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Fast and fur-ious engineering next-generation canine cars Emma E Goodman
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Goodman, Emma E., author.
- Language:
- English
- Subjects (All):
- Immunology.
- Biomedical engineering.
- Cellular biology.
- Oncology.
- 0982.
- 0541.
- 0379.
- 0992.
- Local Subjects:
- Immunology.
- Biomedical engineering.
- Cellular biology.
- Oncology.
- 0982.
- 0541.
- 0379.
- 0992.
- Genre:
- Academic theses
- Physical Description:
- 1 online resource (99 pages)
- Contained In:
- Dissertations Abstracts International 87-12B
- Place of Publication:
- Ann Arbor : ProQuest Dissertations and Theses, 2026
- Language Note:
- English
- Summary:
- Comparative oncology has advanced cancer immunotherapy, although cellular mechanisms governing chimeric antigen receptor T cell (CART) therapy in canines are poorly understood. In a first-in-canine trial, anti-CD20 CART with canine 41BB-CD3ζ (cBBζ) domains induced CD20-negative lymphoma outgrowth but did not persist or deplete B-cells, demonstrating a need for improved canine CARTs. Here, we employ a mechanistic investigation into canine CART culture formulation and compositional designs, as targetable areas for therapeutic enhancement.We first define the immunophenotypic outcomes of canine T cells subjected to differing activation stimuli and cytokine conditioning programs. We validate a cross-reactive CD86 agonist for use in canine (CAR) T cell studies, while showing that IL2/21 versus IL7/15 support produce similar T cell differentiation and proliferation patterns. We also show that canine T cells are amenable to retroviral, but not lentiviral, gene transfer. These data informed revised CART manufacturing protocols that we used in our mechanistic CART studies.We later define the cytotoxic profiles of canine CARTs expressing distinct intracellular signaling components. We find that inclusion of human (h) 41BB-CD3ζ (hBBζ) domains supports greater in vitro and in vivo potency, associated with marked CD8 outgrowth, as compared with cCD28-CD3ζ (c28ζ) or cBBζ domains. We demonstrate that hBBζ signaling gives rise to potent CD8 CARTs through induction of an FCER1G/FcεRγI+ innate-like transcriptional program. We also reveal that Syk-NFκB signaling regulates FcεRγI activity and expression, and hBBζ engages greater NFκB signaling than cBBζ to induce FCER1G expression. Structurally, hBBζ CARTs interact with the endogenous T cell receptor (TCR) CD3ζ chains to potentiate NFκB signaling. Our data provide the preclinical rationale for a next-in-dog clinical trial and reveal important mechanistic insights relevant to human and canine CART biology
- Notes:
- Source: Dissertations Abstracts International, Volume: 87-12, Section: B.
- Advisors: Payne, Aimee S. Committee members: O'Connor, Roddy; Mason, Nicola J.; Bailis, Will; Siegel, Don
- Ph.D. University of Pennsylvania 2026
- Vendor supplied data
- Local Notes:
- School code: 0175
- ISBN:
- 9798247980919
- Access Restriction:
- Restricted for use by site license
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