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Selection of new immunotherapy targets for NK/T cell lymphoma.

ABSTRACT: Extranodal NK/T cell lymphoma, nasal type, is a rare type of non-Hodgkin's lymphoma (NHL), and the aetiology is not fully understood. Although the clinical outcome of anthracycline-based chemotherapy was dismal because of multidrug resistance (MDR). Novel therapeutic strategies including L-asparaginase-containing regimens, radiotherapy, sequential chemotherapy and radiotherapy, and concurrent chemoradiotherapy (CCRT) have remarkably improved outcomes. However, the overall survival (OS) rate of advanced stage patients is not satisfactory compared with patients with non-advanced-stage disease. Immunotherapy is a promising treatment for ENKTCL. Indeed, it has been proven that targeted therapies such as anti-CD30 antibodies and naked anti-CD38 antibodies are effective. In addition to these therapies that target cell surface antigens, therapies targeting intracellular signalling pathways and the microenvironment are considerably beneficial. EBV-driven overexpression of latent membrane proteins [LMP1 and LMP2] activates the pro-proliferation NF-?B/MAPK signalling pathway and leads to high PD-L1 expression. Binding of PD-L1 to PD-1 expressing cytotoxic T cells causes apoptosis and inactivation of T lymphocytes, achieving immune escape. On the basis of this mechanism, a variety of small molecular inhibitors, such as anti-PD-1 antibodies, NF-?B inhibitors, EBV antigens, and LMP1 and LMP2 antigens, can be applied. Via another signalling pathway the JAK/STAT pathway, upregulation and activation and mutation of genes promotes proliferation and ENKTCL lymphomagenesis, and JAK inhibitors have thus been applied. This article reviews recent advances in ENKTCL immunotherapy as a promising treatment for this fatal disease.

SUBMITTER: Lv K

PROVIDER: S-EPMC7724344 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Selection of new immunotherapy targets for NK/T cell lymphoma.

Lv Kebing K Li Xin X Yu Hui H Chen Xinfeng X Zhang Mingzhi M Wu Xiaolong X

American journal of translational research 20201115 11

Extranodal NK/T cell lymphoma, nasal type, is a rare type of non-Hodgkin's lymphoma (NHL), and the aetiology is not fully understood. Although the clinical outcome of anthracycline-based chemotherapy was dismal because of multidrug resistance (MDR). Novel therapeutic strategies including L-asparaginase-containing regimens, radiotherapy, sequential chemotherapy and radiotherapy, and concurrent chemoradiotherapy (CCRT) have remarkably improved outcomes. However, the overall survival (OS) rate of a ...[more]

PMID: 33312349

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Project description:Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3? and CD56. While the disease is reported worldwide, there is a significant geographic variation with its highest incidence in East Asian countries possibly related to the frequent early childhood exposure of Epstein-Barr virus (EBV) and specific ethnic-genetical background, which contributes to the tumorigenesis. Historically, anthracycline-based chemotherapy such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) was used, but resulted in poor outcomes. This is due in part to intrinsic ENKTCL resistance to anthracycline caused by high expression levels of P-glycoprotein. The recent application of combined modality therapy with concurrent or sequential radiation therapy for early stage disease, along with non-anthracycline-based chemotherapy regimens consisting of drugs independent of P-glycoprotein have significantly improved clinical outcomes. Particularly, this neoplasm shows high sensitivity to l-asparaginase as NK-cells lack asparagine synthase activity. Even still, outcomes of patients with advanced stage disease or those with relapsed/recurrent disease are dismal with overall survival of generally a few months. Thus, novel therapies are needed for this population. Clinical activity of targeted antibodies along with antibody-drug conjugates, such as daratumumab (naked anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody conjugated with auristatin E), have been reported. Further promising data have been shown with checkpoint inhibitors as high levels of programmed death-ligand 1 expression are observed in ENKTCL due to EBV-driven overexpression of the latent membrane proteins [latent membrane protein 1 (LMP1) and LMP2] with activation of the NF-?B/MAPK pathways. Initial case series with programmed death 1 inhibitors showed an overall response rate of 100% in seven relapsed patients including five with a complete response (CR). Furthermore, cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 have shown encouraging results with durable CRs as either maintenance therapy after initial induction chemotherapy or in the relapsed/refractory setting. In this paper, we review this exciting field of novel immunotherapy options against ENKTCL that hopefully will change the treatment paradigm in this deadly disease.

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Selection of new immunotherapy targets for NK/T cell lymphoma.

Publications

Selection of new immunotherapy targets for NK/T cell lymphoma.

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