Статья

IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype

Darya Alizadeh1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaRobyn A. Wong1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaXin Yang1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaDongrui Wang1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaJoseph R. Pecoraro1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaCheng-Fu Kuo1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaBrenda Aguilar1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaYue Qi3Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute and Medical Center, Duarte, CaliforniaDavid K. Ann2Irell and Manella Graduate School of Biological Sciences, Duarte, CaliforniaRenate Starr1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaRyan Urak2Irell and Manella Graduate School of Biological Sciences, Duarte, CaliforniaXiuli Wang1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaStephen J. Forman1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, CaliforniaChristine E. Brown1Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope, Duarte, California

2019en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1158/2326-6066.cir-18-0466

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar