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| Status |
Public on Feb 01, 2019 |
| Title |
Antagonism of IAPs enhances CAR T cell efficacy |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Chimeric antigen receptor (CAR) T cell therapy has proven highly successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrate that antagonizing Inhibitor of Apoptosis Proteins (IAPs) with the clinical smac-mimetic, birinapant, significantly enhanced the anti-tumor activity of CAR T cells in a TNF-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T cell-derived TNF. Importantly, combining CAR T cell therapy with birinapant dramatically reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrate the synergistic potential of combining CAR T cell therapy with smac-mimetics. Taken together, we identify CAR T cell-derived TNF as a potent anti-tumor effector, which can be further harnessed by smac-mimetics.
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| Overall design |
MC38 HER2/ AU565 cells were either left untreated or incubated with CAR T cells [no smac-mimetics] (in triplicate/ duplicate) at a 2:1 effector-target ratio for 6 hrs followed by 3’ RNA-Seq of viable cells.
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| Contributor(s) |
Oliaro J, Zethoven M |
| Citation(s) |
30651288 |
| |
| Submission date |
Dec 19, 2018 |
| Last update date |
May 04, 2019 |
| Contact name |
Jane Oliaro |
| E-mail(s) |
jane.oliaro@petermac.org
|
| Organization name |
Peter MacCallum Cancer Centre
|
| Street address |
305 Grattan Street
|
| City |
Melbourne |
| State/province |
Victoria |
| ZIP/Postal code |
3000 |
| Country |
Australia |
| |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA510825 |
| SRA |
SRP173953 |
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