Cargando…
IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma
Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single a...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936235/ https://www.ncbi.nlm.nih.gov/pubmed/36817432 http://dx.doi.org/10.3389/fimmu.2023.1085547 |
_version_ | 1784890193298325504 |
---|---|
author | Swan, Sheridan L. Mehta, Nalini Ilich, Ekaterina Shen, Steven H. Wilkinson, Daniel S. Anderson, Alexa R. Segura, Tatiana Sanchez-Perez, Luis Sampson, John H. Bellamkonda, Ravi V. |
author_facet | Swan, Sheridan L. Mehta, Nalini Ilich, Ekaterina Shen, Steven H. Wilkinson, Daniel S. Anderson, Alexa R. Segura, Tatiana Sanchez-Perez, Luis Sampson, John H. Bellamkonda, Ravi V. |
author_sort | Swan, Sheridan L. |
collection | PubMed |
description | Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma. |
format | Online Article Text |
id | pubmed-9936235 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99362352023-02-18 IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma Swan, Sheridan L. Mehta, Nalini Ilich, Ekaterina Shen, Steven H. Wilkinson, Daniel S. Anderson, Alexa R. Segura, Tatiana Sanchez-Perez, Luis Sampson, John H. Bellamkonda, Ravi V. Front Immunol Immunology Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma. Frontiers Media S.A. 2023-02-03 /pmc/articles/PMC9936235/ /pubmed/36817432 http://dx.doi.org/10.3389/fimmu.2023.1085547 Text en Copyright © 2023 Swan, Mehta, Ilich, Shen, Wilkinson, Anderson, Segura, Sanchez-Perez, Sampson and Bellamkonda https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Swan, Sheridan L. Mehta, Nalini Ilich, Ekaterina Shen, Steven H. Wilkinson, Daniel S. Anderson, Alexa R. Segura, Tatiana Sanchez-Perez, Luis Sampson, John H. Bellamkonda, Ravi V. IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma |
title | IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma |
title_full | IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma |
title_fullStr | IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma |
title_full_unstemmed | IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma |
title_short | IL7 and IL7 Flt3L co-expressing CAR T cells improve therapeutic efficacy in mouse EGFRvIII heterogeneous glioblastoma |
title_sort | il7 and il7 flt3l co-expressing car t cells improve therapeutic efficacy in mouse egfrviii heterogeneous glioblastoma |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936235/ https://www.ncbi.nlm.nih.gov/pubmed/36817432 http://dx.doi.org/10.3389/fimmu.2023.1085547 |
work_keys_str_mv | AT swansheridanl il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT mehtanalini il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT ilichekaterina il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT shenstevenh il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT wilkinsondaniels il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT andersonalexar il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT seguratatiana il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT sanchezperezluis il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT sampsonjohnh il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma AT bellamkondaraviv il7andil7flt3lcoexpressingcartcellsimprovetherapeuticefficacyinmouseegfrviiiheterogeneousglioblastoma |