Onea Alexandra S, Jazirehi Ali R
Department of Surgery, Division of Surgical Oncology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles (UCLA) Los Angeles, CA 90095.
Am J Cancer Res. 2016 Jan 15;6(2):403-24. eCollection 2016.
Recovery rates for B-cell Non-Hodgkin's Lymphoma (NHL) are up to 70% with current standard-of-care treatments including rituximab (chimeric anti-CD20 monoclonal antibody) in combination with chemotherapy (R-CHOP). However, patients who do not respond to first-line treatment or develop resistance have a very poor prognosis. This signifies the need for the development of an optimal treatment approach for relapsed/refractory B-NHL. Novel CD19- chimeric antigen receptor (CAR) T-cell redirected immunotherapy is an attractive option for this subset of patients. Anti-CD19 CAR T-cell therapy has already had remarkable efficacy in various leukemias as well as encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. In going forward with additional clinical trials, complementary treatments that may circumvent potential resistance mechanisms should be used alongside anti-CD19 T-cells in order to prevent relapse with resistant strains of disease. Some such supplementary tactics include conditioning with lymphodepletion agents, sensitizing with kinase inhibitors and Bcl-2 inhibitors, enhancing function with multispecific CAR T-cells and CD40 ligand-expressing CAR T-cells, and safeguarding with lymphoma stem cell-targeted treatments. A therapy regimen involving anti-CD19 CAR T-cells and one or more auxiliary treatments could dramatically improve prognoses for patients with relapsed/refractory B-cell NHL. This approach has the potential to revolutionize B-NHL salvage therapy in much the same way rituximab did for first-line treatments.
采用包括利妥昔单抗(嵌合抗CD20单克隆抗体)联合化疗(R-CHOP)在内的当前标准治疗方案,B细胞非霍奇金淋巴瘤(NHL)的缓解率高达70%。然而,对一线治疗无反应或产生耐药性的患者预后非常差。这表明需要为复发/难治性B-NHL开发一种最佳治疗方法。新型CD19嵌合抗原受体(CAR)T细胞重定向免疫疗法对这部分患者来说是一个有吸引力的选择。抗CD19 CAR T细胞疗法在各种白血病中已经取得了显著疗效,在复发/难治性NHL的I期临床试验中也取得了令人鼓舞的结果。在推进更多临床试验时,应将可能规避潜在耐药机制的辅助治疗与抗CD19 T细胞联合使用,以防止耐药菌株导致疾病复发。一些这样的辅助策略包括使用淋巴细胞清除剂进行预处理、用激酶抑制剂和Bcl-2抑制剂致敏、用多特异性CAR T细胞和表达CD40配体的CAR T细胞增强功能,以及用靶向淋巴瘤干细胞的治疗进行保护。一种涉及抗CD19 CAR T细胞和一种或多种辅助治疗的治疗方案可能会显著改善复发/难治性B细胞NHL患者的预后。这种方法有可能像利妥昔单抗用于一线治疗那样,彻底改变B-NHL挽救治疗。
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