Fibrin gel enhances the antitumor effects of chimeric antigen receptor T cells in glioblastoma.
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ABSTRACT:
SUBMITTER: Ogunnaike EA
PROVIDER: S-EPMC8494441 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
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Fibrin gel enhances the antitumor effects of chimeric antigen receptor T cells in glioblastoma.
Ogunnaike Edikan A EA Valdivia Alain A Yazdimamaghani Mostafa M Leon Ernesto E Nandi Seema S Hudson Hannah H Du Hongwei H Khagi Simon S Gu Zhen Z Savoldo Barbara B Ligler Frances S FS Hingtgen Shawn S Dotti Gianpietro G
Science advances 20211006 41
Regional delivery of chimeric antigen receptor (CAR) T cells in glioblastoma represents a rational therapeutic approach as an alternative to intravenous administration to avoid the blood-brain barrier impediment. Here, we developed a fibrin gel that accommodates CAR-T cell loading and promotes their gradual release. Using a model of subtotal glioblastoma resection, we demonstrated that the fibrin-based gel delivery of CAR-T cells within the surgical cavity enables superior antitumor activity com ...[more]
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Project description:The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CAR T (CART19)-cell functions. Our results demonstrate that T cells and CAR T cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CAR T cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CAR T cells, reduction of Th2 cytokines, reversal of CAR T-cell inhibition, and promotion of CAR T-cell effector functions. AXL inhibition is a novel strategy to enhance CAR T-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CAR T-cell inhibition through selective targeting of M2-polarized macrophages.
| S-EPMC10530462 | biostudies-literature