The study investigated anti-CD7 CAR T cells for treating T-cell acute lymphoblastic leukemia (T-ALL), highlighting their advanced potential but also noting significant drawbacks such as severe T cell aplasia and the risk of CD7-negative relapse. Researchers screened 25 candidate antigens in pediatric and adolescent patients, identifying CD28 as a prevalent marker, present on 81.5% of blasts but only 3.7% on healthy lymphoid progenitors. Notably, CD28 was found on the effector T cells.
By employing CRISPR-Cas9 to knock out CD28 in donor T cells with a high efficiency of 94%, the edited cells maintained normal expansion but lost cytotoxicity towards CD80-overexpressing targets. Two receptor designs displayed comparable effectiveness to anti-CD7 CAR T cells in preclinical models, with the anti-CD28 cells showing a reduced impact on CD8 T cells and NK cells while depleting CD4 cell subsets, particularly Th2 and Th17.
Additionally, both constructs demonstrated efficacy against multiple myeloma lines. One promising construct utilized the superagonist scFv of TGN1412 but did not trigger bystander activation in co-cultures with wild-type T cells, suggesting that CD28-positive cells were effectively eliminated before triggering any adverse effects.
The research was led by Semjon Willier and Tobias Feuchtinger, and the findings were published in Nature Communications.
