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.

Autor:	Gargett T; Translational Oncology Laboratory Centre for Cancer Biology, SA Pathology, and University of South Australia, Adelaide, South Australia. Electronic address: Tessa.Gargett@health.sa.gov.au., Yu W; Translational Oncology Laboratory Centre for Cancer Biology, SA Pathology, and University of South Australia, Adelaide, South Australia., Dotti G; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Feigin Center, Houston, Texas, USA; Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA., Yvon ES; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Feigin Center, Houston, Texas, USA; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Christo SN; Experimental Therapeutics Laboratory, Sansom Institute and Hanson Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia., Hayball JD; Experimental Therapeutics Laboratory, Sansom Institute and Hanson Institute, School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia; Robinson Research Institute, Discipline of Obstetrics and Gynecology, School of Medicine, University of Adelaide, Adelaide, South Australia; Discipline of Medicine, University of Adelaide, Adelaide, South Australia., Lewis ID; Discipline of Medicine, University of Adelaide, Adelaide, South Australia., Brenner MK; Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Feigin Center, Houston, Texas, USA., Brown MP; Translational Oncology Laboratory Centre for Cancer Biology, SA Pathology, and University of South Australia, Adelaide, South Australia; Discipline of Medicine, University of Adelaide, Adelaide, South Australia; Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, South Australia.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2016 Jun; Vol. 24 (6), pp. 1135-1149. Date of Electronic Publication: 2016 Mar 29.
DOI:	10.1038/mt.2016.63
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu