无症状期淋巴浆细胞淋巴瘤主动免疫治疗的 I 期研究：用编码抗原-趋化因子融合的 DNA 疫苗：研究方案。
Phase I study of an active immunotherapy for asymptomatic phase Lymphoplasmacytic lymphoma with DNA vaccines encoding antigen-chemokine fusion: study protocol.
机构信息
Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Stem Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
出版信息
BMC Cancer. 2018 Feb 13;18(1):187. doi: 10.1186/s12885-018-4094-2.
BACKGROUND
There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Lymphoplasmacytic lymphoma (LPL) is a low grade, incurable disease featuring an abnormal proliferation of Immunoglobulin (Ig)-producing malignant cells. Asymptomatic patients are currently managed by a "watchful waiting" approach, as available therapies provide no survival advantage if started before symptoms develop. Idiotypic determinants of a lymphoma surface Ig, formed by the interaction of the variable regions of heavy and light chains, can be used as a tumor-specific marker and effective vaccination using idiotypes was demonstrated in a positive controlled phase III trial.
METHODS
These variable region genes can be cloned and used as a DNA vaccine, a delivery system holding tremendous potential for streamlining vaccine production. To increase vaccination potency, we are targeting antigen-presenting cells (APCs) by fusing the antigen with a sequence encoding a chemokine (MIP-3α), which binds an endocytic surface receptor on APCs. Asymptomatic phase LPL is an excellent model to test our vaccine since patients have not received chemotherapeutics that interfere with innate immune function and have low tumor burden. We are evaluating the safety of this next-generation DNA vaccine in a first-in-human clinical trial currently enrolling asymptomatic LPL patients. To elucidate the mode of action of this vaccine, we will assess its ability to generate tumor-specific immune responses and examine changes in the immune profile of both the peripheral blood and bone marrow.
DISCUSSION
This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and inform development of other personalized approaches.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT01209871; registered on September 24, 2010.
背景
癌症疫苗再次受到关注。对免疫检查点阻断有反应的患者通常伴有大量浸润 T 细胞并表达高负荷的新生抗原的肿瘤，这表明免疫系统参与了这些药物的治疗效果；这一发现强烈支持使用癌症疫苗策略。淋巴浆细胞淋巴瘤（LPL）是一种低级别、无法治愈的疾病，其特征是免疫球蛋白（Ig）产生的恶性细胞异常增殖。目前，无症状患者采用“静观其变”的方法进行管理，因为如果在症状出现之前开始治疗，现有疗法并不能提供生存优势。淋巴瘤表面 Ig 的独特决定簇由重链和轻链的可变区相互作用形成，可用作肿瘤特异性标志物，使用独特型进行有效疫苗接种已在一项阳性对照 III 期试验中得到证实。
方法
这些可变区基因可被克隆并用作 DNA 疫苗，该疫苗的输送系统具有极大的简化疫苗生产的潜力。为了提高疫苗效力，我们通过将抗原与编码趋化因子（MIP-3α）的序列融合来靶向抗原呈递细胞（APC），该序列与 APC 上的内吞表面受体结合。无症状期 LPL 是测试我们疫苗的绝佳模型，因为患者尚未接受干扰固有免疫功能的化疗药物治疗，并且肿瘤负担较低。我们正在对无症状 LPL 患者进行的首次人体临床试验中评估这种下一代 DNA 疫苗的安全性。为了阐明这种疫苗的作用机制，我们将评估其生成肿瘤特异性免疫反应的能力，并检查外周血和骨髓中免疫谱的变化。
讨论
这种疫苗可能会改变当前无症状 LPL 患者的临床管理模式，并为开发其他个性化方法提供信息。
试验注册
ClinicalTrials.gov 标识符 NCT01209871；于 2010 年 9 月 24 日注册。
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