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GEO help: Mouse over screen elements for information. |
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| Status |
Public on May 15, 2024 |
| Title |
IL-18-secreting multi-antigen targeting CAR T-cells eliminate antigen-low myeloma in an immunocompetent mouse model [in vivo] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T-cells in leukemia and lymphoma, CAR T-cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to low expression of BCMA on myeloma cells, suggesting that novel approaches to better address antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the pro-inflammatory cytokine interleukin-18 (IL-18) and multi-antigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T-cells targeting the myeloma-associated antigens BCMA and B-cell activating factor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed. In contrast, IL-18-secreting CAR T-cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T-cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type I and II interferon signaling, and utilized macrophages to mediate anti-myeloma activity. Simultaneous targeting of weakly expressed BCMA and BAFF-R with dual-CAR T-cells enhanced T-cell:target cell avidity, increased overall CAR signal strength, and stimulated anti-myeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multi-antigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.
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| Overall design |
scRNA and CITE-seq analysis of CD45+ mouse bone marrow following treatment with CAR T cells engineered to secrete IL-18
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| Web link |
https://pubmed.ncbi.nlm.nih.gov/38579288/
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| Contributor(s) |
Ng BD, Rajagopalan A, Kousa AI, Fischman JS, Chen S, Massa A, Manuele D, Elias HK, Galiano M, Lemarquis AL, Boardman AP, DeWolf S, Pierce J, Bogen B, James SE, van den Brink MR |
| Citation(s) |
38579288 |
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| Submission date |
Oct 31, 2023 |
| Last update date |
May 16, 2024 |
| Contact name |
Anastasia I Kousa |
| E-mail(s) |
akousa@coh.org
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| Organization name |
City of Hope
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| Department |
Hematology / HCT
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| Lab |
The Marcel van den Brink Lab
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| Street address |
1500 E Duarte Rd
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| City |
Duarte |
| State/province |
CA |
| ZIP/Postal code |
91010 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1034126 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE246682_20230508_MM_IL-18_singlecell.h5ad.gz |
341.8 Mb |
(ftp)(http) |
H5AD |
| GSE246682_Mac_mono.h5ad.gz |
34.4 Mb |
(ftp)(http) |
H5AD |
| GSE246682_RAW.tar |
1.2 Gb |
(http)(custom) |
TAR (of H5, H5AD, MTX, TSV) |
| GSE246682_T_cells.h5ad.gz |
92.0 Mb |
(ftp)(http) |
H5AD |
| GSE246682_adata_Tirier_Nat_comm_2021_filtered.h5ad.gz |
441.0 Mb |
(ftp)(http) |
H5AD |
| GSE246682_adata_Tirier_Nat_comm_2021_filtered_magic.h5ad.gz |
5.1 Mb |
(ftp)(http) |
H5AD |
SRA Run Selector |
| Raw data are available in SRA |
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