Fang KKL, Lee J, Khatri I, et al. Targeting T-Cell Malignancies Using Allogeneic Double-Negative CD4-CAR-T Cells. Journal for ImmunoTherapy of Cancer. 2023; (doi: 10.1136/jitc-2023-007277).
Research illustrates how pairing allogeneic double-negative T cells (DNTs) with chimeric antigen receptor (CAR) T cells may represent a viable adoptive cell therapy for relapsed/refractory T-cell malignancies. CAR treatment in this setting has lagged, partly due to the potential for fratricide or self-killing of CAR-T cells targeting T-lineage antigens. However, allogeneic DNTs have been deemed safe as an off-the-shelf adoptive cell therapy and are also good candidates for CAR transduction. Scientists compared the antitumor activity of DNTs alone and in conjunction with anti-CD4-CAR (CAR4). While allogeneic DNTs induced endogenous antitumor cytotoxicity against T-cell acute lymphoblastic leukemia (T-ALL), peripheral T-cell lymphoma (PTCL), and primary T-ALL blasts in vitro, high doses of DNTs were needed to achieve similar effect in vivo. Transducing DNTs with CAR4 only amplified their potency. CAR4-DNTs, which can be engineered without the risk of fratricide, demonstrated superior cytotoxicity against CD4+ T-ALL and PTCL both in vivo and in vitro, effectively slowing tumor progression and prolonging survival in xenograft models. The researchers believe their findings unlock the potential in using allogeneic DNTs and CAR4-DNTs to treat T-cell malignancies.