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Cancer Discov. 2019 Apr;9(4):492-499. doi: 10.1158/2159-8290.CD-18-1314. Epub 2019 Jan 10.

Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers.

Author information

1
Division of Oncology, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
2
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
3
Division of Oncology, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. barrettd@email.chop.edu.

Abstract

Translational data on chimeric antigen receptor (CAR) T-cell trials indicate that the presence of naïve T cells in the premanufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T-cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naïve and stem central memory cells expanded well in vitro, but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful ex vivo stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the ex vivo manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type. SIGNIFICANCE: Cumulative chemotherapy cycles deplete naïve T cells in many pediatric cancer regimens, reducing expansion potential associated with successful adoptive cellular therapies. Naïve T-cell deficits can be seen at diagnosis as well, implying immune deficits that exist prior to chemotherapy, which may also affect the development of immune-based therapies.See related commentary by Leick and Maus, p. 466.This article is highlighted in the In This Issue feature, p. 453.

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