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

• Published in: Nature medicine Vol. 28; no. 2; pp. 345 - 352
• Main Authors: Mansilla-Soto, Jorge, Eyquem, Justin, Haubner, Sascha, Hamieh, Mohamad, Feucht, Judith, Paillon, Noémie, Zucchetti, Andrés Ernesto, Li, Zhuoning, Sjöstrand, Maria, Lindenbergh, Pieter L, Saetersmoen, Michelle, Dobrin, Anton, Maurin, Mathieu, Iyer, Archana, Garcia Angus, Andreina, Miele, Matthew M, Zhao, Zeguo, Giavridis, Theodoros, van der Stegen, Sjoukje J C, Tamzalit, Fella, Rivière, Isabelle, Huse, Morgan, Hendrickson, Ronald C, Hivroz, Claire, Sadelain, Michel
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.02.2022
• Subjects: Acute myeloid leukemia; Animal models; Animals; Antigens; Antigens, CD19; Automobiles; CD19 antigen; CD28 antigen; CD3 antigen; CD70 antigen; CD80 antigen; Cell culture; Cell surface; Chains; Chimeric antigen receptors; Histocompatibility antigen HLA; Histocompatibility Antigens; Humans; Immunotherapy, Adoptive; Leukemia; Leukemia, Myeloid, Acute; Light chains; Loci; Lymphocytes; Lymphocytes T; Mice; Peripheral blood; Receptors; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen - metabolism; Sensitivity; Surface antigens; T cell receptors; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-021-01621-1

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.