Leucine zipper-based immunomagnetic purification of CAR T cells displaying multiple receptors Journal Article
| Authors: | James, S. E.; Chen, S.; Ng, B. D.; Fischman, J. S.; Jahn, L.; Boardman, A. P.; Rajagopalan, A.; Elias, H. K.; Massa, A.; Manuele, D.; Nichols, K. B.; Lazrak, A.; Lee, N.; Roche, A. M.; McFarland, A. G.; Petrichenko, A.; Everett, J. K.; Bushman, F. D.; Fei, T.; Kousa, A. I.; Lemarquis, A. L.; DeWolf, S.; Peled, J. U.; Vardhana, S. A.; Klebanoff, C. A.; van den Brink, M. R. M. |
| Article Title: | Leucine zipper-based immunomagnetic purification of CAR T cells displaying multiple receptors |
| Abstract: | Resistance to chimaeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms, most notably antigen loss and tumour-induced immune suppression. It has been suggested that T cells expressing multiple CARs may overcome the resistance of tumours and that T cells expressing receptors that switch inhibitory immune-checkpoint signals into costimulatory signals may enhance the activity of the T cells in the tumour microenvironment. However, engineering multiple features into a single T cell product is difficult because of the transgene-packaging constraints of current gene-delivery vectors. Here we describe a cell-sorting method that leverages leucine zippers for the selective single-step immunomagnetic purification of cells co-transduced with two vectors. Such ‘Zip sorting’ facilitated the generation of T cells simultaneously expressing up to four CARs and coexpressing up to three ‘switch’ receptors. In syngeneic mouse models, T cells with multiple CARs and multiple switch receptors eliminated antigenically heterogeneous populations of leukaemia cells coexpressing multiple inhibitory ligands. By combining diverse therapeutic strategies, Zip-sorted multi-CAR multi-switch-receptor T cells can overcome multiple mechanisms of CAR T cell resistance. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | immune system; antigens; cell therapy; mammals; t-cells; antigen receptors; immune suppression; cell engineering; tumor microenvironments; leucine zippers; air purification; cell products; co-stimulatory signal; immunomagnetic; multiple features; multiple receptors |
| Journal Title: | Nature Biomedical Engineering |
| Volume: | 8 |
| Issue: | 12 |
| ISSN: | 2157-846X |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-12-01 |
| Start Page: | 1592 |
| End Page: | 1614 |
| Language: | English |
| DOI: | 10.1038/s41551-024-01287-3 |
| PROVIDER: | scopus |
| PUBMED: | 39715901 |
| PMCID: | PMC11917073 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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