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IPH43 : mAbs anti-MICA .Treatment of cancer - Innate Pharma

Innate Pharma
Gestionnaire: artfact
Créé: Février 16 '13
artfact Gold
artfact Mars 5 '14

IPH43 : mAbs anti-MICA .Treatment of cancer

 

IPH43, programme d'anticorps anti-MICA

 

IPH43 est un programme de développement d’anticorps thérapeutique  first-in-class anti-MICA dans des indications d’oncologie. MICA est le ligand du récepteur activateur NKG2D sur les cellules NK. Il est spécifiquement exprimé par les cellules tumorales dans de nombreuses indications de tumeurs solides ayant une forte prévalence comme le sein, le poumon ou le cancer colorectal.

C’est une molécule hautement polymorphique et Innate Pharma a généré un panel d’anticorps reconnaissant ses différentes formes avec une haute affinité.

Ces anticorps vont maintenant être testés et optimisés afin de sélectionner le meilleur candidat pour le développement.

MICA is specifically expressed on many

tumors and not in normal tissues

Chemotherapeutic agents upregulate MICA

expression

Newly generated anti-MICA mAb display high

affinities, are pan-alleles and can mediate

direct cytotoxic effect through ADCC and/or

CDC and demonstrate

in vivo

efficacy

Additional modes of action of anti-MICA mAb

are currently investigated including:

Neutralization of soluble MICA (direct effect

or inhibition of shedding)

Restoration of NKG2D expression and

function

Associated biomarker strategy: MICA

expression on tumor, sMICA in serum

 

 

 

BREVET

Cette invention concerne des méthodes permettant de traiter les affections médiées par des cellules exprimant MICA en utilisant des anticorps, des fragments d'anticorps et leurs dérivés qui se lient spécifiquement à MICA. L'invention concerne également des anticorps, des cellules produisant ces anticorps, des méthodes de fabrication de ces anticorps, des fragments, des variants et des dérivés de ces anticorps, et des compositions pharmaceutiques les
 contenant.

 

http://patentscope.wipo.int/search/fr/detail.jsf?docId=WO201 3117647&recNum=3&office=&queryString=innate+pharma&prevFilter=&a mp;sortOption=Date+de+pub.+antichronologique&maxRec=191

 

ABSTRACT SICT 2013 INNATE PHARMA

http://www.immunotherapyofcancer.org/content/pdf/2051-1426-1-S 1-P41.pdf

 

http:///.../sitc2013_mica_0.pdf

 

ABSTRACT AACR  2014-03-05

http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=43093ed7-e897-420c-8290-d793bea27c2b&cKey=668b24dd-ffef-4389-84e8-dfe3d37ca060&mKey=6ffe1446-a164-476a-92e7-c26446874d93

 

 

 

 

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artfact Gold
artfact Mars 5 '14

the NKG2D-mediated pathway may be a powerful target for the treatment of cancer.published online: 3 MAR 2014

 

http://onlinelibrary.wiley.com/doi/10.1002/ijc.28775/abstract;jsessionid=1E27705655F5AA1D06EDCE39ECBC966C.f01t02?deniedAccessCustomisedMessage=&userIsAuthenticated=false

 

NKG2D signaling in cancer immunosurveillance

1.                               Alejandro López-Soto*, Leticia Huergo-Zapico, Andrea Acebes-Huerta, Mónica Villa-Alvarez, Segundo Gonzalez .First 

·                                  

 

The immune system is able to detect and eliminate transformed cells. The activating receptor NKG2D is particularly relevant for cancer immunosurveillance. NKG2D ligand expression renders tumor cells more susceptible to be killed by NK and T cells, and correlates with the clinical outcome of the disease. However, tumors develop mechanisms to overcome the NKG2D-mediated immune response, which has been associated with poor prognosis and impairment of the clinical benefits of immunotherapy in many human cancers. The highly specific pattern of expression displayed by the NKG2D ligands, mainly confined to tumor cells, together with the strong immune response triggered by this receptor clearly supports the idea that the NKG2D-mediated pathway may be a powerful target for the treatment of cancer. This review draws together the most recent discoveries concerning the biology of the NKG2D signaling and their therapeutic relevance in the context of cancer.

 

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artfact Gold
artfact Mars 5 '14
Les cibles thérapeutiques sont variées ,les tumeurs solides .

Dans la hiérarchie des tumeurs surexprimant Mica ,vient en tete le K du Sein suivi du K colo rectal ,cad deux des 4 ou 5 cancers les plus répandus . les % de surexpression de Mica sont trés élevés (de mémoire ,sup. à80%


Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition.

Mamessier E, Sylvain A, Bertucci F, Castellano R, Finetti P, Houvenaeghel G, Charaffe-Jaufret E, Birnbaum D, Moretta A, Olive D.

Author information Abstract

Breast cancer is the leading cause of death for women between the ages of 35 to 65. This is mostly due to intertumor heterogeneity and the lack of specific therapies for all subtypes. However, some breast cancers with an unexpected good prognosis are associated with enhanced antitumor immunity in situ. We studied whether breast cancer subtypes might have different susceptibilities to natural killer (NK) cells' antitumor immunity. We collected a large public set of microarray data for primary breast tumors and determined NK cell ligand expression. We found that despite heterogeneous levels of inhibitory HLA members, NKG2D ligands and DNAM ligands are expressed in virtually all breast tumor subtypes. Functional experiments in breast cancer subtypes expressing various levels of NK cell ligands showed that NK-mediated cytotoxicity is mainly HLA, NKG2D, and DNAM dependent. In parallel, we showed that cell lines and primary breast tumor cells secrete soluble inhibitory factors that alter NK cell functions. Finally, we showed that these mechanisms of escape occur in vivo in the MMTV-Neu model of spontaneous murine breast cancer. Our study shows that breast cancer cells, independent of the subtype, have developed different mechanisms to escape from NK cells' antitumor immunity. These results emphasize the role of NK cells in breast tumor clearance and underlie the importance of devising future therapy aiming at enhancing NK cell-mediated recognition in parallel with the prevention of the tumor-editing process.

http://www.ncbi.nlm.nih.gov/pubmed/21937679
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Francis
Francis Mars 8 '14
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artfact Gold
artfact Juin 3 '14
ya ce qui faut à l'immunopole ;-)

 Daniel Baty et "nanobodies" 


vu au pharo en décembre . son intervention avait pas mal surpris l'assemblée scientifique.


http://crcm.marseille.inserm.fr/equipesde-recherche/daniel-baty-etpatrick-chames/

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artfact Gold
artfact Juillet 17 '14
un dossier anti MICA  "concurrent" . 

que j'ai posté sur bourso.

trés intéresant (et,malheureusement sans réponse des intéréssés ...)


a plusieurs titres .

"on" sait que l'anti Mica était connu de tous ,mais que personne n'avait fait le job. 

on apprend que dans le cadre du suivi des mélanomes, l'antiMica a été étudié et qu'une équipe argumente et envisage ...

puis que la mème élargit sa réflexion pour généraliser à l'ensemble des cancers ....mais on est alors en 2014, ....

et Innate l'a déja fait (le job).


first in class...oui ; tant qu'on est devant.

mathieu blery a un cahier des charges a respecter  et c'est un gars ,qui "vu d'avion" (sic ,dans nos échanges) sait vous le faire comprendre !!


c'est surtout une validation anti mica  venant des équipes US les plus pointues ,sur un suivi de mélanome traité par ipi !!!


ccl: Innate opportuniste a pris tout le monde de vitesse .

mais ya du monde derrière et il ne faut pas chomer  .

 

ça n'est que mon interprétation .. 


le dossier ;


"Dossier Anti Mica - Mélanome -Boston - Glenn Dranoff,"

Brevet 
 2010
http://patentscope.wipo.int/...=US43243015&recN um=17&maxRec=61&office=&prevFilter=&sortOption=Pub+Date+Desc& ;queryString=Glenn+Dranoff&tab=NationalBiblio

 Abstracts » 2012 ASCO Annual Meeting
Isolation of human anti-MICA antibody from cancer patients responding to 
 immunotherapies.
http://meetinglibrary.asco.org/content/98709-114


http://www.curemelanoma.org/...-Reduced-for-Web.pdf
 

http://www.dana-farber.org/...w-strategies-in-tumo r-vaccines.aspx


 

--------fevrier 2014 ------------------


 Developing anti-MICA antibody immunotherapy
MRA Team Science Award leader Glenn Dranoff,
Dana-Farber Cancer Institute, reported on work to
develop novel antibodies for melanoma immunothera
py. Dranoff described this project as illustrative of how
“bringing together basic and translational scientists can
achieve far more than either discipline alone.” Their
work is based on the finding that some patients who
respond well to ipilimumab developed antibodies to 
a protein called MHC class I chain-related protein 
A (MICA). MICA is up-regulated on the tumor cell
surface after cell injury and is the ligand for NKG2D
expressed on cytotoxic lymphocytes; their interaction
results in cytolysis and inflammatory cytokine produc
tion. In collaboration with Kai Wucherpfennig, Dranoff
isolated a panel of human anti-MICA monoclonal
antibodies of which a subset showed broad reactivity.
These antibodies inhibited MICA shedding from
melanoma cells, antagonized the immunosuppressive
effects of soluble MICA present in the sera of
melanoma patients, promoted NKG2D-dependent
killing of melanoma cells by human peripheral blood
mononuclear cells, and inhibited tumor growth in model
systems. The team plans to bring these antibodies into
the clinic in the near future, and they have promising
potential to be combined with other therapies, such 
as HDAC inhibitors or CTLA-4 blockade.


2014 toujours

Now, Dranoff is working with Kai Wucherpfennig, MD, PhD, of theDepartment of Cancer Immunology and AIDS, to isolate and analyze the anti-MICA antibodies. Wucherpfennig, who has made major contributions to the basic understanding of how immune cells recognize antigens at the molecular level, recently developed a technique to isolate the one in ten thousand immune cells that reacts to a specific antigen. Using blood samples from immunized patients, the researchers are looking for the proverbial needle in a haystack, Wucherpfennig says. If they are successful, it will give them the ability to produce a recombinant anti-MICA antibody in unlimited amounts that can be rigorously tested for anti-tumor activity.


Ce message du forum a été modifié par artfact Septembre 9 '14
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Thrust31 Gold
Thrust31 Juillet 18 '14
Bonjour Bruno,

On est toujours pas mal par rapport à l'anti-MICA (ça bosse chez Dana Farber qui est un partenaire), et je comprends pourquoi tu mets concurrent entre guillemets.

J'ai qd même l'impression que tant que tu n'as pas sorti ton étude dans les "médias" médicaux, tu es forcément en retard… Donc IPH ne peut se contenter d'attendre la rentrée pour annoncer qqch

Merci en tout cas pour cet article

Bonne journée

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Francis
Francis Juillet 18 '14
Aucun doute qu'ils feront le nécessaire pour rester en tête ;)
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artfact Gold
artfact Juillet 18 '14
je ne lache pas cette affaire et .... le droit de savoir  ,puisque tout ce dossier est public alors qu'Innate ne l'évoque jamais . 

ils avaient donné un délai de 15 mois il me semble ,pour finaliser leurs dossiers IPH 43  / définitions des cibles ,tenant compte  de la concurrence , en clair ,de ne pas aller la ou il y a déja beaucoup d'essais .... ama ,je ne sais pourquoi ;-) ils ne vont pas viser le mélanome . 


tout ça devrait nous mener fin 2014 ,début 2015. 

On discutait cet hiver ,avant IPH 22 , du rententissement des phases cliniques IPH 43 sur les finances ,

et sur la visibilité financière . ils nous répondaient alors qu'ils ne pouvaient pas anticiper ,car tout allait dépendre des cibles choisies . ils envisageaient des trials en propre si les cibles était "petites",peu couteuses ,et un partenariat en cas inverse (les pples cibles étant énormes ,en particulier le sein et le colon si j'ai bonne mémoire .)


 Innate a un excédent de 10M€ aprés AK de juin .

 

Ce message du forum a été modifié par artfact Septembre 4 '14
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artfact Gold
artfact Décembre 27 '14
fidèle au RDV  ... 

Aucune nouvelle d'Innate ,pas plus que de Boston ...


 chercher ailleurs  !!


CANCER IMMUNOLOGY AND IMMUNOTHERAPY:DELIVERING THE PROMISE
October 9–10, 2014Masur and Lipsett Auditorium, Building 10National Institutes of Health, Bethesda, MD



A lire les trois pages de programme , on se dit  que notre niche Innée  est

- bien vérouillée , et ça va exploser ...ou 

- illusoire ...et on va se planter .


Réduit à une demi heure de conf.  :


Session 4: Other Approaches to Cancer Immunotherapy

 11:30 Jeffrey Miller, University of Minnesota, Minneapolis, MNEducating and Targeting NK Cells In Vivo to Exploit Their Activity forCancer and Transplantation Therapy


et encore , Miller est trés orienté NK-greffe  ,mais auteur ,par ailleurs ,d'articles trés intéressants sur les KARS  ,comme dirait oru ;-)


PD1 mania US et dapatatif à toutes les sauces ...


les US ....ils ont des ruées ....l'or , le gaz de schiste , l'anti PD1  ...on sait le devenir des deux premiers  ;-) 





well ... suffit de faire un ptit tour sur le poster 79  !!!



Targeting Soluble NKG2D Ligand Prevents Cancer Progression and EliminatesMetastasis in a 'humanized' Spontaneous Pre-clinical Cancer Model Medical University of South Carolina and Hollings Cancer Center, Charleston,




"With a sMIC-specific antibody, we further demonstrated that


 targeting sMIC can effectively inhibit the progression of primary tumor and eradicate established metastatic tumors through restoring NK peripheral homeostasis and potentiate CD8 and CD4 T cell anti-tumor immunity.


 Furthermore, we found that the

enhanced CD4 and CD8 anti-tumor response is NK-dependent.


 Together, our study suggests that: 


1) the impact of sMIC should be accounted in current cancer immunotherapy trials and practice;

 2) NK cellsplay an important role in sustaining adaptive immunity against cancer"




http://ncifrederick.cancer.gov/events/CancerImmunology/AbstractBook.pdf


pas belle la vie  ?????????????????


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artfact Gold
artfact Février 24 '15
si vous n'étiez pas jusque la convaincus, lisez  .... 
Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype

Gang Xiao14Xuanjun Wang2Jun Sheng2Shengjun Lu15Xuezhong Yu13 andJennifer D Wu13*

  • *

Journal of Hematology & Oncology 2015, 8:13  doi:10.1186/s13045-015-0110-z

Published: 20 February 2015


Expression of surface NKG2D ligand MIC on tumor cells is deemed to stimulate NK and co-stimulate CD8 T cell anti-tumor immunity. Human cancer cells however frequently adopt a proteinase-mediated shedding strategy to generate soluble MIC (sMIC) to circumvent host immunity. High levels of sMIC have been shown to correlate with advanced disease stages in cancer patients. The underlying mechanism is currently understood as systemic downregulation of NKG2D expression on CD8 T and NK cells and perturbing NK cell periphery maintenance. Herein we report a novel mechanism by which sMIC poses immune suppressive effect on host immunity and tumor microenvironment. We demonstrate that sMIC facilitates expansion of myeloid-derived suppressor cells (MDSCs) and skews macrophages to the more immune suppressive alternative phenotype through activation of STAT3. These findings further endorse that sMIC is an important therapeutic target for cancer immunotherapy.


http://www.jhoonline.org/content/8/1/13/abstract


Le programme IPH 43 vaut de l'or !!!

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artfact Gold
artfact Mai 9 '15

Entre temps , Glenn Drannof a quitté Boston , quid de ses études sur anti-mica ??


et on a vu passer  l'abstarct  de J WU  à l'AACR 


Presentation Abstract


Abstract Number:2468

Presentation Title:

Antibody targeting soluble NKG2D ligand sMIC induces regression of primary tumors and eliminates metastasis in multiple pre-clinical cancer models


Presentation Time:Monday, Apr 20, 2015, 1:00 PM - 5:00 PMLocation:Section 25Poster Board Number:10Author Block:Jennifer D. Wu, Fahmin Basher, Mark Rubinstein. Medical University of South Carolina, Charleston, 


SCAbstract Body:Expression of the MHC I-chain related molecules A and B (MICA/B) on epithelial cell surface in response to transformation or DNA damage can signal the immune system of the abnormality and thus initiate active immune surveillance by Natural Killer (NK) cells and cytotoxicity T cells. We and others have shown that malignant tumor cells can shed MICA/B to down regulate NKG2D expression and negatively impact NK and CD8 T cell function in cancer patients. Increased tumor-specific shedding of cell surface NKG2D ligand, MHC I chain related molecule (MIC), is associated with advanced stage and metastasis in many types of epithelial cancer . High serum levels of soluble MIC (sMIC) insults the immune system not only by down-regulating NKG2D expression on natural killer (NK) cells and effector T cells but also perturbing NK cell peripheral maintenance. Whether sMIC is an effective cancer therapeutic target has not been addressed due to the lack of specific sMIC-blocking reagent and clinically relevant pre-clinical animal models. Using a “humanized” clinically relevant spontaneous prostate carcinoma TRAMP/MIC bi-transgenic mouse model and multiple engineered syngeneic transplantable tumor models, we unprecedentedly show that therapy with a sMIC-specific monoclonal antibody induced rapid regression of primary tumors and metastasis without systemic toxicity. The therapy revamped a myriad of anti-tumor immune responses including NK cell homeostatic renewal and function, CD4 T cells to Th1 and Th17 responses. Using the well-defined melanoma model, we further show that anti-sMIC therapy augments Pmel-1 antigen-specific CD8 T cell responses. Notably, depletion of NK cells mitigated the therapeutic effect of anti-sMIC antibody and the effector function of both CD4 and CD8 T cells. We conclude that sMIC is an effective therapeutic target to potentiate innate and adoptive immune responses against MIC+ malignancies.

Ce message du forum a été modifié par artfact Mai 9 '15
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artfact Gold
artfact Mai 9 '15

IPH 43 cible  MICA ,recepteur situé sur la cellule cancéreuse .

mais ,au fil du temps , ces MICA sont "externalisés" et deviennent solubles ,circulants 

( sMICA) .

Ils participent alors à la dérégulation/échappement  immunitaire dans ce que l'on appelle le micro environnement tumoral , parmi (et en interactions avec) différentes cellules et agents "chimiques" au service de la tumeur.  


une nouvelle méthode d'étude in vitro est proposée dans cette publication , prenant en compte  l'aspect volumique (3D) en opposition aux 2D classiques . 

ce faisant ,on se retrouve en configuration in vivo-like  ,ce qui permet de mieux apprécier ce micro environnement , mieux quantifier les recepteurs circulants ,mais aussi préciser la topographie des NKs (quantifier le degré d' infiltration intra tumorale ...)

un nouvel outil qui n'a pas du échapper à Innate .


L'étude est effectuée  à travers la logique NKG2D -MICA-sMICA , ce pourquoi je la présente  dans cette file , preuve, une fois de plus , que cette cible est trés importante . 

(mème approche pour d'autres récepteurs , en particulier NKp30- B7H6 )



publié le 3 mai 2015


http://www.biomedcentral.com/1471-2407/15/351

AbstractBackground

The complex cellular networks within tumors, the cytokine milieu, and tumor immune escape mechanisms affecting infiltration and anti-tumor activity of immune cells are of great interest to understand tumor formation and to decipher novel access points for cancer therapy. However, cellular in vitro assays, which rely on monolayer cultures of mammalian cell lines, neglect the three-dimensional architecture of a tumor, thus limiting their validity for the in vivo situation.

Methods

Three-dimensional in vivo-like tumor spheroid were established from human cervical carcinoma cell lines as proof of concept to investigate infiltration and cytotoxicity of NK cells in a 96-well plate format, which is applicable for high-throughput screening. Tumor spheroids were monitored for NK cell infiltration and cytotoxicity by flow cytometry. Infiltrated NK cells, could be recovered by magnetic cell separation.

Results

The tumor spheroids were stable over several days with minor alterations in phenotypic appearance. The tumor spheroids expressed high levels of cellular ligands for the natural killer (NK) group 2D receptor (NKG2D), mediating spheroid destruction by primary human NK cells. Interestingly, destruction of a three-dimensional tumor spheroid took much longer when compared to the parental monolayer cultures. Moreover, destruction of tumor spheroids was accompanied by infiltration of a fraction of NK cells, which could be recovered at high purity.

Conclusion

Tumor spheroids represent a versatile in vivo-like model system to study cytotoxicity and infiltration of immune cells in high-throughput screening. This system might proof useful for the investigation of the modulatory potential of soluble factors and cells of the tumor microenvironment on immune cell activity as well as profiling of patient-/donor-derived immune cells to personalize cellular immunotherapy.

Keywords: NK cell; tumor immune escape; tumor infiltration; tumor spheroid; 3D culture; innate immune system; NKG2D; ligand shedding



²²²²²²²²²EXTRAITS , à lire ²²²²²²²²²²     mdr


Taken together, tumor spheroids are a more appropriate model system for in vivo tumors than conventional monolayer cultures and allow for stable, reproducible, long-term co-culture with NK cells and also with other immune cells. The presented methods offer the possibility to use the tumor spheroid model system in different ways. Single tumor spheroids can be used i) to monitor tumor growth, ii) to investigate immunosurveillance and associated immune escape by soluble mediators, iii) to investigate tumor spheroid infiltration and spheroid destruction, and iv) to analyze cellular interaction networks by fluorescence microscopy and flow cytometry. Most importantly, infiltrated NK cell subpopulations can be quantified and characterized after isolation. In addition, spheroids can be sectioned and stained for NK cell infiltration as well as for apoptosis by immunohistochemistry. The tumor spheroid model system and the described methods can be adapted to many cell lines of different solid cancer entities of epithelial origin (a comprehensive list of suitable cell lines can be found at [38],[66]) as well as to different cytotoxic lymphocyte populations. Furthermore, stromal cells and other cell types that might affect the tumor micromilieu can be included to introduce further complexity of the tumor microenvironment.
Therefore, tumor spheroids represent a versatile in vivo-like model system to study cytotoxicity and infiltration of immune cells and might proof useful for the investigation of the modulatory potential of soluble factors and cells of the tumor microenvironment on immune cell activity as well as profiling of patient-/donor-derived immune cells to personalize cellular immunotherapy.

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artfact Gold
artfact Mai 9 '15

QUE nous dit Innate  depuis 18 mois ???   RIEN  !!!!  aprés un abstract au printemps 2014!!

..... 


RA 2014 édité il y aun mois ou deux 

: IPH43 vers la sélection d’un candidat médicament  ...... Les équipes travaillent actuellement à choisir le meilleur anticorps parmi tous ceux générés pour passer ensuite en préclinique réglementaire.Inchangé depuis novembre 2013 ( délai de 16-18 mois annoncé initialement)
quelques phrases d'Hervé Brailly : "dans l'année " , et passage en préclinique réglementaire  en "fin d'année "
une petite nouveauté dans ce rapport d'activité  2014 :
 "En plus de détruire les cellules tumorales, IPH43 pourrait avoir un rôle immuno-modulateur en supprimant d’autres catégories de cellules qui inhibent la réaction immunitaire."
ici , ama , on sse réfère à #14  

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artfact Gold
artfact Juin 25 '15
 Nouvelle publication sur S MICA  !!


Non-blocking monoclonal antibody targeting soluble MIC revamps endogenous innate and adaptive anti-tumor responses and eliminates primary and metastatic tumors
version google trad revisitée  !!!

 .Un  anticorps monoclonal non bloquant  ciblant MIC soluble  refond les réponses anti-tumorales innée et adaptative endogènes et élimine les tumeurs primaires et métastatiques  Le sMIC (Mica circulant) dérivé  d'une tumeur humaine   est hautement immuno suppresseur  chez les patients atteints de cancer et est en corrélation avec un mauvais pronostic. Cependant, l'effet thérapeutique du ciblage sMIC n'a pas été déterminé , en raison de la limitation que les souris n  expriment pas d'homologues de MIC humain . Cette étude est d'évaluer l'effet thérapeutique d'un anticorps monoclonal ciblant SMIC dans un modèle animal transgénique cliniquement pertinent . Conception expérimentale: Nous avons traité le / souris bi-transgéniques exprimant conçu MIC TRAMP "humanisé" MIC à des stades avancés de la maladie avec un non-bloquant anticorps monoclonal anti-MIC (mAb) sMIC-neutralisation et évalué l'efficacité thérapeutique et mécanismes associés. 
Résultats: Un sMIC neutralisant non-bloquant anti-MIC MAB induit efficacement  la régression des tumeurs primaires et élimine les métastases  sans induire de toxicité systémique.
 L'effet thérapeutique est conféré par la refonte des réponses immunitaires anti-tumorales endogènes, illustrés par la restauration NK homéostasie et la fonction des cellules, l'amélioration de la sensibilité des cellules tumorales MIC + l'action tueuse des cellules NK, de relancer et maintenir les réponses    antigèniques spécifiques des CD8 Tcells  , en augmentant les réponses TH1 des  CD4 Tcells, l'amorçage des cellules dendritiques   pour présentation de l'antigène, et le remodelage du microenvironnement de la tumeur d'être plus immuno-réactif. 
Conclusions: la thérapie avec un sMIC neutralisant non-bloquant anti-MIC mAb peut effectuer une  réponse  immunitaire  anti-tumorale  contre les tumeurs avancées MIC+. Notre étude fournit  un rationnel  solide pour traduire SMIC neutralisant mAb thérapeutique en cliniques, seul  ou en combinaison avec des immunothérapies standard actuelles  .

 http://clincancerres.aacrjournals.org/...CCR-15-0845.abstract

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artfact Gold
artfact Mars 15 '16
petit passage sur cette file . 


On a donc un abstract à l'AACR 2016


 - Abstract n° 1491 : IPH4301, an antibody targeting MICA and MICB exhibits potent cytotoxic activity and immunomodulatory properties for the treatment of cancer 

Jennifer WU (Charleston) est co auteur de l'abstract  . Elle apparait dans cette file dés décembre 2014  (on s'y réfère trois fois #12  #13  #14   ... c'était le bon  "cheval"  ;-)




Pour  fan de Jennifer :


Immunoediting Accelerates Prostate Cancer Metastasis: Mechanisms and Perspective New Therapy

 

 Jennifer Wu, PhD and James Norris, PhD

Affiliations: Medical University of South Carolina and Hollings Cancer Center, Charleston, SC 29425

Background. Expression of the MHC I-chain related molecules A and B (MICA/B) on human epithelial cell surface in response to transformation or DNA damage can signal the immune system of the abnormality and thus initiate active immune surveillance by Natural Killer (NK) cells and cytotoxicity T cells [1]. Paradoxically, in prostate carcinoma, MIC was also abundantly expressed and yet disease progressed, indicating a compromise in tumor immune surveillance. We have found that circulating soluble MIC (sMIC) as a result of tumor shedding can sabotage host immunity by eliminating NK cell immunity and producing immune suppressive tumor microenvironment. In prostate cancer patients, elevated serum levels of sMIC not only correlated with disease stages of primary tumors but also correlated with metastatic diseases [2, 3]. Concomitantly, NK cell function was severely impaired in men with high grade of prostate cancer and diminished in men with metastatic diseases [2, 3]. These studies suggest that sMIC is a potential therapeutic target for metastatic prostate cancer. Methods and Results. To address the therapeutic potential of targeting sMIC for treating metastatic prostate cancer, we generated “humanized” transgenic animal model expressing native forms of human MIC in the prostate of spontaneous mouse carcinoma. With this model, we recapitulated the biology of sMIC-mediated tumor immunoediting in prostate cancer patients [3]. Very excitingly, an antibody neutralizing serum sMIC in the “humanized” mouse model induced significant regression of established primary prostate tumors and prevented metastasis. Conclusion. Our findings suggest that an antibody neutralizing sMIC can be an effective treatment for metastatic prostate cancer. We are currently testing whether a therapy of combing sMIC neutralizing antibody with co-targeting cancer cell lipid metabolism to sensitize tumor cell to apoptotic signals can achieve long-lasting curative effect for metastatic prostate cancer [4]. Funding Sources. Supported by DOD-USMRC IDEA Development Award W81XWH-06-1-0014, NCI Temin Award 1K01CA116002, NCI 2R01CA149405, NCI 5P01CA097132, and A. David Mazzone — PCF Challenge Award.

 

 Conflict of interest disclosure.

 J. Wu holds patents of targeting sMIC; J.

Norris holds patents of targeting cancer cell lipid metabolism. Wu and Norris co-hold a pending patent of combined treatment.

 J. Wu is the President and owner of CanCure LLC.

 J. Norris is the President and holds share of Sphingogene LLC.

 

 

 

 

Antibody targeting soluble NKG2D ligand sMIC refuels and invigorates the endogenous immune system to fight cancer

Human tumor-derived soluble NKG2D sMIC paralyzes the immune system through multiple pathways. Targeting soluble MIC with a non-blocking neutralizing anti-MIC antibody effectuated and revamped endogenous innate and adoptive anti-tumor responses. Therapy induced regression of primary tumors and eliminated metastasis in pre-clinical models.

http:///...4?journalCode=koni20

Nov
2015
NONBLOCKING MONOCLONAL ANTIBODY TARGETING SOLUBLE MIC REVAMPS ENDOGENOUS INNATE AND ADAPTIVE ANTITUMOR RESPONSES AND ELIMINATES PRIMARY AND METASTATIC TUMORS.

Clin Cancer Res 2015 Nov 23;21(21):4819-30. Epub 2015 Jun 23.
Shengjun Lu, Jinyu Zhang, Dai Liu, Guangfu Li, , Zihai Li, Jennifer D Wu

The human tumor-derived soluble MHC I-chain-related molecule (sMIC) is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. This study is to evaluate the therapeutic effect of a monoclonal antibody (mAb) targeting sMIC in a clinically relevant transgenic animal model.

    

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631684

 http://dx.doi.org/10.1158/1078-0432.CCR-15-0845


Apr
2015
SOLUBLE NKG2D LIGAND PROMOTES MDSC EXPANSION AND SKEWS MACROPHAGE TO THE ALTERNATIVELY ACTIVATED PHENOTYPE.

J Hematol Oncol 2015 20;8:13. Epub 2015 Feb 20.
Gang Xiao, Xuanjun Wang, Jun Sheng, Shengjun Lu, Xuezhong Yu, Jennifer D Wu

Expression of surface NKG2D ligand MIC on tumor cells is deemed to stimulate NK and co-stimulate CD8 T cell anti-tumor immunity. Human cancer cells however frequently adopt a proteinase-mediated shedding strategy to generate soluble MIC (sMIC) to circumvent host immunity. High levels of sMIC have been shown to correlate with advanced disease stages in cancer patients.

    

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342005

 

http://dx.doi.org/10.1186/s13045-015-0110-z

 

Mar
2015
NKG2D LIGANDS IN TUMOR IMMUNITY: TWO SIDES OF A COIN.

Front Immunol 2015 4;6:97. Epub 2015 Mar 4.
Jinyu Zhang, Fahmin Basher, Jennifer D Wu

The activating/co-stimulatory receptor NKG2D (natural-killer group 2, member D) is expressed on the surface of all human NK, NKT, CD8(+) T, and subsets of γδ(+) T cells. The significance of NKG2D function in tumor immunity has been well demonstrated in experimental animal models. However, the role of human NKG2D ligands in regulating tumor immunity and cancer prognosis had been controversial in the literature.

    

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349182

 http://dx.doi.org/10.3389/fimmu.2015.00097

  

Nov
2014
PROLIFERATION AND ENRICHMENT OF CD133(+) GLIOBLASTOMA CANCER STEM CELLS ON 3D CHITOSAN-ALGINATE SCAFFOLDS.

Biomaterials 2014 Nov 7;35(33):9137-43. Epub 2014 Aug 7.
Forrest M Kievit, Stephen J Florczyk, Matthew C Leung, Kui Wang, Jennifer D Wu, John R Silber,Richard G Ellenbogen, Jerry S H Lee, Miqin Zhang

Emerging evidence implicates cancer stem cells (CSCs) as primary determinants of the clinical behavior of human cancers, representing an ideal target for next-generation anti-cancer therapies. However CSCs are difficult to propagate in vitro, severely limiting the study of CSC biology and drug development. Here we report that growing cells from glioblastoma (GBM) cell lines on three dimensional (3D) porous chitosan-alginate (CA) scaffolds dramatically promotes the proliferation and enrichment of cells possessing the hallmarks of CSCs.

    

 

Ce message du forum a été modifié par artfact Mars 15 '16
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artfact Gold
artfact Juillet 20 '16
Sur le thème :

Beyond immune checkpoint: Targeting soluble NKG2D ligands for cancer immunotherapy,

deux conf  de J WU  avenir:


28 - 30 juillet  Melbourne

http://cancerimmunology.conferenceseries.com/abstract/2016/beyond-immune-checkpoint-targeting-soluble-nkg2d-ligands-for-cancer-immunotherapy


21 - 23 oct  Baltimore 

https://unitedscientificgroup.com/conferences/crt-2016/pdfs/CRT-2016-Program.pdf

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Francis
Francis Novembre 1 '18
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