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Cancers 2018, 10(6), 200; https://doi.org/10.3390/cancers10060200

Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors

Department of Surgery, Division of Surgical Oncology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
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Received: 11 April 2018 / Revised: 14 May 2018 / Accepted: 12 June 2018 / Published: 14 June 2018
(This article belongs to the Special Issue CAR-T Cell Therapy-Novel Approaches and Challenges)
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Abstract

Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8+ T cells (CTL)-resistance in NHL remain elusive. CD19CAR transduced primary human CTLs kill CD19+ human NHLs in a CD19- and caspase-dependent manner, mainly via the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway. To understand the dynamics of the development of resistance, we analyzed several anti-CD19CAR CTL-resistant NHL sublines (R-NHL) derived by serial exposure of sensitive parental lines to excessive numbers of anti-CD19CAR CTLs followed by a limiting dilution analysis. The R-NHLs retained surface CD19 expression and were efficiently recognized by CD19CAR CTLs. However, R-NHLs developed cross-resistance to CD19CAR transduced human primary CTLs and the Jurkat human T cell line, activated Jurkat, and lymphokine activated killer (LAK) cells, suggesting the acquisition of resistance is independent of CD19-loss and might be due to aberrant apoptotic machinery. We hypothesize that the R-NHL refractoriness to CD19CAR CTL killing could be partially rescued by small molecule sensitizers with apoptotic-gene regulatory effects. Chromatin modifiers and Celecoxib partially reversed the resistance of R-NHL cells to the cytotoxic effects of anti-CD19CAR CTLs and rhTRAIL. These in vitro results, though they require further examination, may provide a rational biological basis for combination treatment in the management of CD19CAR CTL-based therapy of NHL. View Full-Text
Keywords: chimeric antigen receptor; non-Hodgkin’s lymphoma; adoptive cell transfer; apoptosis; signal transduction; immunotherapy; resistance; B cell hematological malignancies; Celebrex; histone deacetylase inhibitor chimeric antigen receptor; non-Hodgkin’s lymphoma; adoptive cell transfer; apoptosis; signal transduction; immunotherapy; resistance; B cell hematological malignancies; Celebrex; histone deacetylase inhibitor
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Torres-Collado, A.X.; Jazirehi, A.R. Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors. Cancers 2018, 10, 200.

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