GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected from Activation-induced Cell Death by PD-1 Blockade

Tessa Gargett, Wenbo Yu, Gianpietro Dotti, Eric S. Yvon, Susan N. Christo, John D. Hayball, Ian D. Lewis, Malcolm K. Brenner, Michael P. Brown

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1 + tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients.

Original languageEnglish (US)
Pages (from-to)1135-1149
Number of pages15
JournalMolecular Therapy
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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