Q3155054 (Q3155054): Difference between revisions
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(Created claim: summary (P836): The success of ACT-TILs in the treatment of advanced melanoma encourages the extension of this therapy to other neoplastic diseases that are difficult to cure. But, unlike melanoma, TILs extracted from other tumors are poorly expanded and have little antitumor reactivity. Our goal is to improve the antitumor efficacy of ACT-TIL by: (1) the selection of tumor-specific TILs repertoire with greater therapeutic efficacy; and (2) the rejuvenation of...) |
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The success of ACT-TILs in the treatment of advanced melanoma encourages the extension of this therapy to other neoplastic diseases that are difficult to cure. But, unlike melanoma, TILs extracted from other tumors are poorly expanded and have little antitumor reactivity. Our goal is to improve the antitumor efficacy of ACT-TIL by: (1) the selection of tumor-specific TILs repertoire with greater therapeutic efficacy; and (2) the rejuvenation of the TILs. For Objective 1, we propose to select populations of TILs by the expression of subrogated biomarkers of antitumoral specifics (Mi) and markers of T lymphocytes (LT) young memory (Mii). Like Mi, we will study different costimulus molecules (OX40/ICOS/CD137/GITR...) and inhibition molecules (PD1/CTLA4/LAG3/TIM3...), expressed by LTs recently activated or with antigenic experience. As Mii we will analyse distinctive surface markers of LT mother memory (TSCM) and central memory (TCM), since these populations are the least differentiated and have the greatest capacity for persistence and antitumor efficacy. The selected LTs will be expanded and characterised in vitro and their therapeutic efficacy will be checked by ACT. Gene expression of isolated populations will also be analysed in order to understand their genetic program and identify potentially adjustable targets. For Objective 2, with the help of retroviruses, we will genetically modify TILs to overexpress transcription factors characteristic of TSCM/TCM, and we will study their rejuvenating effect by analysing the acquisition of pro-TSCM/TCM factors, the ability to proliferate and their therapeutic efficacy by ACT. In order to put our study into a translational perspective, we will work with preclinical models of ovarian and metastatic colon cancer, and with human TILs of these pathologies. (English) | |||||||||||||||
| Property / summary: The success of ACT-TILs in the treatment of advanced melanoma encourages the extension of this therapy to other neoplastic diseases that are difficult to cure. But, unlike melanoma, TILs extracted from other tumors are poorly expanded and have little antitumor reactivity. Our goal is to improve the antitumor efficacy of ACT-TIL by: (1) the selection of tumor-specific TILs repertoire with greater therapeutic efficacy; and (2) the rejuvenation of the TILs. For Objective 1, we propose to select populations of TILs by the expression of subrogated biomarkers of antitumoral specifics (Mi) and markers of T lymphocytes (LT) young memory (Mii). Like Mi, we will study different costimulus molecules (OX40/ICOS/CD137/GITR...) and inhibition molecules (PD1/CTLA4/LAG3/TIM3...), expressed by LTs recently activated or with antigenic experience. As Mii we will analyse distinctive surface markers of LT mother memory (TSCM) and central memory (TCM), since these populations are the least differentiated and have the greatest capacity for persistence and antitumor efficacy. The selected LTs will be expanded and characterised in vitro and their therapeutic efficacy will be checked by ACT. Gene expression of isolated populations will also be analysed in order to understand their genetic program and identify potentially adjustable targets. For Objective 2, with the help of retroviruses, we will genetically modify TILs to overexpress transcription factors characteristic of TSCM/TCM, and we will study their rejuvenating effect by analysing the acquisition of pro-TSCM/TCM factors, the ability to proliferate and their therapeutic efficacy by ACT. In order to put our study into a translational perspective, we will work with preclinical models of ovarian and metastatic colon cancer, and with human TILs of these pathologies. (English) / rank | |||||||||||||||
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| Property / summary: The success of ACT-TILs in the treatment of advanced melanoma encourages the extension of this therapy to other neoplastic diseases that are difficult to cure. But, unlike melanoma, TILs extracted from other tumors are poorly expanded and have little antitumor reactivity. Our goal is to improve the antitumor efficacy of ACT-TIL by: (1) the selection of tumor-specific TILs repertoire with greater therapeutic efficacy; and (2) the rejuvenation of the TILs. For Objective 1, we propose to select populations of TILs by the expression of subrogated biomarkers of antitumoral specifics (Mi) and markers of T lymphocytes (LT) young memory (Mii). Like Mi, we will study different costimulus molecules (OX40/ICOS/CD137/GITR...) and inhibition molecules (PD1/CTLA4/LAG3/TIM3...), expressed by LTs recently activated or with antigenic experience. As Mii we will analyse distinctive surface markers of LT mother memory (TSCM) and central memory (TCM), since these populations are the least differentiated and have the greatest capacity for persistence and antitumor efficacy. The selected LTs will be expanded and characterised in vitro and their therapeutic efficacy will be checked by ACT. Gene expression of isolated populations will also be analysed in order to understand their genetic program and identify potentially adjustable targets. For Objective 2, with the help of retroviruses, we will genetically modify TILs to overexpress transcription factors characteristic of TSCM/TCM, and we will study their rejuvenating effect by analysing the acquisition of pro-TSCM/TCM factors, the ability to proliferate and their therapeutic efficacy by ACT. In order to put our study into a translational perspective, we will work with preclinical models of ovarian and metastatic colon cancer, and with human TILs of these pathologies. (English) / qualifier | |||||||||||||||
point in time: 12 October 2021
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Revision as of 15:07, 12 October 2021
Project Q3155054 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | No label defined |
Project Q3155054 in Spain |
Statements
38,250.0 Euro
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76,500.0 Euro
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50.0 percent
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1 January 2016
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31 March 2020
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FUNDACION INSTITUTO DE INVESTIGACION SANITARIA DE NAVARRA
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42°49'6.42"N, 1°38'39.34"W
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31201
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El éxito de la ACT-TILs en el tratamiento del melanoma avanzado anima a extender esta terapia a otras enfermedades neoplásicas de difícil curación. Pero, a diferencia de lo que ocurre en melanoma, los TILs extraídos de otros tumores se expanden mal y tienen poca reactividad antitumoral. Nuestro objetivo es mejorar la eficacia antitumoral de la ACT-TIL mediante: (1) la selección del repertorio de TILs específicos de tumor con mayor eficacia terapéutica; y (2) el rejuvenecimiento de los TILs. Para el objetivo 1, proponemos seleccionar poblaciones de TILs por la expresión de biomarcadores subrogados de especificad antitumoral (Mi) y marcadores de linfocitos T (LT) memoria joven (Mii). Como Mi, estudiaremos diferentes moléculas de coestímulo (OX40/ICOS/CD137/GITR…) y de inhibición (PD1/CTLA4/LAG3/TIM3…), expresadas por LTs recientemente activados o con experiencia antigénica. Como Mii analizaremos marcadores superficiales distintivos de LT memoria madre (TSCM) y central (TCM), dado que estas poblaciones son las menos diferenciadas y presentan mayor capacidad de persistencia y eficacia antitumoral. Los LTs seleccionados se expandirán y caracterizarán in vitro y se comprobará su eficacia terapéutica por ACT. Se analizará también la expresión génica de las poblaciones aisladas a fin de conocer su programa genético e identificar dianas potencialmente regulables. Para el objetivo 2, con ayuda de retrovirus, modificaremos genéticamente los TILs para sobreexpresar factores de transcripción característicos de TSCM/TCM, y estudiaremos su efecto rejuvenecedor analizando la adquisición de factores pro-TSCM/TCM, la capacidad de proliferar y su eficacia terapéutica por ACT. Con objeto de poner nuestro estudio en perspectiva traslacional, trabajaremos con modelos preclínicos de cáncer de ovario y colon metastásico, y con TILs humanos de estas patologías. (Spanish)
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The success of ACT-TILs in the treatment of advanced melanoma encourages the extension of this therapy to other neoplastic diseases that are difficult to cure. But, unlike melanoma, TILs extracted from other tumors are poorly expanded and have little antitumor reactivity. Our goal is to improve the antitumor efficacy of ACT-TIL by: (1) the selection of tumor-specific TILs repertoire with greater therapeutic efficacy; and (2) the rejuvenation of the TILs. For Objective 1, we propose to select populations of TILs by the expression of subrogated biomarkers of antitumoral specifics (Mi) and markers of T lymphocytes (LT) young memory (Mii). Like Mi, we will study different costimulus molecules (OX40/ICOS/CD137/GITR...) and inhibition molecules (PD1/CTLA4/LAG3/TIM3...), expressed by LTs recently activated or with antigenic experience. As Mii we will analyse distinctive surface markers of LT mother memory (TSCM) and central memory (TCM), since these populations are the least differentiated and have the greatest capacity for persistence and antitumor efficacy. The selected LTs will be expanded and characterised in vitro and their therapeutic efficacy will be checked by ACT. Gene expression of isolated populations will also be analysed in order to understand their genetic program and identify potentially adjustable targets. For Objective 2, with the help of retroviruses, we will genetically modify TILs to overexpress transcription factors characteristic of TSCM/TCM, and we will study their rejuvenating effect by analysing the acquisition of pro-TSCM/TCM factors, the ability to proliferate and their therapeutic efficacy by ACT. In order to put our study into a translational perspective, we will work with preclinical models of ovarian and metastatic colon cancer, and with human TILs of these pathologies. (English)
12 October 2021
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Pamplona/Iruña
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Identifiers
PI15_02027
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