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

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

Authors:	Mansilla-Soto, J.; Eyquem, J.; Haubner, S.; Hamieh, M.; Feucht, J.; Paillon, N.; Zucchetti, A. E.; Li, Z.; Sjöstrand, M.; Lindenbergh, P. L.; Saetersmoen, M.; Dobrin, A.; Maurin, M.; Iyer, A.; Garcia Angus, A.; Miele, M. M.; Zhao, Z.; Giavridis, T.; van der Stegen, S. J. C.; Tamzalit, F.; Rivière, I.; Huse, M.; Hendrickson, R. C.; Hivroz, C.; Sadelain, M.
Article Title:	HLA-independent T cell receptors for targeting tumors with low antigen density
Abstract:	HLA-independent T cell receptors, in which the heavy and light chains of a chimeric antigen receptor are incorporated into the endogenous T cell receptor locus, are more effective than CD28-based chimeric antigen receptors at targeting tumors with low antigen expression. 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.
Keywords:	protein; therapy; design; b-cell; expression; complex; naive; cd80; car
Journal Title:	Nature Medicine
Volume:	28
Issue:	2
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Date Published:	2022-02-01
Start Page:	345
End Page:	352
Language:	English
ACCESSION:	WOS:000742323900001
DOI:	10.1038/s41591-021-01621-1
PROVIDER:	wos
PUBMED:	35027758
PMCID:	PMC9469647
Notes:	Article -- Source: Wos