Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma

Abstract

Advanced natural killer/T cell lymphoma (NKTL) has demonstrated poor prognosis with currently available therapies. Here, we report the efficacy of anti-programmed death 1 (PD-1) antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced NKTL. Nine patients underwent six 21-day cycles of anti-PD-1 antibody (day 1), pegaspargase 2000 U/m2 (day 1), gemcitabine 1 g/m2 (days 1 and 8) and oxaliplatin 130 mg/m2 (day 1), followed by anti-PD-1 antibody maintenance every 3 weeks. Programmed death-ligand 1 (PD-L1) expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing (NGS) analysis. Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) and computed tomography or magnetic resonance imaging. Eight patients exhibited significant responses, comprising of seven complete remissions and one partial remission (overall response rate: 88.9%). After a median follow-up of 10.6 months, 6/9 patients (66.7%) remained in complete remission. The most common grade 3/4 adverse events were anemia (33.3%), neutropenia (33.3%), and thrombocytopenia (33.3%); all of which were manageable and resolved. Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression (5/6, 83.3%). NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy. Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D, TET2, and BCORL1 might indicate a poor response to immunochemotherapy. In conclusion, the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL. PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.

Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance

“…Overexpression of ABCG2 has also been reported in head and neck, lung, brain, osteosarcoma, melanoma, and prostate CSCs [ 127 ]. Some studies reported overexpression of ABC transporters also has been identified in side population (SP) of CSCs cells that indicate a stemness phenotype and can be used as candidates for the identification of CSCs [ 15 , 125 , 128 ]. High ABCB1 expression has been observed in SP cells in a number of cancer cell lines compared to other cells [ 123 ].…”

“…For example, upregulation of ABCB1 and also ABCG2 were found in SP cells in pancreatic cancer cell line [ 129 ]. In fact, ABCG2 is known as a marker of CSCs and plays an important role in drug resistance and ABCB1 has also been found in over 50% of resistant tumors [ 19 , 128 ].…”

“…Wnt signaling plays a role in transforming dormant CSCs into active CSCs by increasing cell cycle procedure via β-catenin, enhancing the expression of downstream cyclin D1 and MYC. Additionally, MYC increases the expression of the polycomb repressor complex 1 component Bmi-1 and affects the connection of E2F with cyclin E [ 128 ]. Based on various investigations, the Notch pathway’s activation is specifically involved in developing cell survival, self-renewal, metastasis and inhibiting apoptosis in CSCs [ 135 , 136 ].…”

“…By an activated mTOR signaling pathway, low folate (LF) stress reprograms metabolic signals show the potential to induce the metastasis and tumorigenicity of lung cancer stem-like cells. As a result, drugs, vaccines, antibodies, and CAR-T cells that target these pathways can be used to develop novel targeted therapy [ 128 ]. MELK (a serine/threonine kinase) is expressed in several cancer stem cells populations [ 139 ], which implicated in the survival and drug resistance and tumor recurrence in CSCs.…”

“…Abnormal Hh signaling pathway activation with different aspects of tumorigenesis causes the development and progression of different types of tumors [ 216 ]. Hh signaling also regulates the genes expression of maintaining phenotype and function of CSCs such as Oct4, Sox2 and Bmi1, ALDH1, Wnt2, CCND1, CD44, Twist1, Snail, C-MET, C-MYC and Jagged 1 [ 128 , 217 ]. Nanog is a key transcription factor for maintaining stemness, self-renewal and differentiation of embryonic stem cell and CSCs, also directly control by Hh signaling pathway [ 218 ].…”