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HCMV CAR T cells as a novel platform for glioblastoma cancer immunotherapy / Jesse L. Rodriguez.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Rodriguez, Jesse L., author.
- Language:
- English
- Subjects (All):
- Cellular biology.
- Oncology.
- Molecular biology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Local Subjects:
- Cellular biology.
- Oncology.
- Molecular biology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (119 pages)
- Contained In:
- Dissertations Abstracts International 82-10B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2020.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor. Immunotherapeutic approaches using chimeric antigen receptor (CAR) T cells have shown limited efficacy against GBM due to heterogeneous target antigen expression. We hypothesize that human cytomegalovirus (HCMV) can serve as a therapeutic target for GBM. HCMV can be detected in up to 90% of GBM tumor samples but not the surrounding normal brain tissue. The role of HCMV as a tumor-promoting virus is poorly understood but its presence in the tumor presents a novel approach to developing a therapy for GBM by re-directing T cells to target HCMV. We detected the presence of HCMV in GBM tumor samples via IHC and confirmed expression of HCMV gene UL55/glycoprotein B (gB) in 45% of primary GBM tumors. A CAR was generated and optimized to recognize the HCMV surface antigen gB. In vitro testing of the anti-gB CAR revealed activity against the U87 glioma cell line stably transduced to express gB and CMV-infected human foreskin fibroblasts (HFF) cells. In vivo, gB CARs were able to treat established GBM tumors in a xenograft mouse model. In vitro co-cultures of gB CAR T cells against the human GBM explant, D270, demonstrated tumor recognition and anti-tumor function against primary GBM. gB CAR T cells were able to control D270 tumor growth in vivo despite undetectable levels of antigen expression. Mice displaying stable disease showed improved persistence of engrafted human T cells and tumor infiltration. These results suggest that CAR T cells may be effective in recognizing extremely low abundance antigens, and taken together, the results of this study show the feasibility of using gB CAR T cells as a platform to target HCMV in GBM tumors to treat patients with GBM. Ultimately, the goal of this study is translate these findings into clinical trials.
- Notes:
- Source: Dissertations Abstracts International, Volume: 82-10, Section: B.
- Advisors: June, Carl H.; Posey, Avery D.; Committee members: Nicola Mason; Robert Vonderheide; Michael Milone.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2020.
- Local Notes:
- School code: 0175
- ISBN:
- 9798708751652
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
- This item must not be sold to any third party vendors.
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