A TCR mimic CAR T cell specific for NDC80 is broadly reactive with solid tumors and hematologic malignancies Journal Article
| Authors: | Klatt, M. G.; Dao, T.; Yang, Z.; Liu, J.; Mun, S. S.; Dacek, M. M.; Luo, H.; Gardner, T. J.; Bourne, C.; Peraro, L.; Aretz, Z. E. H.; Korontsvit, T.; Lau, M.; Kharas, M. G.; Liu, C.; Scheinberg, D. A. |
| Article Title: | A TCR mimic CAR T cell specific for NDC80 is broadly reactive with solid tumors and hematologic malignancies |
| Abstract: | Target identification for chimeric antigen receptor (CAR) T-cell therapies remains challenging due to the limited repertoire of tumor-specific surface proteins. Intracellular proteins presented in the context of cell surface HLA provide a wide pool of potential antigens targetable through T-cell receptor mimic antibodies. Mass spectrometry (MS) of HLA ligands from 8 hematologic and nonhematologic cancer cell lines identified a shared, non-immunogenic, HLA-A*02–restricted ligand (ALNEQIARL) derived from the kinetochore-associated NDC80 gene. CAR T cells directed against the ALNEQIARL:HLA-A*02 complex exhibited high sensitivity and specificity for recognition and killing of multiple cancer types, especially those of hematologic origin, and were efficacious in mouse models against a human leukemia and a solid tumor. In contrast, no toxicities toward resting or activated healthy leukocytes as well as hematopoietic stem cells were observed. This shows how MS can inform the design of broadly reactive therapeutic T-cell receptor mimic CAR T-cell therapies that can target multiple cancer types currently not druggable by small molecules, conventional CAR T cells, T cells, or antibodies. © 2022 American Society of Hematology |
| Keywords: | controlled study; human tissue; leukemia; human cell; nonhuman; sensitivity and specificity; neoplasm; neoplasms; t lymphocyte; t-lymphocytes; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; animal experiment; animal model; in vivo study; in vitro study; cancer inhibition; t lymphocyte receptor; hematologic neoplasms; receptors, antigen, t-cell; mesothelioma; hematopoietic stem cell; antibodies; cross reaction; hla a antigen; antibody; leukocyte; adoptive immunotherapy; hla-a antigens; immunotherapy, adoptive; lymphocyte antigen receptor; hematologic disease; cytoskeleton protein; cytoskeletal proteins; liquid chromatography-mass spectrometry; procedures; bacteriophage; ndc80 complex; humans; human; female; article; chimeric antigen receptor t-cell immunotherapy; ndc80 protein, human |
| Journal Title: | Blood |
| Volume: | 140 |
| Issue: | 8 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-08-25 |
| Start Page: | 861 |
| End Page: | 874 |
| Language: | English |
| DOI: | 10.1182/blood.2021012882 |
| PUBMED: | 35427421 |
| PROVIDER: | scopus |
| PMCID: | PMC9412008 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2022 -- Source: Scopus |
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