Highly proliferative and hypodifferentiated CAR-T cells targeting B7–H3 enhance antitumor activity against ovarian and triple-negative breast cancers
Chimeric antigen receptor (CAR)-T cell immunotherapy is highly effective against hematological neoplasms. However, owing to tumor variability, low antigen specificity, and impermanent viability of CAR-T cells, their use in the treatment of solid tumors is limited. Here, a novel CAR-T cell targeting...
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Published in | Cancer letters Vol. 572; p. 216355 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier B.V
28.09.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Chimeric antigen receptor (CAR)-T cell immunotherapy is highly effective against hematological neoplasms. However, owing to tumor variability, low antigen specificity, and impermanent viability of CAR-T cells, their use in the treatment of solid tumors is limited. Here, a novel CAR-T cell targeting B7–H3 and incorporating a 4-1BB costimulatory molecule with STAT3-and STAT5-related activation motifs was constructed using lentivirus transduction. B7–H3, a tumor-associated antigen, and its scFv antibody endowed CAR-T cells with tumor-specific targeting capabilities. Moreover, the integration of the trIL2RB and YRHQ motifs stimulated STAT5 and STAT3 in an antigen-dependent manner, inducing a remarkable increase in the proliferation and survival of CAR-T cells via the activation of the JAK-STAT signaling pathway. Besides, the proportion of less-differentiated T cells increased among BB-trIL2RB-z(YRHQ) CAR-T cells. Moreover, BB-trIL2RB-z(YRHQ) effectively inhibited ovarian cancer (OC) and triple-negative breast cancer (TNBC) in vivo at low doses, without high serum levels of inflammatory cytokines and organ toxicity. Therefore, our study proposes a combination of elements for the construction of superior pluripotent CAR-T cells to provide an effective strategy for the treatment of intractable solid tumors.
We combined a variety of elements to form a CAR targeting B7–H3. These elements improved the proliferation and stemness of CAR-T cells, and effectively inhibited the growth of ovarian and triple-negative breast cancers. [Display omitted]
•Construction of B7–H3-targeted CAR-T cells using a preponderant combination.•The design of CAR enhances the proliferation ability and stemness of CAR-T.•A novel CAR-T targeting B7–H3 exhibits excellent activity in ovarian cancer.•A novel B7–H3-targeted CAR-T inhibits triple negative breast cancer at a low dose. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0304-3835 1872-7980 |
DOI: | 10.1016/j.canlet.2023.216355 |