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.
Highlights
The standard treatment option for non-Hodgkin’s lymphoma (NHL) patients includes the chemotherapy regimen CHOP, which only induces a complete response (CR) in 40% of elderly patients, has an overall survival rate of only35% [1], and is very toxic [2]
Our results further suggest that the unresponsiveness of resistant NHL sublines (R-NHL) to anti-CD19 chimeric antigen receptor (CAR) CTL- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated killing is amenable to various small molecule sensitizing agents which have regulatory effects on apoptotic gene products; resistance could partially be rescued by suberoylanilide hydroxamic acid (SAHA), LBH589, and celecoxib
CTLs and the Jurkat T cell line (Figure 2D,E). These results show that CD19CAR CTL-resistant NHLs develop cross-resistance to the cytotoxic effects of CD19CAR-Jurkat cells, suggesting the use of a and lymphokine activated killer (LAK) cells
Summary
The standard treatment option for non-Hodgkin’s lymphoma (NHL) patients includes the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which only induces a complete response (CR) in 40% of elderly patients, has an overall survival rate of only. 35% [1], and is very toxic [2]. The most effective strategy to increase CHOP efficacy is to combine it with rituximab [R-CHOP] [3]. Rituximab is an effective single-agent in indolent lymphoma patients [4]. A 76% CR rate has been reported in patients treated with R-CHOP compared to a 63% CR rate in Cancers 2018, 10, 200; doi:10.3390/cancers10060200 www.mdpi.com/journal/cancers. Cancers 2018, 10, 200 patients treated with CHOP alone [5]. R-CHOP treatment has shown promise in younger patients. Two groups of 18 to 60-year-olds were given either CHOP or R-CHOP; the R-CHOP group had a 79%
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