Journal Article

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

Iyer, Archana, Giavridis, Theodoros, Zucchetti, Andrés Ernesto, Rivière, Isabelle, Li, Zhuoning, Paillon, Noémie, Dobrin, Anton, Hamieh, Mohamad, Garcia Angus, Andreina, Hivroz, Claire, Sjöstrand, Maria, Mansilla-Soto, Jorge, Feucht, Judith, Haubner, Sascha, Maurin, Mathieu, Saetersmoen, Michelle, Lindenbergh, Pieter L., Miele, Matthew M., Eyquem, Justin, Tamzalit, Fella, Zhao, Zeguo, Huse, Morgan, Hendrickson, Ronald C., Sadelain, Michel, van der Stegen, Sjoukje J. C.

2022

Overview

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. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554 / 631/250/2520 / 631/67/1059/2325 / 692/699/67/1990/283 / Acute myeloid leukemia / Animal models / Animals / Antigens / Antigens, CD19 / Automobiles / Biomedical and Life Sciences / Biomedicine / Cancer Research / 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 / Infectious Diseases / Leukemia / Leukemia, Myeloid, Acute / Light chains / Loci / Lymphocytes / Lymphocytes T / Metabolic Diseases / Mice / Molecular Medicine / Neurosciences / Peripheral blood / Receptors / Receptors, Antigen, T-Cell / Receptors, Chimeric Antigen - metabolism / Sensitivity / Surface antigens / T cell receptors / Tumors / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation