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SRX22323133: GSM7874581: APRIL-BB-1XX_IL-18_HTO; Mus musculus; OTHER
2 ILLUMINA (Illumina NovaSeq 6000) runs: 334.6M spots, 46.2G bases, 16.7Gb downloads

External Id: GSM7874581_r1
Submitted by: The Marcel van den Brink Lab, Department of Immunology, Memorial Sloan Kettering Cancer Center
Study: IL-18-secreting multi-antigen targeting CAR T-cells eliminate antigen-low myeloma in an immunocompetent mouse model [in vivo]
show Abstracthide Abstract
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. Overall design: scRNA and CITE-seq analysis of CD45+ mouse bone marrow following treatment with CAR T cells engineered to secrete IL-18
Sample: APRIL-BB-1XX_IL-18_HTO
SAMN38053179 • SRS19373720 • All experiments • All runs
Organism: Mus musculus
Library:
Name: GSM7874581
Instrument: Illumina NovaSeq 6000
Strategy: OTHER
Source: OTHER
Selection: other
Layout: PAIRED
Construction protocol: CAR T-cell treated mice were harvested for bone marrow on day 7 of experiment (4 days after CAR T-cells). Cells were erythrocyte-lysed and stained with Fc-block. Cells were then labeled with fluorescent antibodies and DAPI for FACS sorting and hashtag oligonucleotide (HTO) antibodies (Biolegend) to barcode each mouse for identification post-sequencing. Cells were FACS-sorted for CD45+/CD3+ T-cells and CD45+/CD3- non-T-cells. Cells were re-pooled at 1:2 T- cells:non-T-cells and stained with FcX (Biolegend) followed by Biolegend TotalSeqA mouse universal cocktail (for CITE-seq). ~100,000 cells from each biological group were submitted for single-cell sequencing (n=3 mice per group, ~30,000 cells /mouse). Single-cell RNA sequencing of FACS-sorted cell suspensions was performed on the Chromium instrument (10X genomics) following the user guide manual for 3′ v3.1. In brief, FACS- sorted cells were washed once with PBS containing 1% bovine serum albumin (BSA) and resuspended in PBS containing 1% BSA to a final concentration of 1,700–2,000 cells per μl. The viability of cells was above 80%, as confirmed with 0.2% (w/v) Trypan Blue staining (Countess II). Cells were captured indroplets. Following reverse transcription and cell barcoding in droplets, emulsions were broken, and cDNA was purified using Dynabeads MyOne SILANE followed by PCR amplification as per manual instruction. About 30,000 cells were targeted for each sample. Samples were multiplexed together on one lane of 10x Chromium (using HTO) and specific extracellular protein epitope characterized (using Antibody Derived Tag, Biolegend TotalSeqA) following a previously published protocol3. Final libraries were sequenced on Illumina NovaSeq S4 platform (R1 – 28 cycles, i7 – 8 cycles, R2 – 90 cycles) at a depth of ~575 million reads per sample. HTO and CITE were sequenced at ~88 million reads per sample.
Runs: 2 runs, 334.6M spots, 46.2G bases, 16.7Gb
Run# of Spots# of BasesSizePublished
SRR26622254167,984,83723.2G8.4Gb2024-05-15
SRR26622255166,632,92623G8.3Gb2024-05-15

ID:
30290604

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