Faculty, Staff and Student Publications
Publication Date
5-20-2024
Journal
The Journal for ImmunoTherapy of Cancer
Abstract
BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.
METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.
RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy.
CONCLUSIONS: Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.
Keywords
Humans, Animals, Mice, Sialic Acid Binding Ig-like Lectin 3, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, Leukemia, Myeloid, Acute, T-Lymphocytes, Xenograft Model Antitumor Assays, Cell Line, Tumor
DOI
10.1136/jitc-2024-009013
PMID
38772686
PMCID
PMC11110598
PubMedCentral® Posted Date
May 2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Immunotherapy Commons, Medical Sciences Commons, Oncology Commons
Comments
Supplementary Material
PMID: 38772686