Developing a membrane-proximal CD33-targeting CAR T cell Journal Article
| Authors: | Freeman, R.; Shahid, S.; Khan, A. G.; Mathew, S. C.; Souness, S.; Burns, E. R.; Um, J. S.; Tanaka, K.; Cai, W.; Yoo, S.; Dunbar, A.; Park, Y.; McAvoy, D.; Hosszu, K. K.; Levine, R. L.; Boelens, J. J.; Lorenz, I. C.; Brentjens, R. J.; Daniyan, A. F. |
| Article Title: | Developing a membrane-proximal CD33-targeting CAR T cell |
| 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. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
| Keywords: | controlled study; leukemia; human cell; overall survival; leukemia, myeloid, acute; nonhuman; binding affinity; cd8+ t lymphocyte; cell proliferation; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; metabolism; animals; mice; interleukin 2; randomized controlled trial; animal model; cohort analysis; cytotoxicity; drug screening; xenograft model antitumor assays; cell line, tumor; cetuximab; enzyme linked immunosorbent assay; monoclonal antibody; immunology; immune response; immunotherapy; gamma interferon; xenograft; epitope; tumor cell line; cell isolation; chimeric antigen receptor; cell therapy; tumor immunity; cytokine production; immunophenotyping; tumor growth; antigen binding; therapy; bioluminescence; adoptive immunotherapy; immunotherapy, adoptive; t lymphocyte activation; cd33 antigen; firefly luciferase; coculture; stromal cell derived factor 1; t cell; cd47 antigen; membrane; binding assay; acute myeloid leukemia; procedures; gemtuzumab; humans; human; male; female; article; ec50; receptors, chimeric antigen; u-937 cell line; adoptive cell therapy - act; chimeric antigen receptor - car; sialic acid binding ig-like lectin 3; cd33 protein, human |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 12 |
| Issue: | 5 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2024-05-01 |
| Start Page: | e009013 |
| Language: | English |
| DOI: | 10.1136/jitc-2024-009013 |
| PUBMED: | 38772686 |
| PROVIDER: | scopus |
| PMCID: | PMC11110598 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
