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Efficacy of B7-H3-Redirected BiTE and CAR-T Immunotherapies Against Extranodal Nasal Natural Killer/T Cell Lymphoma.

ABSTRACT: Extranodal nasal natural killer (NK)/T cell lymphoma (ENKTCL) is a rare but highly aggressive subtype of non-Hodgkin lymphoma (NHL). Nevertheless, despite extensive research, the estimated 5-year overall survival of affected patients remains low. Therefore, new treatment strategies are needed urgently. Recent advances in immunotherapy have the potential to broaden the applications of chimeric antigen receptor-modified T (CAR-T) cells and the bispecific T-cell engaging (BiTE) antibody. Here, we screened a panel of biomarkers including the B7-H3, CD70, TIM-3, VISTA, ICAM-1, and PD-1 in NKTCL cell lines. As a result, we found for the first time that B7-H3 was highly and homogeneously expressed in these cells. Consequently, we constructed a novel anti-B7-H3/CD3 BiTE antibody and B7-H3-redirected CAR-T cells, and evaluated their efficacy against NKTCL cel lines both in vitro and in vivo. Notably, we found that both anti-B7-H3/CD3 BiTE and B7-H3-redirected CAR-T cells effectively targeted and killed NKTCL cells in vitro, and suppressed the growth of NKTCL tumors in NSG mouse models. Thus, B7-H3 might be a promising therapeutic target for treating patients with NKTCL tumors.

SUBMITTER: Zheng M

PROVIDER: S-EPMC7160598 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Efficacy of B7-H3-Redirected BiTE and CAR-T Immunotherapies Against Extranodal Nasal Natural Killer/T Cell Lymphoma.

Zheng Meijun M Yu Lingyu L Hu Juanjuan J Zhang Zongliang Z Wang Haiyang H Lu Dan D Tang Xin X Huang Jianhan J Zhong Kunhong K Wang Zeng Z Li Yisong Y Guo Gang G Liu Shixi S Tong Aiping A Yang Hui H

Translational oncology 20200413 5

Extranodal nasal natural killer (NK)/T cell lymphoma (ENKTCL) is a rare but highly aggressive subtype of non-Hodgkin lymphoma (NHL). Nevertheless, despite extensive research, the estimated 5-year overall survival of affected patients remains low. Therefore, new treatment strategies are needed urgently. Recent advances in immunotherapy have the potential to broaden the applications of chimeric antigen receptor-modified T (CAR-T) cells and the bispecific T-cell engaging (BiTE) antibody. Here, we s ...[more]

PMID: 32298986

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Project description:Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NNKTL) has very unique epidemiological, etiologic, histologic, and clinical characteristics. It is commonly observed in Eastern Asia, but quite rare in the United States and Europe. The progressive necrotic lesions mainly in the nasal cavity, poor prognosis caused by rapid local progression with distant metastases, and angiocentric and polymorphous lymphoreticular infiltrates are the main clinical and histologic features. Phenotypic and genotypic studies revealed that the lymphoma is originated from either NK- or ?? T-cell, both of which express CD56. In 1990, the authors first reported the presence of Epstein-Barr virus (EBV)-DNA and EBV-oncogenic proteins, and EBV has now been recognized to play an etiological role in NNKTL. in vitro studies revealed that a wide variety of cytokines, chemokines, and micro RNAs, which may be produced by EBV-oncogenic proteins in the lymphoma cells, play important roles for tumor progression in NNKTL, and could be therapeutic targets. In addition, it was revealed that the interaction between NNKTL cells and immune cells such as monocytes and macrophages in NNKTL tissues contribute to lymphoma progression. For diagnosis, monitoring the clinical course and predicting prognosis, the measurements of EBV-DNAs and EBV-micro RNAs in sera are very useful. For treatment with early stage, novel concomitant chemoradiotherapy such as DeVIC regimen with local radiotherapy and MPVIC-P regimen using intra-arterial infusion developed with concomitant radiotherapy and the prognosis became noticeably better. However, the prognosis of patients with advanced stage was still poor. Establishment of novel treatments such as the usage of immune checkpoint inhibitor or peptide vaccine with molecular targeting therapy will be necessary. This review addresses recent advances in the molecular understanding of NNKTL to establish novel treatments, in addition to the epidemiologic, clinical, pathological, and EBV features.

Project description:BackgroundExtranodal natural killer/T-cell lymphoma, nasal type is a syndrome of middle face destruction with an association to Epstein-Barr virus. Fungi have been recovered from the diseased tissue now and then but were often seen as a lymphoma-associated secondary infection. However, there are ENKTL-NT cases with the recoveries of fungi and complete recovery with antifungal therapy, which are quite similar to rhino-orbital-cerebral mycosis (ROCM) that often confuses the physicians.MethodsWe searched Medline for English-language manuscripts limited to "human" and "case reports," "letters," "reviews," and "clinical conferences" from 1966 to 2022. We used MeSH terms "lymphoma, extranodal nk-t-cell" [MeSH Terms] or "lethal midline granuloma" [MeSH Terms], in combination with MeSH terms "microbiology" [subheading] or "microbiology" [all fields] or "fungi" [all fields] or "fungi" [MeSH Terms] for ENKTL-NT with infections. We used MeSH terms "Mycoses" in combination with "Nose" [Mesh] OR "Orbital Diseases" [Mesh] for rhino-orbital-cerebral fungal infections.ResultsWe appraised 149 included articles and extracted references related to ENKTL-NT and/or ROCM. Themes and subcategories were subsequently derived. Our findings revealed that ROCM and ENKTL-NT are characterized by progressive and destructive ulcers in the midline face or rhino-orbital structures. ROCM is mainly caused by fungi in the order of Mucorales, and ENKTL-NT is usually associated with Epstein-Barr virus and sometimes fungi. Radiologically, both are characterized by non-specific features of sinusitis, soft tissue infection, and necrosis. Pathologically, ROCM and ENKTL-NT share the same characteristics of inflammation, necrosis, and granuloma. ROCM is characterized by the detection of fungi in tissue, while ENKTL-NT is typically positive for NK/T-cell markers and cytotoxic granule-associated proteins, proliferation, and vascular damage of angioinvasion, which could be incited by Mucor irregularis and Rhizopus arrhizus in patients and mice.ConclusionENKTL-NT and ROCM share many similarities in clinical presentations, radiology, and histopathology, and might have the same etiology. This may explain why the two diseases are tangled together in the reported cases, and suggests the role that the fungi may play in the development of these ENKTL-NT/ROCM diseases. The reason why ENKTL-NT and ROCM are sometimes confused is that the main pathogens of ROCM, Mucor irregularis and Rhizopus arrhizus, are the fungal causative agents of ENKTL-NT.

Project description:PurposeTo investigate the clinicopathological features, survival and prognostic factors of primary intestinal extranodal natural killer/T-cell lymphoma, nasal type (PI-ENKTCL).MethodsClinical and histological characteristics of PI-ENKTCL cases were retrospectively evaluated. Immunohistochemical phenotype and status of Epstein-Barr virus (EBV) and T-cell receptor (TCR) gene rearrangement were examined. The overall survival and prognostic parameters were also analyzed.ResultsFifty-five (2.7%) cases with PI-ENKTCL were identified out of 2017 archived ENKTCL cases, with a median age of 39 years and a male to female ratio of 2.1:1. The most common symptom was abdominal pain (90.9%), accompanied frequently with fever and less commonly with intestinal perforation or B symptoms. Small intestine (50.9%) was the most common site to be involved. 47.3% and 36.4% cases presented with stage I and II diseases, respectively. Histologically, most cases displayed characteristic morphologic changes of ENKTCL. Cytoplasmic CD3, TIA-1 and CD56 expression was found in 100%, 94.5% and 89.1% of cases, respectively. In situ hybridization detection for EBV demonstrated positive results in all cases. Monoclonal TCR gene rearrangement was found in 52.9% of tested cases. Chemotherapy with a DICE or L-asparaginase/peg-asparginase-containing regimen was most often employed. Both advanced tumor stage and B symptoms were independent inferior prognostic factors (p = 0.001 and p = 0.010). Noticeably, 6 cases demonstrated a CD4-positive phenotype. These cases featured a relatively older median age (58 years), predominance of small/medium-sized neoplastic cells, a higher rate of TCR rearrangement and slightly favorable outcome.ConclusionWe reported by far the largest series of PI-ENKTCL, and demonstrated its heterogeneity, aggressive clinical behavior and unsatisfying response to the current therapeutic strategies. Those CD4-positive cases might represent a unique subtype of PI-ENKTCL or distinct entity. Further investigations are required for the better understanding and management of this unusual disease.

Dataset Information

Efficacy of B7-H3-Redirected BiTE and CAR-T Immunotherapies Against Extranodal Nasal Natural Killer/T Cell Lymphoma.

Publications

Efficacy of B7-H3-Redirected BiTE and CAR-T Immunotherapies Against Extranodal Nasal Natural Killer/T Cell Lymphoma.

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