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Manufacturing Chimeric Antigen Receptor (CAR) T Cells for Adoptive Immunotherapy
Published on: December 17, 2019
mRNA-dendritic cell antigen vaccine potentiates CD38 CAR-T Cell therapy for relapsed/refractory acute myeloid
Yu Lu1,2, Xin Cai3, Yanhui Li3
1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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.
