Novel Immunotherapy Options for Extranodal NK/T-Cell Lymphoma

Abstract

Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3ε 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-κB/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.

Extranodal NK/T-Cell Lymphomas: The Role of Natural Killer Cells and EBV in Lymphomagenesis

“…Another therapeutic approach is treatment with the SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) regimen [39]. Moreover, though treatment with conventional chemotherapy or radiation therapy does appear to increase survival, other therapies, some still investigative, have been explored, including hematopoietic cell transplantation, immune check-point blockade/PD-1, and CD30-and CD38-targeted antibody blockade [40]. Patients with localized ENKTL predominantly undergo combined modality therapy with concurrent radiation therapy and chemotherapy, whereas patients with disseminated disease are suggested to receive a combination chemotherapy regimen including L-asparaginase [40].…”

“…Moreover, though treatment with conventional chemotherapy or radiation therapy does appear to increase survival, other therapies, some still investigative, have been explored, including hematopoietic cell transplantation, immune check-point blockade/PD-1, and CD30-and CD38-targeted antibody blockade [40]. Patients with localized ENKTL predominantly undergo combined modality therapy with concurrent radiation therapy and chemotherapy, whereas patients with disseminated disease are suggested to receive a combination chemotherapy regimen including L-asparaginase [40]. Resistance to Adriamycin-and cyclophosphamide-based chemotherapy regimens are a well-described occurrence due to high expression of the multidrug resistance (MDR)1/ABCB 1 gene and its product, P-glycoprotein [40,41].…”

“…Patients with localized ENKTL predominantly undergo combined modality therapy with concurrent radiation therapy and chemotherapy, whereas patients with disseminated disease are suggested to receive a combination chemotherapy regimen including L-asparaginase [40]. Resistance to Adriamycin-and cyclophosphamide-based chemotherapy regimens are a well-described occurrence due to high expression of the multidrug resistance (MDR)1/ABCB 1 gene and its product, P-glycoprotein [40,41]. L-asparaginase therapy is a frequent addition to combined modality therapy given the high sensitivity to this agent thought to be secondary to lack of asparagine synthase activity by NK cells [40].…”

“…Resistance to Adriamycin-and cyclophosphamide-based chemotherapy regimens are a well-described occurrence due to high expression of the multidrug resistance (MDR)1/ABCB 1 gene and its product, P-glycoprotein [40,41]. L-asparaginase therapy is a frequent addition to combined modality therapy given the high sensitivity to this agent thought to be secondary to lack of asparagine synthase activity by NK cells [40]. Specific therapeutic strategies as they pertain to the various pathogenetic mechanisms in ENKTL are described next and summarized in Table 1.…”

Aberrant Expression of Prohibitin Is Related to Prognosis of Nasal Extranodal Natural Killer/T Cell Lymphoma, Nasal Type

“…There are only a few biomarkers for prognostic disease prediction. No standardized therapy has yet been established [3][4][5][6][7]. Hence, studying the molecular tumorigenesis of nasal ENKTCL and discovering an effective diagnostic marker and prognostic predictors as well as a novel therapeutic disease target is urgent.…”