ROLE OF TCR AFFINITY

Study and modification of T-cell receptor structure to enhance anti-tumor activity

 Coordinatore BAR ILAN UNIVERSITY 

 Organization address address: BAR ILAN UNIVERSITY CAMPUS
city: RAMAT GAN
postcode: 52900

contact info
Titolo: Ms.
Nome: Estelle
Cognome: Waise
Email: send email
Telefono: 97235317439
Fax: 97236353277

 Nazionalità Coordinatore Israel [IL]
 Totale costo 100˙000 €
 EC contributo 100˙000 €
 Programma FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
 Code Call FP7-PEOPLE-2007-4-3-IRG
 Funding Scheme MC-IRG
 Anno di inizio 2008
 Periodo (anno-mese-giorno) 2008-10-01   -   2012-09-30

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    BAR ILAN UNIVERSITY

 Organization address address: BAR ILAN UNIVERSITY CAMPUS
city: RAMAT GAN
postcode: 52900

contact info
Titolo: Ms.
Nome: Estelle
Cognome: Waise
Email: send email
Telefono: 97235317439
Fax: 97236353277

IL (RAMAT GAN) coordinator 0.00

Mappa

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transduced    affinity    cells    transfer    reactive    mounting    cancer    model    isolate    mutant    shown    lymphocyte    ability    patients    tcr    affinities    melanoma    cytotoxic    tumor    function    anti    optimal    tcrs    regression    cell    lymphocytes    treatment    receptor    context    immune    influence   

 Obiettivo del progetto (Objective)

'Adoptive cell transfer of tumor-reactive lymphocytes has been shown to mediate the regression of large solid tumors in cancer patients. To overcome the need to isolate and expand tumor-reactive lymphocytes that pre-exist in the patient, it is possible to engineer cells to express a tumor-specific T-cell receptor - TCR, thus reprogramming their specificity. This pioneering therapeutic approach has been demonstrated to cause cancer regression in terminal melanoma patients that were refractory to previous treatments. However, little is known about TCR affinity requirements for mounting an optimal immune response in this context. While high affinity TCR may confer to the host lymphocyte excellent cytotoxic ability, several studies have shown that a too-high affinity may actually be detrimental to T-cell function. We therefore hypothesize that T-cell receptor affinity can influence the cytotoxic activity of lymphocytes in TCR-transfer treatment and that it is possible to define an optimal range or threshold of TCR affinity for mounting an efficient anti-tumor response. To test this, we propose to use the ovalbumine specific OT1 TCR model and to construct a CDR3-modified TCR library that will be retrovirally transduced into a reporter cell line. By combining the efficacy of a high-throughput screening method and the direct selection of mutant TCR ex-vivo, we are planning to isolate several TCRs with different affinities. These molecules will be transduced and expressed in primary lymphocytes to assess their biological function in-vitro. Using the B16-OVA melanoma model, we will adoptively transfer lymphocyte populations expressing mutant TCRs with different affinities and compare their activity in order to study the influence of TCR affinity on anti-tumor cytotoxic response. Thus, we expect to answer both fundamental and translational questions related to the ability of the immune system to recognize and eliminate tumor cells in the context of TCR-transfer treatment.'

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