Liu Hongtao, Zha Yuanyuan, Choudhury Noura, Malnassy Gregory, Fulton Noreen, Green Margaret, Park Jae-Hyun, Nakamura Yusuke, Larson Richard A, Salazar Andres M, Odenike Olatoyosi, Gajewski Thomas F, Stock Wendy
1Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland, MC 2115, Chicago, IL 60637-1470 USA.
2HIM Facility at University of Chicago, University of Chicago Medical Center, Chicago, IL USA.
Exp Hematol Oncol. 2018 Jan 11;7:1. doi: 10.1186/s40164-018-0093-x. eCollection 2018.
The optimal strategy for vaccination to induce CD8 T cell responses against WT1 is not known.
A pilot randomized study in HLA-A02 patients to receive vaccination with WT1 in Montanide or in poly ICLC, a TLR3 agonist, to explore the novel immune adjuvant was conducted. Seven patients were randomized. Four patients received WT1 in Montanide, and three with WT1 in poly ICLC. Five patients were in morphologic remission and two had residual morphologic disease at the study entry.
All patients finished the induction phase without any major toxicity except mild transient local injection reaction. One patient on the Montanide arm developed aseptic ulceration at two vaccine sites which healed without antibiotics. Three of 4 patients on the Montanide arm had a decreased expression of WT1 after WT1 vaccination, and two of them demonstrated generation of WT1-specific cytotoxic CD8 T cell responses with biased TCR beta chain enrichment. In contrast, no obvious WT1-specific immune responses were detected in two patients on the poly ICLC arm, nor was there clonal enrichment by TCR alpha/beta sequencing; however, these patients did also have decreased WT1 expression and remained in remission several years after the initiation of treatment.
WT1 peptide vaccine with Montanide as an adjuvant induces detectable WT1-specific CD8 T cell responses with clonal TCR enrichment, which may be capable of controlling leukemia recurrence in the setting of minimal residual disease. Poly ICLC may induce anti-leukemic activity in the absence of detectable WT1 specific CD8 T cell responses. NCT01842139, 7/3/2012 retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT01842139.
诱导针对WT1的CD8 T细胞应答的最佳疫苗接种策略尚不清楚。
在HLA - A02患者中进行了一项初步随机研究，以探索新型免疫佐剂，让患者接种含Montanide的WT1疫苗或含Toll样受体3（TLR3）激动剂聚肌胞苷酸（poly ICLC）的WT1疫苗。7名患者被随机分组。4名患者接受含Montanide的WT1疫苗，3名患者接受含poly ICLC的WT1疫苗。5名患者处于形态学缓解期，2名患者在研究开始时存在形态学残留疾病。
所有患者均完成诱导期，除了轻度短暂局部注射反应外无任何重大毒性。Montanide组的1名患者在两个疫苗接种部位出现无菌性溃疡，无需使用抗生素即可愈合。Montanide组4名患者中有3名在接种WT1疫苗后WT1表达降低，其中2名表现出WT1特异性细胞毒性CD8 T细胞应答，伴有TCRβ链富集偏向。相比之下，poly ICLC组的2名患者未检测到明显的WT1特异性免疫应答，通过TCRα/β测序也未发现克隆富集；然而，这些患者的WT1表达也降低，并且在治疗开始后的几年中仍处于缓解状态。
以Montanide为佐剂的WT1肽疫苗可诱导可检测到且伴有克隆性TCR富集的WT1特异性CD8 T细胞应答，这可能能够在微小残留病情况下控制白血病复发。在未检测到WT1特异性CD8 T细胞应答的情况下，poly ICLC可能诱导抗白血病活性（本研究在2012年7月3日进行回顾性注册；NCT01842139；https://clinicaltrials.gov/ct2/show/NCT01842139） 。
