T cells engineered with chimeric antigen receptors (CAR-T) have had breakthrough successes in cancer immunotherapy with FDA approvals. Still, the high cost of personalized CAR-T cell therapy hinders the accessibility from the public as a therapeutic option, and the lack of uniquely defined cancer-specific antigens brings the risk of life-threatening on-target, off-tumor toxicity. Changing the immune cell therapy platform to Natural Killer cells (NK cells) can be an option to develop allogenic off-the-shelf cell therapy. To reduce the on-target, off-tumor toxicity, developing an inhibitory CAR (iCAR) for cell therapy is necessary for precise logic computation and implementation of iCAR can broaden the spectrum of treatable cancers. This dissertation optimized the primary NK cell expansion platform with autologous PBMC and set robust virus transduction using pseudotyped retrovirus on the primary NK cells to use the NK cells as the cell therapy platform. I engineered iCAR candidates to suppress in response to a “safety antigen” on healthy cells, first in T cells and validated in NK cells, showing its efficacy against various versions of activating CAR (aCAR) drove killing of targets expressing activating antigen, while an inhibitory CAR (iCAR) suppressed cytotoxicity against targets expressing a safety antigen. Therapeutic immune cells equipped with the right pair of aCAR and iCAR platform will improve safety for currently validated cancer antigens and enable new therapies for previously unaddressed indications. / 2024-05-23T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/44764 |
| Date | 23 May 2022 |
| Creators | Lee, Seunghee |
| Contributors | Wong, Wilson W. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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