The Yin and Yang of CAR T Cell Dysfunction: Hyperinflammation and Immunosenescence Julia Han Noll

Format:

Book

Thesis/Dissertation

Author/Creator:

Noll, Julia Han, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

0306.

0982.

0992.

Local Subjects:

0306.

0982.

0992.

Physical Description:

1 electronic resource (221 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated curative potential in hematologic malignancies, yet their clinical impact remains inconsistent across disease contexts. This thesis investigates two distinct but inflammation-driven forms of CAR T-cell dysfunction-senescence and hyperinflammation-that limit efficacy and safety in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), respectively. In CLL, CAR T cells exhibit a senescent phenotype at baseline, marked by loss of costimulatory molecules, DNA damage accumulation, and a pro-inflammatory secretome. These features impair proliferation and persistence, contributing to poor clinical response. Using single-cell and bulk RNA sequencing, high-dimensional flow cytometry, and functional assays, this work identifies premature T-cell aging as a driver of CAR T cell dysfunction. Therapeutically, senescence can be partially reversed by ibrutinib, a BTK inhibitor that restores effector cytokine production and improves CAR T-cell function. In contrast, MM patients treated with BCMA-directed CAR T-cell products experience a spectrum of unique immune-related adverse events, including neurotoxicity and enterocolitis, which are driven by hyperactivated CD4+ CAR T cells with early expansion, tissue infiltration, and elevated inflammatory signaling. Analysis of clinical biomarkers and patient tissues links immune-related adverse events to high peak lymphocyte counts and skewed CD4+ T-cell phenotypes at baseline, suggesting these both as predictive markers and intervention possibility. This thesis defines a spectrum of CAR T-cell dysfunction shaped by inflammation, with therapeutic strategies tailored to ameliorate senescence in CLL and limit toxicity in MM. These findings provide a framework for tuning CAR T-cell responses based on disease context to improve efficacy and safety across hematologic malignancies

Notes:

Advisors: Fraietta, Joseph A. Committee members: Mason, Nicola; Ma, Leyuan; Beatty, Gregory; Byrne, Katelyn T.

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276007342

Access Restriction:

Restricted for use by site license