Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205.
Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the dendritic cell receptor DEC-205.
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DOI：
10.1126/scitranslmed.3008068
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发表时间：
2014-04-16
影响因子：
17.1
通讯作者：
Keler T
中科院分区：
文献类型：
--
作者：
Dhodapkar MV;Sznol M;Zhao B;Wang D;Carvajal RD;Keohan ML;Chuang E;Sanborn RE;Lutzky J;Powderly J;Kluger H;Tejwani S;Green J;Ramakrishna V;Crocker A;Vitale L;Yellin M;Davis T;Keler T
由于免疫检查点抑制剂的成功，基于免疫的癌症疗法引起了人们的极大兴趣。本研究的目的是利用树突状细胞（DC）通过有效摄取和呈递内吞物质启动T细胞免疫的能力来增强抗癌免疫。在DC活化剂存在下，使用受体特异性单克隆抗体（mAb）将肿瘤相关抗原递送至DC在临床前模型中激发了稳健的抗原特异性免疫应答。DEC-205（CD 205）是DC上表达的分子，其在抗原加工和呈递中的作用已被广泛研究。CDX-1401是一种疫苗，由DEC-205特异性人mAb与全长肿瘤抗原NY-ESO-1融合而成。该I期试验评估了递增剂量的CDX-1401与Toll样受体（TLR）激动剂瑞喹莫特（TLR 7/8）和Hiltonol（聚ICLC，TLR 3）在45名患有现有疗法难治性晚期恶性肿瘤的患者中的安全性、免疫原性和临床活性。在不同剂量水平和佐剂组合下，治疗诱导了确诊为NY-ESO-1表达肿瘤的患者对NY-ESO-1的体液和细胞免疫。未报告剂量限制性或3级毒性。13例患者病情稳定，中位持续时间为6.7个月（范围：2.4+至13.4个月）。2例患者肿瘤消退（靶病变缩小约20%）。在CDX-1401给药后3个月内接受免疫检查点抑制剂治疗的8名患者中，有6名患者的肿瘤客观消退。这项针对DC的蛋白疫苗的首次人体研究证明了其可行性，安全性和生物活性，并为包括免疫检查点阻断在内的联合免疫治疗策略提供了理论基础。
Immune-based therapies for cancer are generating substantial interest because of the success of immune checkpoint inhibitors. This study aimed to enhance anticancer immunity by exploiting the capacity of dendritic cells (DCs) to initiate T cell immunity by efficient uptake and presentation of endocytosed material. Delivery of tumor-associated antigens to DCs using receptor-specific monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits robust antigen-specific immune responses in preclinical models. DEC-205 (CD205), a molecule expressed on DCs, has been extensively studied for its role in antigen processing and presentation. CDX-1401 is a vaccine composed of a human mAb specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase 1 trial assessed the safety, immunogenicity, and clinical activity of escalating doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8) and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies refractory to available therapies. Treatment induced humoral and cellular immunity to NY-ESO-1 in patients with confirmed NY-ESO-1–expressing tumors across various dose levels and adjuvant combinations. No dose-limiting or grade 3 toxicities were reported. Thirteen patients experienced stabilization of disease, with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients had tumor regression (~20% shrinkage in target lesions). Six of eight patients who received immune-checkpoint inhibitors within 3 months after CDX-1401 administration had objective tumor regression. This first-in-human study of a protein vaccine targeting DCs demonstrates its feasibility, safety, and biological activity and provides rationale for combination immunotherapy strategies including immune checkpoint blockade.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.1083/jcb.151.3.673
发表时间：
2000-10-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mahnke K;Guo M;Lee S;Sepulveda H;Swain SL;Nussenzweig M;Steinman RM
通讯作者：
Steinman RM
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
15.3
作者：
Bonifaz, L;Bonnyay, D;Mahnke, K;Rivera, M;Nussenzweig, MC;Steinman, RM
通讯作者：
Steinman, RM
DOI：
10.1084/jem.194.6.769
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hawiger D;Inaba K;Dorsett Y;Guo M;Mahnke K;Rivera M;Ravetch JV;Steinman RM;Nussenzweig MC
通讯作者：
Nussenzweig MC