HLA-independent T cell receptors for targeting tumors with low antigen density.

Autor: Mansilla-Soto J; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. mansillj@mskcc.org.; Immunology Program, Sloan Kettering Institute, New York, NY, USA. mansillj@mskcc.org., Eyquem J; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA.; Department of Medicine, Division of Hemato-Oncology, University of California San Francisco, San Francisco, CA, USA., Haubner S; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Hamieh M; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Feucht J; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA.; Cluster of Excellence iFIT, University Children's Hospital Tübingen, Tübingen, Germany., Paillon N; Institute Curie, Université PSL, U932 INSERM, Integrative Analysis of T cell Activation Team, Paris, France., Zucchetti AE; Institute Curie, Université PSL, U932 INSERM, Integrative Analysis of T cell Activation Team, Paris, France., Li Z; Microchemistry and Proteomics Core Laboratory, Sloan Kettering Institute, New York, NY, USA., Sjöstrand M; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Lindenbergh PL; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Saetersmoen M; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA.; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Dobrin A; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Maurin M; Institute Curie, Université PSL, U932 INSERM, Integrative Analysis of T cell Activation Team, Paris, France., Iyer A; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Garcia Angus A; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Miele MM; Microchemistry and Proteomics Core Laboratory, Sloan Kettering Institute, New York, NY, USA., Zhao Z; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Giavridis T; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA.; Mnemo Therapeutics, New York, NY, USA., van der Stegen SJC; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Tamzalit F; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Rivière I; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Huse M; Immunology Program, Sloan Kettering Institute, New York, NY, USA., Hendrickson RC; Microchemistry and Proteomics Core Laboratory, Sloan Kettering Institute, New York, NY, USA.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Hivroz C; Institute Curie, Université PSL, U932 INSERM, Integrative Analysis of T cell Activation Team, Paris, France., Sadelain M; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. m-sadelain@ski.mskcc.org.; Immunology Program, Sloan Kettering Institute, New York, NY, USA. m-sadelain@ski.mskcc.org.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2022 Feb; Vol. 28 (2), pp. 345-352. Date of Electronic Publication: 2022 Jan 13.
DOI: 10.1038/s41591-021-01621-1
Abstrakt: Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor-CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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