IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS

Chimeric antigen receptor (CAR) T-cell therapy carries the promise of a broadly applicable, targeted, yet molecular pathway-independent, intervention for pediatric central nervous system (CNS) tumors. The BrainChild pipeline at Seattle Children’s utilizes engineered CAR T-cells directed against the...

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Publicado no:Neuro Oncol
Main Authors: Vitanza, Nicholas, Gust, Juliane, Leary, Sarah, Pinto, Navin, Lee, Amy, Hauptman, Jason, Ojemann, Jeff, Elliott, Leslie, Finney, Olivia, Lindgren, Catherine, Hossain, Zahid, Pierce, Robert, Lieberman, Nicole, Crane, Courtney, Johnson, Adam, Gardner, Rebecca, Finn, Laura, Park, Julie, Jensen, Michael
Formato: Artigo
Idioma:Inglês
Publicado em: Oxford University Press 2018
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Abstracts
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC6012094/
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1093/neuonc/noy059.327
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spelling pubmed-60120942019-06-01 IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS Vitanza, Nicholas Gust, Juliane Leary, Sarah Pinto, Navin Lee, Amy Hauptman, Jason Ojemann, Jeff Elliott, Leslie Finney, Olivia Lindgren, Catherine Hossain, Zahid Pierce, Robert Lieberman, Nicole Crane, Courtney Johnson, Adam Gardner, Rebecca Finn, Laura Park, Julie Jensen, Michael Neuro Oncol Abstracts Chimeric antigen receptor (CAR) T-cell therapy carries the promise of a broadly applicable, targeted, yet molecular pathway-independent, intervention for pediatric central nervous system (CNS) tumors. The BrainChild pipeline at Seattle Children’s utilizes engineered CAR T-cells directed against the surface epitopes HER2, EGFR, B7-H3 and IL13Ralpha2, which are commonly expressed in pediatric CNS tumors including high-grade glioma, diffuse intrinsic pontine glioma, medulloblastoma, and ependymoma. Using in vitro and in vivo preclinical modeling, we have optimized the efficacy and specificity of the CAR constructs. The extracellular target-specific scFv domain for the HER2-specific and EGFR-specific CARs are derived from trastuzumab and an EGFR806 antibody, respectively. Third-generation CAR T-cells with medium-length (HER2-CAR) and short (EGFR806-CAR) spacers coupled to an intracellular 4-1BBζ domain result in complete and durable tumor eradication in mouse xenograft CNS tumor models. We now are poised to begin enrolling Phase 1 clinical trials for children and young adults with recurrent or refractory CNS tumors expressing the respective target epitopes. We will deliver locoregional adoptive therapy with autologous CD4 and CD8 T cells lentivirally transduced with the optimized CAR constructs. Using a dose-escalation regimen, CAR T-cells will be injected on a weekly schedule via indwelling catheters into the tumor resection cavity or the ventricular system. The primary objectives are safety and feasibility, along with secondary and exploratory objectives to define the CAR T-cell distribution in the CSF and peripheral circulation, target epitope expression across tumor populations, progression free and overall survival, and biomarkers of anti-tumor CAR T-cell activity. Oxford University Press 2018-06 2018-06-22 /pmc/articles/PMC6012094/ http://dx.doi.org/10.1093/neuonc/noy059.327 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com https://academic.oup.com/journals/pages/about_us/legal/notices This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
institution US NLM
collection PubMed Central
language Inglês
format Artigo
topic Abstracts
spellingShingle Abstracts
Vitanza, Nicholas
Gust, Juliane
Leary, Sarah
Pinto, Navin
Lee, Amy
Hauptman, Jason
Ojemann, Jeff
Elliott, Leslie
Finney, Olivia
Lindgren, Catherine
Hossain, Zahid
Pierce, Robert
Lieberman, Nicole
Crane, Courtney
Johnson, Adam
Gardner, Rebecca
Finn, Laura
Park, Julie
Jensen, Michael
IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS
description Chimeric antigen receptor (CAR) T-cell therapy carries the promise of a broadly applicable, targeted, yet molecular pathway-independent, intervention for pediatric central nervous system (CNS) tumors. The BrainChild pipeline at Seattle Children’s utilizes engineered CAR T-cells directed against the surface epitopes HER2, EGFR, B7-H3 and IL13Ralpha2, which are commonly expressed in pediatric CNS tumors including high-grade glioma, diffuse intrinsic pontine glioma, medulloblastoma, and ependymoma. Using in vitro and in vivo preclinical modeling, we have optimized the efficacy and specificity of the CAR constructs. The extracellular target-specific scFv domain for the HER2-specific and EGFR-specific CARs are derived from trastuzumab and an EGFR806 antibody, respectively. Third-generation CAR T-cells with medium-length (HER2-CAR) and short (EGFR806-CAR) spacers coupled to an intracellular 4-1BBζ domain result in complete and durable tumor eradication in mouse xenograft CNS tumor models. We now are poised to begin enrolling Phase 1 clinical trials for children and young adults with recurrent or refractory CNS tumors expressing the respective target epitopes. We will deliver locoregional adoptive therapy with autologous CD4 and CD8 T cells lentivirally transduced with the optimized CAR constructs. Using a dose-escalation regimen, CAR T-cells will be injected on a weekly schedule via indwelling catheters into the tumor resection cavity or the ventricular system. The primary objectives are safety and feasibility, along with secondary and exploratory objectives to define the CAR T-cell distribution in the CSF and peripheral circulation, target epitope expression across tumor populations, progression free and overall survival, and biomarkers of anti-tumor CAR T-cell activity.
author Vitanza, Nicholas
Gust, Juliane
Leary, Sarah
Pinto, Navin
Lee, Amy
Hauptman, Jason
Ojemann, Jeff
Elliott, Leslie
Finney, Olivia
Lindgren, Catherine
Hossain, Zahid
Pierce, Robert
Lieberman, Nicole
Crane, Courtney
Johnson, Adam
Gardner, Rebecca
Finn, Laura
Park, Julie
Jensen, Michael
author_facet Vitanza, Nicholas
Gust, Juliane
Leary, Sarah
Pinto, Navin
Lee, Amy
Hauptman, Jason
Ojemann, Jeff
Elliott, Leslie
Finney, Olivia
Lindgren, Catherine
Hossain, Zahid
Pierce, Robert
Lieberman, Nicole
Crane, Courtney
Johnson, Adam
Gardner, Rebecca
Finn, Laura
Park, Julie
Jensen, Michael
author_sort Vitanza, Nicholas
title IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS
title_short IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS
title_full IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS
title_fullStr IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS
title_full_unstemmed IMMU-11. BRAINCHILD PIPELINE: LOCOREGIONAL IMMUNOTHERAPY WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS FOR RECURRENT/REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS
title_sort immu-11. brainchild pipeline: locoregional immunotherapy with chimeric antigen receptor (car) t-cells for recurrent/refractory central nervous system tumors
publisher Oxford University Press
container_title Neuro Oncol
publishDate 2018
url https://ncbi.nlm.nih.gov/pmc/articles/PMC6012094/
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1093/neuonc/noy059.327
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