Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study

BackgroundInterleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells.MethodsIL13 was modified on the...

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Autores principales:	Kiwan Kim, Ho-Shin Gwak, Nayoung Han, Eun Kyung Hong, Beom K. Choi, Sangeun Lee, Soyoung Choi, Ju-Hwang Park, Ji-Hye Seok, Yeongha Jeon, Hyuntae Cho, Song-Jae Lee, Yura Lee, Ki Taek Nam, Seong-Won Song
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	chimeric antigen receptor T cell immunohistochemistry interleukin-13 malignant glioma immunotherapy Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/dc3012fd96854bd3994a62b55e0a09fb
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spelling	oai:doaj.org-article:dc3012fd96854bd3994a62b55e0a09fb2021-11-08T06:01:34ZChimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study1664-322410.3389/fimmu.2021.715000https://doaj.org/article/dc3012fd96854bd3994a62b55e0a09fb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.715000/fullhttps://doaj.org/toc/1664-3224BackgroundInterleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells.MethodsIL13 was modified on the extracellular domain by substitution of amino acids with E13K, R66D, S69D, and R109K and stably transfected into human T cells using a retroviral vector. The in vitro efficacy of YYB-103 CAR T cells was tested in cell lines with differing IL13Rα1 and IL13Rα2 expression. The in vivo efficacy of intracerebroventricular (i.c.v.) and intravenous (i.v.) routes of YYB-103 CAR T-cell administration were tested in orthotopic MG mouse models. Immunohistochemical staining of MG was performed using WHO grade 3/4 surgical specimens from 53 patients. IL13Rα2 expression was quantified by H-score calculated from staining intensity and percentage of positive cells.ResultsBinding affinity assay of YYB-103 verified apparently nil binding to IL13Rα1, which was more selective than previously reported IL13 modification (E13Y). YYB-103 CAR T cells showed selective toxicity toward co-cultured U87MG (IL13Rα1+/IL13Rα2+) cells but not A431 (IL13Rα1+/IL13Rα2−) cells. Consistently, YYB-103 CAR T cells suppressed tumor growth in nude mice receiving orthotopic injection of U87 MG cells. Both i.c.v. and i.v. injections of YYB-103 CAR T cells reduced tumor volume and prolonged overall survival of tumor-bearing mice. The median H-score for IL13Rα2 in patient-derived MG tissue was 5 (mean, 57.5; SD, 87.2; range, 0 to 300).ConclusionThis preclinical study demonstrates the efficacy of IL13Rα2-targeted YYB-103 CAR T cells against MG cells. The use of modified IL13 to construct a CAR facilitated the selective targeting of IL13Rα2-expressing MG cells while sparing IL13Rα1-expressing cells. Notably, YYB-103 CAR T cells exhibited effective blood–brain barrier crossing, suggesting compatibility with i.v. administration rather than intracranial injection. Additionally, the high H-score for IL13Rα2 in glioblastoma, especially in conjunction with the poor prognostic markers of wild-type isocitrate dehydrogenase-1 (IDH-1) and unmethylated O6-methyl guanine methyl-transferase (MGMT), could be used to determine the eligibility of patients with recurrent glioblastoma for a future clinical trial of YYB-103 CAR T cells.Kiwan KimHo-Shin GwakNayoung HanEun Kyung HongBeom K. ChoiSangeun LeeSoyoung ChoiJu-Hwang ParkJi-Hye SeokYeongha JeonHyuntae ChoSong-Jae LeeYura LeeKi Taek NamSeong-Won SongFrontiers Media S.A.articlechimeric antigen receptor T cellimmunohistochemistryinterleukin-13malignant gliomaimmunotherapyImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chimeric antigen receptor T cell immunohistochemistry interleukin-13 malignant glioma immunotherapy Immunologic diseases. Allergy RC581-607
spellingShingle	chimeric antigen receptor T cell immunohistochemistry interleukin-13 malignant glioma immunotherapy Immunologic diseases. Allergy RC581-607 Kiwan Kim Ho-Shin Gwak Nayoung Han Eun Kyung Hong Beom K. Choi Sangeun Lee Soyoung Choi Ju-Hwang Park Ji-Hye Seok Yeongha Jeon Hyuntae Cho Song-Jae Lee Yura Lee Ki Taek Nam Seong-Won Song Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study
description	BackgroundInterleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells.MethodsIL13 was modified on the extracellular domain by substitution of amino acids with E13K, R66D, S69D, and R109K and stably transfected into human T cells using a retroviral vector. The in vitro efficacy of YYB-103 CAR T cells was tested in cell lines with differing IL13Rα1 and IL13Rα2 expression. The in vivo efficacy of intracerebroventricular (i.c.v.) and intravenous (i.v.) routes of YYB-103 CAR T-cell administration were tested in orthotopic MG mouse models. Immunohistochemical staining of MG was performed using WHO grade 3/4 surgical specimens from 53 patients. IL13Rα2 expression was quantified by H-score calculated from staining intensity and percentage of positive cells.ResultsBinding affinity assay of YYB-103 verified apparently nil binding to IL13Rα1, which was more selective than previously reported IL13 modification (E13Y). YYB-103 CAR T cells showed selective toxicity toward co-cultured U87MG (IL13Rα1+/IL13Rα2+) cells but not A431 (IL13Rα1+/IL13Rα2−) cells. Consistently, YYB-103 CAR T cells suppressed tumor growth in nude mice receiving orthotopic injection of U87 MG cells. Both i.c.v. and i.v. injections of YYB-103 CAR T cells reduced tumor volume and prolonged overall survival of tumor-bearing mice. The median H-score for IL13Rα2 in patient-derived MG tissue was 5 (mean, 57.5; SD, 87.2; range, 0 to 300).ConclusionThis preclinical study demonstrates the efficacy of IL13Rα2-targeted YYB-103 CAR T cells against MG cells. The use of modified IL13 to construct a CAR facilitated the selective targeting of IL13Rα2-expressing MG cells while sparing IL13Rα1-expressing cells. Notably, YYB-103 CAR T cells exhibited effective blood–brain barrier crossing, suggesting compatibility with i.v. administration rather than intracranial injection. Additionally, the high H-score for IL13Rα2 in glioblastoma, especially in conjunction with the poor prognostic markers of wild-type isocitrate dehydrogenase-1 (IDH-1) and unmethylated O6-methyl guanine methyl-transferase (MGMT), could be used to determine the eligibility of patients with recurrent glioblastoma for a future clinical trial of YYB-103 CAR T cells.
format	article
author	Kiwan Kim Ho-Shin Gwak Nayoung Han Eun Kyung Hong Beom K. Choi Sangeun Lee Soyoung Choi Ju-Hwang Park Ji-Hye Seok Yeongha Jeon Hyuntae Cho Song-Jae Lee Yura Lee Ki Taek Nam Seong-Won Song
author_facet	Kiwan Kim Ho-Shin Gwak Nayoung Han Eun Kyung Hong Beom K. Choi Sangeun Lee Soyoung Choi Ju-Hwang Park Ji-Hye Seok Yeongha Jeon Hyuntae Cho Song-Jae Lee Yura Lee Ki Taek Nam Seong-Won Song
author_sort	Kiwan Kim
title	Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study
title_short	Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study
title_full	Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study
title_fullStr	Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study
title_full_unstemmed	Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study
title_sort	chimeric antigen receptor t cells with modified interleukin-13 preferentially recognize il13rα2 and suppress malignant glioma: a preclinical study
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/dc3012fd96854bd3994a62b55e0a09fb
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Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study

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