Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9

Nature Communications
Lintao LiuQing Yi

Abstract

CAR-T cell therapy is effective for hematologic malignancies. However, considerable numbers of patients relapse after the treatment, partially due to poor expansion and limited persistence of CAR-T cells in vivo. Here, we demonstrate that human CAR-T cells polarized and expanded under a Th9-culture condition (T9 CAR-T) have an enhanced antitumor activity against established tumors. Compared to IL2-polarized (T1) cells, T9 CAR-T cells secrete IL9 but little IFN-γ, express central memory phenotype and lower levels of exhaustion markers, and display robust proliferative capacity. Consequently, T9 CAR-T cells mediate a greater antitumor activity than T1 CAR-T cells against established hematologic and solid tumors in vivo. After transfer, T9 CAR-T cells migrate effectively to tumors, differentiate to IFN-γ and granzyme-B secreting effector memory T cells but remain as long-lived and hyperproliferative T cells. Our findings are important for the improvement of CAR-T cell-based immunotherapy for human cancers.

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Citations

Mar 7, 2021·Journal of Personalized Medicine·Karthik Nath, Maher K Gandhi
Mar 23, 2021·The Cancer Journal·Alysa N EvansSarwish Rafiq
Apr 25, 2021·Seminars in Immunology·Isis Benoit-Lizon, Lionel Apetoh
May 28, 2021·Biologics : Targets & Therapy·Maya GloverJohn Maher
Jun 29, 2021·Frontiers in Immunology·Matthew Bell, Stephen Gottschalk
Jul 18, 2021·Journal for Immunotherapy of Cancer·Oliver SchanzDominik Wolf

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Methods Mentioned

BETA
PCR
flow cytometry
Assay
RNASeq
Transfection
leukapheresis
xenograft
tail blood collection

Software Mentioned

gplots
GraphPad Prism
GSEA
FlowJo
Bowtie
RSEM
SOAPnuke
DEseq2
R
RNASeq

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