Matches in SemOpenAlex for { <https://semopenalex.org/work/W4282959219> ?p ?o ?g. }
Showing items 1 to 82 of
82
with 100 items per page.
- W4282959219 endingPage "2824" @default.
- W4282959219 startingPage "2824" @default.
- W4282959219 abstract "Abstract CAR T cell therapy has demonstrated clinical efficacy against hematological malignancies. However, prominent barriers including poor T cell effector function, lack of proliferation, and limited CAR T cell persistence have prevented CAR T cell therapies from reaching their full curative potential, especially in solid tumors. Interleukin-2 (IL-2) is a potent stimulator of T cell proliferation, survival, and cytotoxic function, thereby making it an attractive cytokine to support CAR T cell therapy. However, therapeutic use of IL-2 is limited by systemic toxicity due its promiscuous activation of undesired immune cell populations, including non-tumor reactive T cells and NK cells. To facilitate selective ex vivo and in vivo expansion of engineered T cells we have developed a human orthogonal (ortho) ligand/receptor system consisting of a IL-2 mutein (STK-009) that does not significantly stimulate cells expressing wild type IL-2 receptor and a mutated IL-2 Receptor Beta (orthoIL-2Rβ) that responds to STK-009 but not wild type IL-2. This system enables in vivo IL-2 signaling in engineered cells that express the orthoIL-2Rβ while avoiding stimulation of native T cells and NK cells. Previously, we demonstrated the ability of the STK-009/orthoIL-2Rβ receptor pair to selectively enhance the anti-tumor efficacy of orthoIL-2Rβ (hoRb) expressing CD19 CAR T cells (SYNCAR-001) in preclinical lymphoma mouse models. We also demonstrated that STK-009 is selective for the orthoIL-2Rβ expressing cells and therefore in a non-human primate model does not stimulate native T or NK cells. Here, we demonstrate the ability of the STK-009/hoRb system to enhance the anti-tumor activity and persistence of anti-glypican 3 (GPC3) CAR T cells. GPC3 overexpression is associated with various malignancies such as hepatocellular carcinoma (HCC), pediatric sarcomas, and non small cell lung carcinoma (NSCLC). Clinical trials of GPC3 CAR T therapy are ongoing, but early data suggests a need to boost CAR T cell function and persistence to achieve significant clinical responses. We incorporated the hoRb downstream of an anti-GPC3_28z CAR via a T2A cleavage peptide (SYNCAR-002). In vivo, STK-009 administration enhanced the anti-tumor efficacy of SYNCAR-002 in highly aggressive subcutaneous and intraperitoneal HCC models. STK-009 treatment resulted in significant expansion of SYNCAR-002 and drove infiltration of SYNCAR-002 into tumors. STK-009 treatment also induced intratumoral granzyme B+ and IFN-γ+ production by SYNCAR-002 indicating activation of effector T cell function. These findings validate that the orthogonal IL-2 platform has the potential to improve the efficacy and durability of CAR T therapy for solid tumor targets such as GPC3 by selectively expanding CAR-T cells in vivo, driving CAR-T cells into the tumor, and activating CAR-T cells in the tumor microenvironment. Citation Format: Paul-Joseph Aspuria, Marie Semana, Sandro Vivona, Mahalaksmi Ramadass, Navneet Ratti, Romina Riener, Michele Bauer, Mohammed Ali, Deepti Rokkam, Rob A. Kastelein, Patrick J. Lupardus, Martin Oft. Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance anti-GPC3 CAR T cells to drive complete responses in solid epithelial tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2824." @default.
- W4282959219 created "2022-06-17" @default.
- W4282959219 creator A5000219144 @default.
- W4282959219 creator A5001217519 @default.
- W4282959219 creator A5017522049 @default.
- W4282959219 creator A5021268908 @default.
- W4282959219 creator A5021895713 @default.
- W4282959219 creator A5022698692 @default.
- W4282959219 creator A5039559852 @default.
- W4282959219 creator A5051487266 @default.
- W4282959219 creator A5055737349 @default.
- W4282959219 creator A5055885214 @default.
- W4282959219 creator A5068464930 @default.
- W4282959219 creator A5081672596 @default.
- W4282959219 date "2022-06-15" @default.
- W4282959219 modified "2023-09-26" @default.
- W4282959219 title "Abstract 2824: Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance anti-GPC3 CAR T cells to drive complete responses in solid epithelial tumor models" @default.
- W4282959219 doi "https://doi.org/10.1158/1538-7445.am2022-2824" @default.
- W4282959219 hasPublicationYear "2022" @default.
- W4282959219 type Work @default.
- W4282959219 citedByCount "0" @default.
- W4282959219 crossrefType "journal-article" @default.
- W4282959219 hasAuthorship W4282959219A5000219144 @default.
- W4282959219 hasAuthorship W4282959219A5001217519 @default.
- W4282959219 hasAuthorship W4282959219A5017522049 @default.
- W4282959219 hasAuthorship W4282959219A5021268908 @default.
- W4282959219 hasAuthorship W4282959219A5021895713 @default.
- W4282959219 hasAuthorship W4282959219A5022698692 @default.
- W4282959219 hasAuthorship W4282959219A5039559852 @default.
- W4282959219 hasAuthorship W4282959219A5051487266 @default.
- W4282959219 hasAuthorship W4282959219A5055737349 @default.
- W4282959219 hasAuthorship W4282959219A5055885214 @default.
- W4282959219 hasAuthorship W4282959219A5068464930 @default.
- W4282959219 hasAuthorship W4282959219A5081672596 @default.
- W4282959219 hasConcept C150903083 @default.
- W4282959219 hasConcept C154317977 @default.
- W4282959219 hasConcept C202751555 @default.
- W4282959219 hasConcept C203014093 @default.
- W4282959219 hasConcept C207001950 @default.
- W4282959219 hasConcept C2776090121 @default.
- W4282959219 hasConcept C2776107976 @default.
- W4282959219 hasConcept C2777371288 @default.
- W4282959219 hasConcept C2778690821 @default.
- W4282959219 hasConcept C3875195 @default.
- W4282959219 hasConcept C502942594 @default.
- W4282959219 hasConcept C55493867 @default.
- W4282959219 hasConcept C86803240 @default.
- W4282959219 hasConcept C8891405 @default.
- W4282959219 hasConceptScore W4282959219C150903083 @default.
- W4282959219 hasConceptScore W4282959219C154317977 @default.
- W4282959219 hasConceptScore W4282959219C202751555 @default.
- W4282959219 hasConceptScore W4282959219C203014093 @default.
- W4282959219 hasConceptScore W4282959219C207001950 @default.
- W4282959219 hasConceptScore W4282959219C2776090121 @default.
- W4282959219 hasConceptScore W4282959219C2776107976 @default.
- W4282959219 hasConceptScore W4282959219C2777371288 @default.
- W4282959219 hasConceptScore W4282959219C2778690821 @default.
- W4282959219 hasConceptScore W4282959219C3875195 @default.
- W4282959219 hasConceptScore W4282959219C502942594 @default.
- W4282959219 hasConceptScore W4282959219C55493867 @default.
- W4282959219 hasConceptScore W4282959219C86803240 @default.
- W4282959219 hasConceptScore W4282959219C8891405 @default.
- W4282959219 hasIssue "12_Supplement" @default.
- W4282959219 hasLocation W42829592191 @default.
- W4282959219 hasOpenAccess W4282959219 @default.
- W4282959219 hasPrimaryLocation W42829592191 @default.
- W4282959219 hasRelatedWork W181678093 @default.
- W4282959219 hasRelatedWork W1993985418 @default.
- W4282959219 hasRelatedWork W2005666125 @default.
- W4282959219 hasRelatedWork W2047209980 @default.
- W4282959219 hasRelatedWork W2052769723 @default.
- W4282959219 hasRelatedWork W2095433947 @default.
- W4282959219 hasRelatedWork W3017248443 @default.
- W4282959219 hasRelatedWork W3137476328 @default.
- W4282959219 hasRelatedWork W2185732136 @default.
- W4282959219 hasRelatedWork W2396811992 @default.
- W4282959219 hasVolume "82" @default.
- W4282959219 isParatext "false" @default.
- W4282959219 isRetracted "false" @default.
- W4282959219 workType "article" @default.