IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype

D Alizadeh, RA Wong, X Yang, D Wang… - Cancer immunology …, 2019 - AACR
D Alizadeh, RA Wong, X Yang, D Wang, JR Pecoraro, CF Kuo, B Aguilar, Y Qi, DK Ann…
Cancer immunology research, 2019AACR
Improvements in the quality and fitness of chimeric antigen receptor (CAR)-engineered T
cells, through CAR design or manufacturing optimizations, could enhance the therapeutic
potential of CAR-T cells. One parameter influencing the effectiveness of CAR-T cell therapy
is the differentiation status of the final product: CAR-T cells that are less-differentiated and
less exhausted are more therapeutically effective. In the current study, we demonstrate that
CAR-T cells expanded in IL15 (CAR-T/IL15) preserve a less-differentiated stem cell memory …
Abstract
Improvements in the quality and fitness of chimeric antigen receptor (CAR)-engineered T cells, through CAR design or manufacturing optimizations, could enhance the therapeutic potential of CAR-T cells. One parameter influencing the effectiveness of CAR-T cell therapy is the differentiation status of the final product: CAR-T cells that are less-differentiated and less exhausted are more therapeutically effective. In the current study, we demonstrate that CAR-T cells expanded in IL15 (CAR-T/IL15) preserve a less-differentiated stem cell memory (Tscm) phenotype, defined by expression of CD62L+CD45RA+ CCR7+, as compared with cells cultured in IL2 (CAR-T/IL2). CAR-T/IL15 cells exhibited reduced expression of exhaustion markers, higher antiapoptotic properties, and increased proliferative capacity upon antigen challenge. Furthermore, CAR-T/IL15 cells exhibited decreased mTORC1 activity, reduced expression of glycolytic enzymes and improved mitochondrial fitness. CAR-T/IL2 cells cultured in rapamycin (mTORC1 inhibitor) shared phenotypic features with CAR-T/IL15 cells, suggesting that IL15-mediated reduction of mTORC1 activity is responsible for preserving the Tscm phenotype. CAR-T/IL15 cells promoted superior antitumor responses in vivo in comparison with CAR-T/IL2 cells. Inclusion of cytokines IL7 and/or IL21 in addition to IL15 reduced the beneficial effects of IL15 on CAR-T phenotype and antitumor potency. Our findings show that IL15 preserves the CAR-T cell Tscm phenotype and improves their metabolic fitness, which results in superior in vivo antitumor activity, thus opening an avenue that may improve future adoptive T-cell therapies.
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