mRNA-dendritic cell antigen vaccine potentiates CD38 CAR-T Cell therapy for relapsed/refractory acute myeloid leukemia.

BACKGROUND

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising strategy for management of relapsed/refractory acute myeloid leukemia (R/R AML). Safety and preliminary activity of CD38-targeted CAR-T cells in R/R AML were demonstrated in our prior study; however, relapse with CD38-positive blasts persisted, which was partly associated with insufficient effector function and persistence of CAR-T cells. Given that CAR-T cell hypofunction is promoted by inadequate antigen stimulation, a lipid nanoparticle-delivered CD38 mRNA vaccine was developed to enhance CD38 CAR-T cell efficacy via exogenous antigen presentation.

METHODS

The CD38 mRNA-LNP vaccine was prepared, and its biodistribution profile and tolerability were evaluated in BALB/c mice. The capacity of this vaccine to augment the activation, proliferative capacity, memory subset distribution, cytokine secretion, and antileukemic efficacy of CD38-knockout CAR-T cells (Ko-38CAR) was systematically assessed in vitro. Transcriptomic and ATAC-seq analyses were employed to delineate the underlying molecular regulatory networks. In vivo antitumor efficacy was validated in a THP-1 AML xenograft model.

RESULTS

The vaccine (107 nm, 91.67% encapsulation) exhibited splenic APC tropism and induced pulsatile CD38 expression that peaked at 24 h and declined markedly by 48 h. Activation, proliferation, cytotoxicity, and memory differentiation of Ko-38CAR cells were dose-dependently augmented by the vaccine. Furthermore, the vaccine promoted the activation of polyamine metabolism (e.g., ODC1), JAK-STAT and MAPK signaling pathways, upregulated BCL2 expression, and enhanced chromatin accessibility of cell cycle and effector genes in CAR-T cells. In vivo, vaccine administration promoted CAR-T cell expansion, improved tumor control, and prolonged survival.

CONCLUSIONS

CD38 mRNA-LNP vaccine can efficiently deliver pulsatile CD38 antigen to splenic APCs and augment the proliferation, effector function, and persistence of CD38 CAR-T cells through dual CAR and costimulatory signaling, which may represent a promising strategy to overcome CAR-T cell dysfunction in R/R AML.