines (recombinAnt Antigen with second generAtion GlucopyrAnosyl Lipid A in stAble oil-in-wAter emulsion; SLA-SE). Inclusion of RNA in the immunizAtion schedule Also generAted MHCI-restricted T cell responses. ImmunizAtion with LEISH-F2-expressing RNA vAccine followed lAter by subunit vAccine Afforded protection AgAinst chAllenge with LeishmAniA donovAni. Together, these dAtA indicAte the utility of heterologous prime-boost immunizAtion schemes for the induction of potent Antigen-specific CD4 And CD8 T cell responses for protection AgAinst intrAcellulAr pAthogens.

  • The stimulAtory effect of the TLR4-mediAted AdjuvAnt GlucopyrAnosyl Lipid A is well preserved in old Age
    Biogerontology, 2016
    Co-Authors: Birgit Weinberger, Steven G Reed, Clemens Joos, Rhea Coler, Beatrix Grubeck-loebenstein
    Abstract:

    MAny subunit vAccines require AdjuvAnts to improve their limited immunogenicity. VArious AdjuvAnt cAndidAtes tArgeting toll-like receptors (TLRs) Are currently under development including the synthetic TLR4 Agonist GlucopyrAnosyl Lipid A (GLA). GLA hAs been investigAted in the context of influenzA vAccine, which is of pArticulAr importAnce for the elderly populAtion. This study investigAtes the effect of GLA on Antigen-presenting cells from young (mediAn Age 29 yeArs, rAnge 26–33 yeArs) And older (mediAn Age 72 yeArs, rAnge 61–78 yeArs) Adults. TreAtment with GLA efficiently increAses the expression of co-stimulAtory molecules on humAn monocyte-derived dendritic cells (DC) As well As on ex vivo myeloid DC. Expression of co-stimulAtory molecules is less pronounced on ex vivo monocytes. Production of pro-inflAmmAtory cytokines (IL-6, TNF-α, IL-12) As well As of the Anti-inflAmmAtory cytokine IL-10 is induced in monocyte-derived DC. In PBMC cultures myeloid DC And to An even greAter extent monocytes produce TNF-α And IL-6 After stimulAtion with GLA. Production of IL-12 cAn Also be observed in these cultures. There Are no Age-relAted differences in the cApAcity of GLA to induce expression of co-stimulAtory molecules or production of cytokines by humAn Antigen-presenting cells. Therefore, TLR4 Agonists like GLA Are pArticulArly promising cAndidAtes As AdjuvAnts of vAccines designed for elderly individuAls.

  • SchistosomiAsis vAccine cAndidAte Sm14/GLA-SE: phAse 1 sAfety And immunogenicity clinicAl triAl in heAlthy, mAle Adults
    Vaccine, 2015
    Co-Authors: Marilia Santini-oliveira, Steven G Reed, Patricia M. Pinto, Rhea N. Coler, Lakshmi Jayashankar, Jucara C. Parra, Valdilea G. Veloso, Marcia A. Ciol, Robert Bergquist, Miriam Tendler
    Abstract:

    AbstrAct Design SAfety And immunogenicity of A recombinAnt 14 kDA, fAtty Acid-binding protein(FABP) from SchistosomA mAnsoni (rSm14) were evAluAted through An open, non-plAcebo-controlled, dose-stAndArdized triAl, performed At A single reseArch site. The vAccine wAs formulAted with GlucopyrAnosyl Lipid A (GLA) AdjuvAnt in An oil-in-wAter emulsion (SE) And investigAted in 20 mAle volunteers from A non-endemic AreA for schistosomiAsis in the stAte of Rio de JAneiro, BrAzil. Fifty microgrAm rSm14 with 10 μg GLA-SE (rSm14/GLA-SE)/dose were given intrAmusculArly three times with 30-dAy intervAls. PArticipAnts were Assessed clinicAlly, biochemicAlly And immunologicAlly for up to 120 dAys. Methods PArticipAnts were screened for inclusion by physicAl exAminAtion, hAemAtology And blood chemistry; then followed to Assess Adverse events And immunogenicity. SerA were tested for IgG (totAl And isotypes) And IgE. T cell induction of cytokines IL-2, IL-5, IL-10, IFNγ And TNFα wAs Assessed by Milliplex kit And flow cytometry. Results The investigAtionAl product showed high tolerAbility; some self-limited, mild Adverse events were observed during And After vAccine AdministrAtion. SignificAnt increAses in Sm14-specific totAl IgG, IgG1 And IgG3 were observed 30 dAys After the first vAccinAtion with specific IgG2 And IgG4 After 60 dAys. An increAse in IgE Antibodies wAs not observed At Any time point. The IgG response wAs Augmented After the second dose And 88% of All vAccinAted subjects hAd developed high Anti-Sm14 IgG titres 90 dAys After the first injection. From dAy 60 And onwArds, there wAs An increAse in CD4 + T cells producing single cytokines, pArticulArly TNFα And IL-2, with no significAnt increAse of multi-functionAl TH1 cells. Conclusion ClinicAl triAl dAtA on tolerAbility And specific immune responses After vAccinAtion of Adult, mAle volunteers in A non-endemic AreA for schistosomiAsis with rSm14/GLA-SE, support this product As A sAfe, strongly immunogenic vAccine AgAinst schistosomiAsis pAving the wAy for follow-up PhAse 2 triAls. Study registrAtion ID: NCT01154049 At http://www.clinicAltriAls.gov .

  • GlucopyrAnosyl Lipid A AdjuvAnt SignificAntly EnhAnces HIV Specific T And B Cell Responses Elicited by A DNA-MVA-Protein VAccine Regimen
    PloS one, 2014
    Co-Authors: Paul F. Mckay, Steven G Reed, Darrick Carter, Alethea Cope, Jamie F.s. Mann, Sarah B. Joseph, Mariano Esteban, Roger Tatoud, Jonathan Weber, Robin J. Shattock
    Abstract:

    Using A unique vAccine Antigen mAtched And single HIV ClAde C ApproAch we hAve Assessed the immunogenicity of A DNA-poxvirus-protein strAtegy in mice And rAbbits, Administering MVA And protein immunizAtions either sequentiAlly or simultAneously And in the presence of A novel TLR4 AdjuvAnt, GLA-AF. Mice were vAccinAted with combinAtions of HIV env/gAg-pol-nef plAsmid DNA followed by MVA-C (HIV env/gAg-pol-nef) with HIV CN54gp140 protein (+/−GLA-AF AdjuvAnt) And either co-Administered in different muscles of the sAme AnimAl with MVA-C or given sequentiAlly At 3-week intervAls. The DNA prime estAblished A populAtion of B cells thAt were Able to mount A stAtisticAlly significAnt AnAmnestic response to the boost vAccines. The greAtest Antigen-specific Antibody response wAs observed in AnimAls thAt received All vAccine components. Moreover, A high proportion of the totAl mucosAl IgG (20 – 50%) present in the vAginAl vAult of these vAccinAted AnimAls wAs vAccine Antigen-specific. The potent elicitAtion of Antigen-specific immune responses to this vAccine modAlity wAs Also confirmed in rAbbits. ImportAntly, co-AdministrAtion of MVA-C with the GLA-AF AdjuvAnted HIV CN54gp140 protein significAntly Augmented the Antigen-specific T cell responses to the GAg Antigen, A trAnsgene product expressed by the MVA-C vector in A sepArAte quAdriceps muscle. We hAve demonstrAted thAt co-AdministrAtion of MVA And GLA-AF AdjuvAnted HIV CN54gp140 protein wAs equAlly effective in the generAtion of humorAl responses As A sequentiAl vAccinAtion modAlity thus shortening And simplifying the immunizAtion schedule. In Addition, A significAnt further benefit of the condensed vAccinAtion regime wAs thAt T cell responses to proteins expressed by the MVA-C were potently enhAnced, An effect thAt wAs likely due to enhAnced immunostimulAtion in the presence of systemic GLA-AF.

  • evAluAtion of sAfety And immunogenicity of recombinAnt influenzA hemAgglutinin h5 indonesiA 05 2005 formulAted with And without A stAble oil in wAter emulsion contAining GlucopyrAnosyl Lipid A se glA AdjuvAnt
    Vaccine, 2013
    Co-Authors: John J. Treanor, Brandon Essink, Steven Hull, Ruvim Izikson, Karen L. Goldenthal, Robert Kohberger, Peter A Patriarca, Steven G Reed, Lisa M. Dunkle
    Abstract:

    AbstrAct BAckground Expression of recombinAnt hemAgglutinin (rHA) in insect cells represents A technology with proven efficAcy in seAsonAl influenzA And with the potentiAl for A rApid response to the emergence of new, pAndemic strAins. We evAluAted the sAfety And immunogenicity of rHA vAccine (H5/IndonesiA/5/05) produced in SF+ insect cells using A bAculovirus expression vector system (BEVS). The rHA vAccine wAs tested with And without the AdjuvAnt GlucopyrAnosyl Lipid A/stAble emulsion (GLA/SE). Methods HeAlthy Adults 18–49 were rAndomized to two IM doses on DAys 0 And 21 of plAcebo; unAdjuvAnted rHA 135 μg or 45 μg, or rHA 45 μg, 15 μg, 7.5 μg or 3.8 μg with GLA/SE. A pioneer group wAs monitored through DAy 42 before rAndomizing remAining subjects. H5-specific Antibody wAs determined by hemAgglutinAtion inhibition (HAI) And microneutrAlizAtion (MN) on DAys 0, 21 And 42. Results 392 subjects were rAndomized, of whom 380 (97%) received two doses And 386 (98%) completed 12 months of follow-up. Injection site pAin And tenderness were seen in 50–70% of rHA + GLA/SE recipients And 4–9% of rHA Alone And plAcebo recipients, but most complAints were mild to moderAte in intensity. After two doses, the proportions of subjects with HAI titers ≥1:40 were 32% And 15% in the unAdjuvAnted 135 μg And 45 μg groups, And 82%, 75%, 66%, And 72% in those receiving 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE. The geometric meAn titers (GMTs) of HAI Antibody on DAy 42 were 128, 95, 69, And 72 in the 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE groups, respectively. Conclusions rHA GLA/SE wAs well tolerAted And immunogenic in heAlthy Adults, And GLA/SE substAntiAlly improved the serum Antibody response. rHA expressed using BEVS recombinAnt DNA plAtform technology represents A promising strAtegy for pAndemic control.

Jan Ter Meulen - One of the best experts on this subject based on the ideXlab platform.

  • Toll-Like Receptor 4 Expression on LymphomA Cells Is CriticAl for TherApeutic Activity of IntrAtumorAl TherApy With Synthetic TLR4 Agonist GlucopyrAnosyl Lipid A.
    Frontiers in oncology, 2020
    Co-Authors: Alec Betancur, Michael Chen, Jan Ter Meulen
    Abstract:

    IntrAtumorAl (IT) injections of GlucopyrAnosyl Lipid A (G100), A synthetic toll-like receptor 4 (TLR4) Agonist formulAted in A stAble emulsion, resulted in T-cell inflAmmAtion of the tumor microenvironment (TME) And complete cure of 60% of mice with lArge estAblished A20 lymphomAs. Strong AbscopAl effects on un-injected lesions were observed in A bilAterAl tumor model And surviving mice resisted A secondAry tumor chAllenge. Depletion of CD8 T-cells, but not CD4 or NK cells, AbrogAted the Anti-tumor effect. Unexpectedly, TLR4 knock-out rendered A20 tumors completely non-responsive to G100. In vitro studies showed thAt GLA hAs direct effect on A20 cells, but not on A20 cells deficient for TLR4. As shown by genotyping And phenotyping AnAlysis, G100 strongly ActivAted Antigen presentAtion functions in A20 cells in vitro And in vivo And induced their Apoptosis in A dose dependent mAnner. SimilArly, the TLR4 positive humAn mAntle cell lymphomA line Mino showed in vitro ActivAtion with G100 thAt wAs blocked with An Anti-TLR4 Antibody. In the A20 model, direct ActivAtion of B-lymphomA cells with G100 is sufficient to induce protective CD8 T-cell responses And TLR4 expressing humAn B-cell lymphomAs mAy be AmenAble to this therApy As well.

  • AbstrAct 4094: The TLR4 Agonist G100 enhAnces rituximAb-mediAted ADCCin vitroAnd hAs synergistic Anti-tumor effects with Anti-CD20 mAbin vivo
    Immunology, 2019
    Co-Authors: Alec Betancur, Jan Ter Meulen
    Abstract:

    BAckground: G100, which contAins the synthetic TLR4 Agonist GlucopyrAnosyl Lipid A (GLA) formulAted in A stAble oil-in-wAter emulsion (SE) for intrAtumorAl therApy, is currently in clinicAl development in combinAtion with pembrolizumAb for the treAtment of B-cell folliculAr lymphomA (FL). The current study wAs undertAken to investigAte the interAction of G100 with rituximAb, the Anti-CD20 mAb thAt is stAndArd-of-cAre treAtment for FL. Methods:In vitro studies were performed using peripherAl blood mononucleAr cells (PBMC) from heAlthy humAn donors to investigAte the effect of GLA-AF (An Aqueous formulAtion of GLA) on nAturAl killer (NK) cell ActivAtion. IFNγ production in NK cells After ActivAtion with plAte-bound Anti-CD16 or tArget K562 leukemiA cells wAs meAsured by intrAcellulAr cytokine stAining (ICS). RituximAb-mediAted Antibody-dependent cellulAr cytotoxicity (ADCC) wAs meAsured using pretreAted or untreAted PBMC And rituximAb-coAted RAji Burkitt’s lymphomA cells As tArget cells. In vivo studies were cArried out in BAlb/c mice with bilAterAl A20 lymphomA. Mice received G100 Alone (10μg, intrAtumorAl, 3 injections/week), Anti-CD20 Alone (clone 5D2, provided by Genentech, 200μg, intrAperitoneAl, 1 injection/week), or G100+Anti-CD20 for A totAl of 3 weeks. Results: IncubAtion of PBMC from 3 different donors with GLA-AF (1 μg/mL) resulted in NK cell ActivAtion As demonstrAted by increAsed IFNγ production, As well As enhAnced response to the K562 tArget cells And Anti-CD16. When PBMC from 5 normAl donors were used in rituximAb-mediAted ADCC AssAy, pretreAted PBMCs hAd significAntly enhAnced lysis of tArget RAji cells compAred to untreAted PBMC (p Conclusions: G100 enhAnces NK cell Activity And rituximAb-mediAted ADCC in humAn PBMC. CombinAtion of G100 And Anti-CD20 mAb hAs synergistic Anti-tumor effects in A mouse lymphomA model. These dAtA support clinicAl testing of G100 with rituximAb in pAtients with FL. CitAtion FormAt: HAiling Lu, Alec BetAncur, JAn ter Meulen. The TLR4 Agonist G100 enhAnces rituximAb-mediAted ADCC in vitro And hAs synergistic Anti-tumor effects with Anti-CD20 mAb in vivo [AbstrAct]. In: Proceedings of the AmericAn AssociAtion for CAncer ReseArch AnnuAl Meeting 2019; 2019 MAr 29-Apr 3; AtlAntA, GA. PhilAdelphiA (PA): AACR; CAncer Res 2019;79(13 Suppl):AbstrAct nr 4094.

  • A novel HSV-2 subunit vAccine induces GLA-dependent CD4 And CD8 T cell responses And protective immunity in mice And guineA pigs
    Vaccine, 2015
    Co-Authors: Jared M. Odegard, Jan Ter Meulen, Patrick A. Flynn, David J. Campbell, Scott H. Robbins, Lichun Dong, Kening Wang, Jeffrey I. Cohen, David M. Koelle
    Abstract:

    AbstrAct BAckground/objectives There is currently no licensed prophylActic or therApeutic vAccine for HSV-2 infection. Methods We developed A novel preclinicAl vAccine cAndidAte, G103, consisting of three recombinAntly expressed HSV-2 proteins (gD And the UL19 And UL25 gene products) AdjuvAnted with the potent synthetic TLR4 Agonist GlucopyrAnosyl Lipid A (GLA) formulAted in stAble emulsion. The vAccine wAs tested for immunogenicity And efficAcy in pre-clinicAl models for preventAtive And therApeutic vAccinAtion. Results VAccinAtion of mice with G103 elicited Antigen-specific binding And neutrAlizing Antibody responses, As well As robust CD4 And CD8 effector And memory T cells. The T cell responses were further boosted by subsequent chAllenge with live virus. ProphylActic immunizAtion completely protected AgAinst lethAl intrAvAginAl HSV-2 infection in mice, with only trAnsient replicAtion of virus in the genitAl mucosA And sterilizing immunity in dorsAl root gAngliA. Supporting the use of G103 therApeuticAlly, the vAccine expAnded both CD4 And CD8 T cells induced in mice by previous infection with HSV-2. In the guineA pig model of recurrent HSV-2 infection, therApeutic immunizAtion with G103 wAs ApproximAtely 50% effective in reducing the number of lesions per AnimAl As well As the overAll lesions score. Conclusions TAken together, the dAtA show thAt G103 is A viAble cAndidAte for development of A novel prophylActic And therApeutic HSV-2 vAccine.

  • AbstrAct 2505: TherApeutic efficAcy of the ZVex™ And GLAAS™ plAtforms in A B16-F10/hCAIX melAnomA mouse model
    Immunology, 2015
    Co-Authors: David J. Campbell, Peter Berglund, Patrick A. Flynn, Scott H. Robbins, Rebecca S. Reeves, Jan Ter Meulen
    Abstract:

    ZVex™ And GLAAS™ Are two dendritic-cell (DC) tArgeting plAtform technologies designed to enhAnce immune responses through the in vivo induction of Antigen specific CD8 And CD4 T-cells, respectively. ZVex™ is A lentivirAl vector pseudotyped with A modified Sindbis virus envelope engineered to deliver tumor Antigen-encoding nucleic Acids to dendritic cells in vivo. GLAAS™(GlucopyrAnosyl Lipid A AdjuvAnt System) ActivAtes DC by binding to the TLR-4 receptor And inducing strong Th1 type CD4 responses AgAinst co-delivered recombinAnt proteins. Currently both plAtform technologies Are being investigAted in phAse I clinicAl triAls in cAncer pAtients. HumAn cArbonic AnhydrAse 9 (hCAIX) is A tumor-AssociAted trAnsmembrAne Antigen thAt is over-expressed on vArious cAncer cell types. We mApped hCAIX specific, multi-functionAl CD8 And CD4 T-cell epitopes within the extrAcellulAr And trAnsmembrAne regions of the protein for the mouse hAplotype H-2b by intrAcellulAr cytokine stAining. Mice lethAlly chAllenged s.c. on the flAnk with A B16-F10 tumor cell line expressing the hCAIX protein (designAted BC.12) fully controlled lArge tumors (>100 mm2) when therApeuticAlly immunized (subcutAneously At the bAse of tAil) with ZVex™ encoding hCAIX or the recombinAnt hCAIX protein with GLAAS™ (either s.c. or i.m.). In both models, tumor control wAs dose-dependent. AdditionAlly, the presence of A strong trAnsmembrAne H-2b restricted CD8 T-cell epitope wAs required for tumor control And regression. hCAIX-specific CD8 T-cell responses were detectAble As fAr out As dAy 67 post chAllenge in mice displAying full regression of tumor. These results demonstrAte proof of concept for ZVex™ And GLAAS™ plAtform technologies in An Aggressive murine melAnomA model. CitAtion FormAt: DAvid J. CAmpbell, RebeccA S. Reeves, PAtrick A. Flynn, Scott H. Robbins, Peter Berglund, JAn H. ter Meulen. TherApeutic efficAcy of the ZVex™ And GLAAS™ plAtforms in A B16-F10/hCAIX melAnomA mouse model. [AbstrAct]. In: Proceedings of the 106th AnnuAl Meeting of the AmericAn AssociAtion for CAncer ReseArch; 2015 Apr 18-22; PhilAdelphiA, PA. PhilAdelphiA (PA): AACR; CAncer Res 2015;75(15 Suppl):AbstrAct nr 2505. doi:10.1158/1538-7445.AM2015-2505

Kunle Odunsi - One of the best experts on this subject based on the ideXlab platform.

  • First-in-humAn phAse 1 dose-escAlAting triAl of G305 in pAtients with AdvAnced solid tumors expressing NY-ESO-1
    Cancer Immunology Immunotherapy, 2019
    Co-Authors: Amit Mahipal, Samuel Ejadi, Sacha Gnjatic, Seunghee Kim-schulze, Jan H. Ter Meulen, Richard Kenney, Kunle Odunsi
    Abstract:

    HumAn tumor cells express Antigens thAt serve As tArgets for the host cellulAr immune system. This phAse 1 dose-escAlAting study wAs conducted to Assess sAfety And tolerAbility of G305, A recombinAnt NY-ESO-1 protein vAccine mixed with GlucopyrAnosyl Lipid A (GLA), A synthetic TLR4 Agonist AdjuvAnt, in A stAble emulsion (SE). Twelve pAtients with solid tumors expressing NY-ESO-1 were treAted using A 3 + 3 design. The NY-ESO-1 dose wAs fixed At 250 µg, while GLA-SE wAs increAsed from 2 to 10 µg. SAfety, immunogenicity, And clinicAl responses were Assessed prior to, during, And At the end of therApy. G305 wAs sAfe And immunogenic At All doses. All relAted AEs were GrAde 1 or 2, with injection site soreness As the most commonly reported event (100%). OverAll, 75% of pAtients developed Antibody response to NY-ESO-1, including six pAtients with increAsed Antibody titer ( ≥ 4-fold rise) And three pAtients with seroconversion from negAtive (titer 

  • A first-in-humAn phAse 1 dose-escAlAting triAl of G305 in pAtients with solid tumors expressing NY-ESO-1.
    Journal of Clinical Oncology, 2015
    Co-Authors: Amit Mahipal, Sacha Gnjatic, Seunghee Kim-schulze, Kunle Odunsi, Richard T. Kenney, Samuel Ejadi
    Abstract:

    HumAn tumor cells express Antigens thAt serve As tArgets for the host cellulAr immune system. This phAse 1 dose-escAlAting study wAs conducted to Assess sAfety And tolerAbility of G305, A recombinAnt NY-ESO-1 protein vAccine mixed with GlucopyrAnosyl Lipid A (GLA), A synthetic TLR4 Agonist AdjuvAnt, in A stAble emulsion (SE). Twelve pAtients with solid tumors expressing NY-ESO-1 were treAted using A 3 + 3 design. The NY-ESO-1 dose wAs fixed At 250 µg, while GLA-SE wAs increAsed from 2 to 10 µg. SAfety, immunogenicity, And clinicAl responses were Assessed prior to, during, And At the end of therApy. G305 wAs sAfe And immunogenic At All doses. All relAted AEs were GrAde 1 or 2, with injection site soreness As the most commonly reported event (100%). OverAll, 75% of pAtients developed Antibody response to NY-ESO-1, including six pAtients with increAsed Antibody titer ( ≥ 4-fold rise) And three pAtients with seroconversion from negAtive (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of pAtients; 33.3% were new responses And 1 wAs boosted ( ≥ 2-fold rise). Following treAtment, 8 of 12 pAtients hAd stAble diseAse for 3 months or more; At the end of 1 yeAr, three pAtients hAd stAble diseAse And nine pAtients were Alive. G305 is A potent immunotherApeutic Agent thAt cAn stimulAte NY-ESO-1-specific Antibody And T-cell responses. The vAccine wAs sAfe At All doses of GLA-SE (2–10 µg) And showed potentiAl clinicAl benefit in this populAtion of pAtients.

Samuel Ejadi - One of the best experts on this subject based on the ideXlab platform.

  • First-in-humAn phAse 1 dose-escAlAting triAl of G305 in pAtients with AdvAnced solid tumors expressing NY-ESO-1
    Cancer Immunology Immunotherapy, 2019
    Co-Authors: Amit Mahipal, Samuel Ejadi, Sacha Gnjatic, Seunghee Kim-schulze, Jan H. Ter Meulen, Richard Kenney, Kunle Odunsi
    Abstract:

    HumAn tumor cells express Antigens thAt serve As tArgets for the host cellulAr immune system. This phAse 1 dose-escAlAting study wAs conducted to Assess sAfety And tolerAbility of G305, A recombinAnt NY-ESO-1 protein vAccine mixed with GlucopyrAnosyl Lipid A (GLA), A synthetic TLR4 Agonist AdjuvAnt, in A stAble emulsion (SE). Twelve pAtients with solid tumors expressing NY-ESO-1 were treAted using A 3 + 3 design. The NY-ESO-1 dose wAs fixed At 250 µg, while GLA-SE wAs increAsed from 2 to 10 µg. SAfety, immunogenicity, And clinicAl responses were Assessed prior to, during, And At the end of therApy. G305 wAs sAfe And immunogenic At All doses. All relAted AEs were GrAde 1 or 2, with injection site soreness As the most commonly reported event (100%). OverAll, 75% of pAtients developed Antibody response to NY-ESO-1, including six pAtients with increAsed Antibody titer ( ≥ 4-fold rise) And three pAtients with seroconversion from negAtive (titer 

  • A first-in-humAn phAse 1 dose-escAlAting triAl of G305 in pAtients with solid tumors expressing NY-ESO-1.
    Journal of Clinical Oncology, 2015
    Co-Authors: Amit Mahipal, Sacha Gnjatic, Seunghee Kim-schulze, Kunle Odunsi, Richard T. Kenney, Samuel Ejadi
    Abstract:

    HumAn tumor cells express Antigens thAt serve As tArgets for the host cellulAr immune system. This phAse 1 dose-escAlAting study wAs conducted to Assess sAfety And tolerAbility of G305, A recombinAnt NY-ESO-1 protein vAccine mixed with GlucopyrAnosyl Lipid A (GLA), A synthetic TLR4 Agonist AdjuvAnt, in A stAble emulsion (SE). Twelve pAtients with solid tumors expressing NY-ESO-1 were treAted using A 3 + 3 design. The NY-ESO-1 dose wAs fixed At 250 µg, while GLA-SE wAs increAsed from 2 to 10 µg. SAfety, immunogenicity, And clinicAl responses were Assessed prior to, during, And At the end of therApy. G305 wAs sAfe And immunogenic At All doses. All relAted AEs were GrAde 1 or 2, with injection site soreness As the most commonly reported event (100%). OverAll, 75% of pAtients developed Antibody response to NY-ESO-1, including six pAtients with increAsed Antibody titer ( ≥ 4-fold rise) And three pAtients with seroconversion from negAtive (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of pAtients; 33.3% were new responses And 1 wAs boosted ( ≥ 2-fold rise). Following treAtment, 8 of 12 pAtients hAd stAble diseAse for 3 months or more; At the end of 1 yeAr, three pAtients hAd stAble diseAse And nine pAtients were Alive. G305 is A potent immunotherApeutic Agent thAt cAn stimulAte NY-ESO-1-specific Antibody And T-cell responses. The vAccine wAs sAfe At All doses of GLA-SE (2–10 µg) And showed potentiAl clinicAl benefit in this populAtion of pAtients.