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

Abstract

<div>Abstract<p>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 <i>in vitro</i>, but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful <i>ex vivo</i> stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the <i>ex vivo</i> manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type.</p>Significance:<p>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.</p><p><i>See related commentary by Leick and Maus, p. 466</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 453</i></p></div>