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Blood. 2019 May 10. pii: blood.2018885863. doi: 10.1182/blood.2018885863. [Epub ahead of print]

Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T cell efficacy.

Author information

1
Experimental Immunology, Academic University Medical Centre, Netherlands.
2
Academic University Medical Centre.
3
Microbiology, University of Pennsylvania, United States.
4
Amsterdam UMC, University of Amsterdam, Netherlands.
5
Hematology, Academic Medical Center, Netherlands.
6
Experimental Immunology, Academical Medical Center, Netherlands.
7
Internal Medicine, Albert Schweitzer hospital, Netherlands.
8
University Hospital Regensburg, Germany.
9
Academic Medical Center.
10
Vanderbilt University Medical Center, United States.
11
University of Pennsylvania School of Medicine, United States.
12
Division of Hematology/Oncology, University of Pennsylvania Medical Center, United States.
13
Pathology and Laboratory Medicine, University of Pennsylvania, United States.
14
Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, on behalf of HOVON Lunenburg Lymphoma Phase I/II Consortium Working Group, Netherlands a.p.kater@amc.uva.nl.
15
Academic Medical Center, Netherlands.

Abstract

In chronic lymphocytic leukemia (CLL), acquired T cell dysfunction impedes development of effective immunotherapeutic strategies, through yet unresolved mechanisms. We have previously shown that CD8+ T cells in CLL exhibit impaired activation and reduced glucose uptake after stimulation. CD8+ T cells in CLL patients are chronically exposed to leukemic B cells, which potentially impacts metabolic homeostasis resulting in aberrant metabolic reprogramming upon stimulation. Here we report that resting CD8+ T cells in CLL have reduced intracellular GLUT1 reserves, and have an altered mitochondrial metabolic profile as displayed by increased mitochondrial respiration, membrane potential, and levels of reactive oxygen species. This coincided with decreased levels of PGC-1α, and in line with that, CLL-derived CD8+ T cells showed impaired mitochondrial biogenesis upon stimulation. In search of a therapeutic correlate of these findings, we analyzed mitochondrial biogenesis in CD19-directed chimeric antigen receptor (CAR) CD8+ T cells prior to infusion in CLL patients (enrolled in NCT01747486 and NCT01029366, https://clinicaltrials.gov). Interestingly, in cases with a subsequent complete response, the infused CD8+ CAR T cells had increased mitochondrial mass compared to non-responders, which positively correlated with the expansion and persistence of CAR T cells. Our findings demonstrate that GLUT1 reserves and mitochondrial fitness of CD8+ T cells are impaired in CLL. Therefore, boosting mitochondrial biogenesis in CAR T cells might improve the efficacy of CAR T cell therapy and other emerging cellular immunotherapies. Please note: the May 10, 2019 Blood First Edition publication of this paper included an incorrect version of the abstract. The correct abstract appears above.

PMID:
31076448
DOI:
10.1182/blood.2018885863

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