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ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA

BACKGROUND AND SIGNIFICANCE: Neuroblastoma is a rare pediatric cancer that forms in immature nerve tissue of infants and accounts for 10 to 15 percent of cancer-related deaths in children. The five-year survival for high-risk neuroblastoma is 50% with current treatment practices being a combination...

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Autores principales: Quan, Alex, Li, Nan, Li, Dan, Spetz, Madeline, Zhang, Hongbing, Liu, Cheng, Ho, Mitchell
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370431/
http://dx.doi.org/10.1093/abt/tbad014.023
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author Quan, Alex
Li, Nan
Li, Dan
Spetz, Madeline
Zhang, Hongbing
Liu, Cheng
Ho, Mitchell
author_facet Quan, Alex
Li, Nan
Li, Dan
Spetz, Madeline
Zhang, Hongbing
Liu, Cheng
Ho, Mitchell
author_sort Quan, Alex
collection PubMed
description BACKGROUND AND SIGNIFICANCE: Neuroblastoma is a rare pediatric cancer that forms in immature nerve tissue of infants and accounts for 10 to 15 percent of cancer-related deaths in children. The five-year survival for high-risk neuroblastoma is 50% with current treatment practices being a combination of surgery, chemotherapy, and radiation. A more effective therapy is therefore needed to improve overall patient outcomes. METHODS: The CT3 mouse antibody that targets GPC2 was previously identified in the lab and has shown activity in the chimeric antigen receptor (CAR) T cell format against neuroblastoma. Humanization of the CT3 antibody was also done through CDR grafting in human germline sequences to prevent potential adverse immunogenic effects when treating patients. In the present study, the CT3 antibody and humanized CT3 (hCT3) antibody were engineered into T cells based on the engineered gamma/delta TCR scaffold (called AbTCR). The activities of the CT3 and hCT3 AbTCRs were tested in luciferase-based cell killing assays and xenograft mouse models. RESULTS: Humanized CT3 retains a comparable binding affinity for GPC2. The hCT3 CAR T cell showed its ability to regress tumor expression in mice. Furthermore, the mice treated with the CT3 AbTCR showed tumor regression while the mice treated with the hCT3 AbTCR became tumor free three weeks after treatment. CONCLUSIONS: Overall, the hCT3 AbTCR T cells are very active when combating neuroblastoma tumors in mice. The efficacy at a low treatment dosage indicates that the GPC2 targeted hCT3 AbTCRs are a promising therapeutic for the treatment of neuroblastoma and other GPC2 positive cancers in patients.
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spelling pubmed-103704312023-07-27 ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA Quan, Alex Li, Nan Li, Dan Spetz, Madeline Zhang, Hongbing Liu, Cheng Ho, Mitchell Antib Ther Abstract BACKGROUND AND SIGNIFICANCE: Neuroblastoma is a rare pediatric cancer that forms in immature nerve tissue of infants and accounts for 10 to 15 percent of cancer-related deaths in children. The five-year survival for high-risk neuroblastoma is 50% with current treatment practices being a combination of surgery, chemotherapy, and radiation. A more effective therapy is therefore needed to improve overall patient outcomes. METHODS: The CT3 mouse antibody that targets GPC2 was previously identified in the lab and has shown activity in the chimeric antigen receptor (CAR) T cell format against neuroblastoma. Humanization of the CT3 antibody was also done through CDR grafting in human germline sequences to prevent potential adverse immunogenic effects when treating patients. In the present study, the CT3 antibody and humanized CT3 (hCT3) antibody were engineered into T cells based on the engineered gamma/delta TCR scaffold (called AbTCR). The activities of the CT3 and hCT3 AbTCRs were tested in luciferase-based cell killing assays and xenograft mouse models. RESULTS: Humanized CT3 retains a comparable binding affinity for GPC2. The hCT3 CAR T cell showed its ability to regress tumor expression in mice. Furthermore, the mice treated with the CT3 AbTCR showed tumor regression while the mice treated with the hCT3 AbTCR became tumor free three weeks after treatment. CONCLUSIONS: Overall, the hCT3 AbTCR T cells are very active when combating neuroblastoma tumors in mice. The efficacy at a low treatment dosage indicates that the GPC2 targeted hCT3 AbTCRs are a promising therapeutic for the treatment of neuroblastoma and other GPC2 positive cancers in patients. Oxford University Press 2023-07-24 /pmc/articles/PMC10370431/ http://dx.doi.org/10.1093/abt/tbad014.023 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For Permissions, please email: journals.permissions@oup.com https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstract
Quan, Alex
Li, Nan
Li, Dan
Spetz, Madeline
Zhang, Hongbing
Liu, Cheng
Ho, Mitchell
ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA
title ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA
title_full ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA
title_fullStr ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA
title_full_unstemmed ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA
title_short ENGINEERING T CELLS TARGETING GPC2 FOR TREATING NEUROBLASTOMA
title_sort engineering t cells targeting gpc2 for treating neuroblastoma
topic Abstract
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370431/
http://dx.doi.org/10.1093/abt/tbad014.023
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