Targeting CD28 on T lineage malignancies with chimeric antigen receptor T cells
Abstract
Currently, no immunotherapy is approved for T cell acute lymphoblastic leukemia (T‑ALL). High initial response rates to CD7‑directed chimeric antigen receptor (CAR) T cells are limited by profound T cell aplasia and CD7‑negative immune escape, underscoring the need for alternative targets. Here, we show that CD28 is overexpressed on T‑ALL blasts from children and adolescents compared with lymphoid progenitors from healthy donors and is uniformly upregulated in nodal T-follicular helper cell lymphomas (nTFHL-AI, nTFHL-F). Using CRISPR/Cas9-mediated CD28 knockout to prevent fratricide, we generate highly functional anti‑CD28 CAR T cells with selective cytotoxicity against CD28⁺ T‑ALL. Anti‑CD28 CAR T cells match anti‑CD7 CAR T cells in vitro and in vivo, but cause markedly less lymphodepletion, largely sparing CD8 T cells and NK cells while preferentially depleting CD4 T cells, particularly TH2 and TH17 subsets. These findings establish CD28 as an actionable target for CAR T cell therapy of T cell malignancies.
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BibTeX
@article{willier2026targeting,
title = {{Targeting CD28 on T lineage malignancies with chimeric antigen receptor T cells}},
author = {Semjon Willier and Julian Färber and Theodora Ispyrlidou and Jonas Wilhelm and Eileen Mayer and Dana Stenger and Jannika Seiferling and Annika E. Brien and Sophia Nikolaides and Paulina Ferrada-Ernst and Jens Dominik Maile and Binje Vick and Andreas Carr and Franziska Blaeschke and Dirk H. Busch and Peter Spieler and Thomas Nerreter and Ramin Lotfi and Martina Rudelius and Theresa Kaeuferle and Christoph Klein and Gabriele Escherich and Irmela Jeremias and Ulrike Burk and Tobias Feuchtinger},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78312-3},
url = {https://www.nature.com/articles/s41467-026-78312-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting CD28 on T lineage malignancies with chimeric antigen receptor T cells
AU - Semjon Willier
AU - Julian Färber
AU - Theodora Ispyrlidou
AU - Jonas Wilhelm
AU - Eileen Mayer
AU - Dana Stenger
AU - Jannika Seiferling
AU - Annika E. Brien
AU - Sophia Nikolaides
AU - Paulina Ferrada-Ernst
AU - Jens Dominik Maile
AU - Binje Vick
AU - Andreas Carr
AU - Franziska Blaeschke
AU - Dirk H. Busch
AU - Peter Spieler
AU - Thomas Nerreter
AU - Ramin Lotfi
AU - Martina Rudelius
AU - Theresa Kaeuferle
AU - Christoph Klein
AU - Gabriele Escherich
AU - Irmela Jeremias
AU - Ulrike Burk
AU - Tobias Feuchtinger
PY - 2026
DA - 2026/10/08
JO - Nature Communications
DO - 10.1038/s41467-026-78312-3
UR - https://www.nature.com/articles/s41467-026-78312-3
AB - Currently, no immunotherapy is approved for T cell acute lymphoblastic leukemia (T‑ALL). High initial response rates to CD7‑directed chimeric antigen receptor (CAR) T cells are limited by profound T cell aplasia and CD7‑negative immune escape, underscoring the need for alternative targets. Here, we show that CD28 is overexpressed on T‑ALL blasts from children and adolescents compared with lymphoid progenitors from healthy donors and is uniformly upregulated in nodal T-follicular helper cell lymphomas (nTFHL-AI, nTFHL-F). Using CRISPR/Cas9-mediated CD28 knockout to prevent fratricide, we generate highly functional anti‑CD28 CAR T cells with selective cytotoxicity against CD28⁺ T‑ALL. Anti‑CD28 CAR T cells match anti‑CD7 CAR T cells in vitro and in vivo, but cause markedly less lymphodepletion, largely sparing CD8 T cells and NK cells while preferentially depleting CD4 T cells, particularly TH2 and TH17 subsets. These findings establish CD28 as an actionable target for CAR T cell therapy of T cell malignancies.
SN - 2041-1723
ER -