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Assessment of Variable-dose Scheduling Effects on the Kinetics and Homing of Antigen-specific T Cells in Cancer via Optical Imaging
Başlık:
Assessment of Variable-dose Scheduling Effects on the Kinetics and Homing of Antigen-specific T Cells in Cancer via Optical Imaging
Yazar:
Yarovoy, Iven, author.
ISBN:
9780438050075
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (51 pages)
Genel Not:
Source: Masters Abstracts International, Volume: 57-06M(E).
Advisors: Natesh Parashurama Committee members: Sriram Neelamegham.
Özet:
Ovarian Epithelial cancer is the most prevalent form of ovarian cancer overall. It is the leading cause of gynecologic cancer mortality, partly due to its lack of distinctive symptoms. The mainstay for treatment for metastatic ovarian cancer has largely been chemotherapeutics, but recently immunotherapy has surfaced as a potential treatment. The initial results of immunotherapy are promising, with demonstration of low rates of off-target effects and high specificity towards tumors. Nevertheless, there are various hurdles to overcome before immunotherapy becomes a routine and efficacious form of treatment. Preclinical models are valuable for basic studies of adoptive T cell therapies. We propose that molecular imaging can be used to better understand T cell therapies. Molecular imaging is field which employs highly sensitive imaging to image cells noninvasively and quantitatively. Combining molecular imaging with adoptive T cell therapy can enhance our understanding of T cell therapies by helping assess T cell kinetics and trafficking during tumor killing.
We are particularly interested in the effects of dose scheduling and subsequent tumor destruction as a result of antigen-specific adoptive T cell therapy for epithelial ovarian cancer. In fact, clinical trials demonstrate that delivering a T cell dose over a schedule instead of in one singular infusion could lead to improved patient outcomes. In this thesis, we use in vivo and ex vivo imaging to quantitatively measure T cell kinetics and whole body homing/trafficking in a metastatic ovarian cancer model, and the effect of a dose schedule on these parameters. OVA+ IE9-MP1 ovarian tumor cells (metastatic, surface epithelial cell line) were cultured and administered intraperitoneally in female, adult C57BL/6J mice. Primary T cells were harvested from OT-1 TCR mice, a transgenic model in which all CD8+ T cells are antigen-specific for OVA (chicken ovalbumin) antigen. These OVA specific T cells were isolated, therefore only target the OVA+ tumor cells and were tracked by bioluminescence via transduction of the egfp-fluc2 cassette. Based on prior in-vivo experiments, a dose of 1E6 T cells was chosen for its balance of signal and lack of significant tumor killing. In a control group, mice without tumor were treated with 1E6 OT1 T cells. Within the experimental group, one subgroup received 1E6 OT1 T cells in one infusion, whereas the second subgroup received two doses of 5E5 OT1 T cells in order to examine the differences in dose scheduling. The reporter system was then imaged with the IVIS Spectrum bioluminescent imaging system.
Bioluminescent imaging revealed several trends. Primarily, days 1-4 following T cell adoption show slow, tumor-independent increases in signal. After day 4, however, T cell proliferation begins to increase, as visualized by increasing signal. By day 10, there is a large discrepancy between tumor-free and tumor-bearing doses; Tumor-bearing mice, on average, had approximately 2600% more signal originating from the collective ROI relative to tumor-free mice. Trafficking between the dose-scheduling groups showed similar homing distribution, suggesting that clinical approaches of delivering T cells on a schedule is a viable approach to lowering T cell dosing side effects.
Notlar:
School code: 0656
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(694181.1) | 694181-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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