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macrophage, toll-like receptor signaling, chimeric antigen receptor, immunotherapy, mesothelin
The purpose of this study is to evaluate the efficacy of a mesothelin targeting engineered Macrophage Toll-like Receptor Chimeric Antigen Receptor (MOTO-CAR™). Recently, immunotherapies have emerged as a new horizon for treating cancer. The development of T-cell chimeric antigen receptors (CARs) and their success in treating liquid malignancies transformed the field of cancer treatment, but their effectiveness in treating solid malignancies has been limited due to their inability to traffic to the tumor site. Macrophages, however, are known to be actively recruited by tumors. Due to their association with tumors we chose to explore the use of MOTO-CARS™ as an alternative to CAR T-cell therapy. Murine macrophages were transfected with DNA that expresses the MOTO-CAR™ construct. To validate the ability of engineered MOTO-CARs™ to produce and anti-tumor response, MOTO-CARs™ were challenged in vitro with mesolethin positive breast cancer cells (HCC-1806) where they showed significant cancer regression when compared to mock controls (p-value < 0.0001). To confirm that MOTO-CARs™ polarize to an M1 phenotype following activation, the production of TNF-⍺ post challenge was measured using an ELISA and, when compared to mock controls, a significant increase in the production of TNF-⍺ was observed (p-value =0.0093). Finally, the efficacy of MOTO-CARs™ were evaluated in vivo using an NSG mouse model. After administering cells via tail-vein injection, we observed that MOTO-CARs™ trafficked to tumor sites and generated a significant reduction in tumor size (p-value = 0.0006). In conclusion, we report that macrophages, engineered with toll-like receptor-chimeric antigen receptors show strong promise in the battle against solid malignancies.
BYU ScholarsArchive Citation
Townsend, Michelle H.; Skidmore, Jonathan R.; Bennion, Kelsey A.; Wang, Guoying; Ewell, Zachary D.; Lum, David; Boyer, Michael; and O'Neill, Kim L., "Macrophage Toll-Like Receptor Chimeric Antigen Receptor: MOTO-CAR™ Shows Potent Activation and Killing of Triple Negative Breast Cancer Cells" (2020). Library/Life Sciences Undergraduate Poster Competition 2020. 10.
Microbiology and Molecular Biology
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