Thesis
Characterizing escape pathways associated with HIV-specific CAR T cell therapies
Master of Science (M.S.), Drexel University
Aug 2024
DOI:
https://doi.org/10.17918/00010498
Abstract
Chimeric antigen receptor (CAR) T cells have been used as an effective therapy for treatment-refractory cancers but may be a useful intervention for other chronic diseases such as Human Immunodeficiency Virus (HIV) infection. A diverse range of broadly-neutralizing antibodies (bNAbs) exhibiting potent affinity for conserved epitopes on the HIV envelope glycoprotein are available for CAR T cell targeting. This offers the opportunity to engineer an array of HIV-specific CAR T cell products to elucidate bNAb specificities associated with enhanced potency. However, there are challenges when using bNAb-based CAR T cells as a treatment for HIV in vivo, particularly the high mutation rate of HIV reverse transcription during replication. This can lead to the rapid emergence and selection of escape mutations that prevent bNAb CAR recognition of HIV envelope on infected cells, leading to poor clearance and treatment failure. Using humanized mice, we were able to map HIV evolution through amplification and deep sequencing of the HIV env gene at longitudinal timepoints. Moreover, we identified putative escape mutations associated with CAR T cell therapy at all 6 canonical bNAb epitopes, providing a comprehensive picture of HIV evolution in response to Env-targeting CAR T cells. Importantly, characterization of the escape pathways arising in response to each bNAb CAR provides the opportunity to design combination bNAb CAR T cell therapies to target multiple HIV Env epitopes simultaneously to restrict HIV escape and control plasma viremia.
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Details
- Title
- Characterizing escape pathways associated with HIV-specific CAR T cell therapies
- Creators
- Alexandria Brooke Criswell
- Contributors
- Daniel T. Claiborne (Advisor)Luis J. Montaner (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 65 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Medicine (Graduate); College of Medicine; Hematology and Oncology; Drexel University
- Other Identifier
- 991021899615104721