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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Mar 22, 2023 |
| Title |
Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy [scRNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. Here, we identified broad expression of STEAP1 relative to the established theranostic target prostate-specific membrane antigen (PSMA) in a series of lethal metastatic prostate cancers which prompted the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrated reactivity in low antigen density, antitumor activity across multiple metastatic human and mouse prostate cancer models, and preliminary safety in a human STEAP1 knock-in mouse model. In human-in-mouse and mouse-in-mouse studies, STEAP1 CAR T cell therapy yielded effective tumor responses, but antigen escape was appreciated as a recurrent mechanism of treatment resistance and STEAP1 antigen loss was associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein as an adjunct to STEAP1 CAR T cell therapy enhanced antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. In summary, we describe the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, characterize a STEAP1 CAR T cell therapy with preclinical evidence of potency and safety, and nominate a combinatorial immunotherapy strategy to overcome barriers to the efficacy of CAR T cell therapy in advanced prostate cancer.
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| Overall design |
Single cell RNA-Seq (scRNA-Seq) was performed on RM9 tumors treated with either vehicle (control group) and the tumors treated with collagen binding domain fused with interlukin-12 (CBD-IL-12) that represents the treatment group.
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| Contributor(s) |
Bhatia V, Kamat NV, Pariva TE, Wu L, Tsao A, Sasaki K, Sun H, Javier G, Coleman I, Wiest LT, Zhang A, Rudoy D, Gulati R, Patel RA, Roudier MP, True LD, Haffner MC, Nelson PS, Priceman SJ, Ishihara J, Lee JK |
| Citation(s) |
37041154 |
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| Submission date |
Sep 30, 2022 |
| Last update date |
May 03, 2023 |
| Contact name |
John K Lee |
| E-mail(s) |
jklee5@fredhutch.org
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| Phone |
2066676819
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| Organization name |
Fred Hutchinson Cancer Research Center
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| Department |
Human Biology
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| Street address |
1100 Fairview Ave N, E2-112
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| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98109 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE214585 |
Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy |
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| Relations |
| BioProject |
PRJNA885904 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE214584_MergedColumnData_VehicleVsCBD-IL-12_scRNASeq.csv.gz |
340.5 Kb |
(ftp)(http) |
CSV |
| GSE214584_RM9_CBD-IL-12_vs_Vehicle_scRNASeq.csv.gz |
252.2 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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