Development of an anti-HTLV-1 vaccine for the treatment of Adult T-cell Leukemia/Lymphoma
Development of an anti-HTLV-1 vaccine for the treatment of Adult T-cell Leukemia/Lymphoma
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开发治疗成人 T 细胞白血病/淋巴瘤的抗 HTLV-1 疫苗
DOI：
10.1182/blood.v126.23.4010.4010
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发表时间：
2015
期刊：
影响因子：
20.3
通讯作者：
C. Bauche
中科院分区：
文献类型：
--
作者：
D. Revaud;A. Bejanariu;Lamya Loussaief;E. Sarry;A. Zemmar;Guillaume Deplaine;T. Coman;J. Rossignol;O. Hermine;C. Bauche
人类T细胞嗜酸性病毒1（HTLV-1）是成人T细胞白血病/淋巴瘤（ATL）的病原体。ATL患者的治疗选择非常有限，在侵袭性疾病中，常规化疗和骨髓移植的存活率仅为10%至30%。尽管一些临床试验就新疗法的疗效给出了令人鼓舞的结果，但其中大多数是终身的，积极的，未能对长期生存产生重大影响。因此，ATL患者需要新的治疗方法来限制复发和副作用。ATL患者特异性HTLV-1细胞免疫反应明显受损，这可能有助于疾病的发生和进展。因此，刺激针对HTLV-1的免疫应答可以是治疗ATL的适当治疗选择。THERAVECTYS开发了一种抗HTLV-1疫苗，基于其慢病毒载体技术，在肌肉注射后诱导广泛，强烈和持久的细胞免疫应答。THERAVECTYS是第一家启动基于慢病毒载体技术的THV 01疫苗治疗HIV临床试验的公司（NCT 02054286）。获得的结果证明了THV 01在人体中的安全性和免疫原性，以及多功能和多特异性CD 4和CD 8 T细胞应答。抗HTLV-1慢病毒载体THV 02疫苗编码源自Tax、HBZ、p12 I和p30 II蛋白的独特多肽，其参与HTLV-1致病性并已知被HTLV-1感染患者的免疫系统识别。我们的临床前结果已经证明，THV 02可以在C57 Bl/6 j和BalbC小鼠以及Sprague道利大鼠中诱导细胞免疫应答，如IFN-γ Elispot所证明的。在致癌性和监管GLP临床前毒性研究期间，已经证明了THV 02疫苗的安全性。生物分布和散毒研究表明，注射后THV 02的扩散非常有限，其快速清除且在体液中不扩散。由于没有相关的ATL免疫活性动物模型可用于评估THV 02的抗肿瘤作用，THERAVECYTS正在使用ATL患者的血液样本开发离体疗效模型。简言之，通过从PBMC分离CD 14阳性细胞并在IL 4和GM-CSF存在下分化来纯化来自ATL患者血液的单核细胞衍生的树突细胞（MDDC）。然后用编码抗HTLV-1抗原的慢病毒载体转导MDDC，并在与自体CD 8 + T细胞共培养以刺激细胞免疫应答之前，在TNF α和PGE 2暴露时诱导成熟。然后，将刺激的CD 8+与自体CD 4 + CD 25 + ATL细胞共培养，并通过流式细胞术监测细胞毒活性。初步结果表明，来自慢性ATL患者的MDDC可以被有效地转导并成熟，如其表面上的CD 40、CD 86、HLA-DR、-A、-B和C标记所证明的。此外，我们观察到了对CD 8+的特异性刺激，即在CD 8+与表达抗HTLV-1抗原的MDDC的共培养物的培养基中IFNg、TNF α、IL 2和穿孔素的增加。这些数据非常令人鼓舞，并首次证明了开发使用ATL血液样品评估疫苗效力的离体模型的可行性。该模型的开发正在进行中，使用了代表该疾病不同亚型的几个ATL供体，并将在会议上介绍。关于THV 02的适应症和安全性特征，THERAVECTYS计划在2015年第4季度开始临床试验。本试验是一项开放标签、剂量递增的I/II期研究，旨在评估THV 02疫苗接种作为ATL患者治疗的安全性和免疫原性（细胞免疫应答）。将考虑所有ATL亚型，因为THV 02疫苗可与常规ATL治疗联合使用。此外，由于THV 02抗原含有衍生自Tax的肽以及HBZ、p12 I和p30 II病毒蛋白，因此无论Tax表达的状态如何，都可以治疗所有ATL患者。作为次要目的，将评估体液免疫应答和临床效果。将研究HTLV-1感染细胞的HTLV-1 RNA表达和克隆性作为探索性目标。最后，在美国进行扩展队列研究之前，将在法国、英国、法属圭亚那、马提尼克岛和瓜德罗普入组最多16例患者。没有相关的利益冲突需要申报。
Human T-cell Lymphotrophic Virus 1 (HTLV-1) is the etiologic agent of Adult-T cell Leukemia/Lymphoma (ATL). Therapeutic options for ATL patients are very limited and in aggressive forms of the disease survival rate is only 10% to 30% with conventional chemotherapies and bone marrow transplantation. Although some clinical trials gave encouraging results regarding the efficacy of new treatments, most of them are lifelong, aggressive and failed to achieve a significant impact on long-term survival. Consequently, new treatments for ATL patients are needed to limit relapses and side effects. Specific HTLV-1 cellular immune response is dramatically impaired in ATL patients, which could favor the initiation and the progression of the disease. Hence, stimulating immune responses against HTLV-1 can be an appropriate therapeutic option to treat ATL. THERAVECTYS has developed an anti-HTLV-1 vaccine, based on its lentiviral vector technology inducing a broad, intense and long-lasting cellular immune response after intra-muscular injection. THERAVECTYS was the first company to have launched a clinical trial based on lentiviral vectors technology with the THV01 vaccine for the treatment of HIV (NCT02054286). Results obtained demonstrated both safety and immunogenicity of THV01 in human, with polyfunctional and multi-specific CD4 and CD8 T-cells responses. The anti-HTLV-1 lentiviral vector, THV02 vaccine, encodes for a unique polypeptide derived from Tax, HBZ, p12I and p30II proteins, involved in HTLV-1 pathogenicity and known to be recognized by the immune system of HTLV-1 infected patients. Our preclinical results have demonstrated that THV02 can induce a cellular immune response in C57Bl/6j and BalbC mice and in Sprague Dawley rats, as demonstrated by IFN-γ Elispot. Safety of the THV02 vaccine has been demonstrated during carcinogenicity and regulatory GLP preclinical toxicity studies. Biodistribution and shedding studies demonstrated the very limited diffusion of THV02 after injection, its fast clearance and a non-dissemination in body fluids. As no relevant ATL immunocompetent animal model is available to assess the anti-tumor effect of THV02, THERAVECYTS is developing an ex-vivo efficacy model using blood samples of ATL patients. Briefly, monocyte-derived dendritic cells (MDDC) from blood of ATL patients are purified by isolation of CD14 positive cells from PBMC and differentiation in the presence of IL4 and GM-CSF. MDDC are then transduced with lentiviral vectors encoding for the anti-HTLV-1 antigen and maturation is induced upon TNFa and PGE2 exposure before the co-culture with autologous CD8+ T-cells for stimulation of the cellular immune response. Then, stimulated CD8+ are co-cultured with autologous CD4+ CD25+ ATL cells and the cytotoxic activity is monitored by flow cytometry. Preliminary results demonstrated that MDDC from a chronic ATL patient can be efficiently transduced and matured as attested by the CD40, CD86, HLA-DR, -A, -B and C markers on their surface. In addition, we have observed a specific stimulation of the CD8+, ie an increase of IFNg, TNFa, IL2 and perforin in the media of the co-culture of CD8+ with MDDC expressing anti-HTLV-1 antigen. These data are very encouraging and demonstrate for the first time the feasibility to develop an ex vivo model to assess vaccine efficacy using ATL blood sample. The development of this model is ongoing using several ATL donors representing the different subtypes of the disease and will be presented at the meeting. Regarding the indication and the safety profile of THV02, THERAVECTYS plans to begin a clinical trial in Q4 2015. This assay will be an open-label, dose escalation phase I/II study to assess the safety and the immunogenicity (cellular immune response) of the THV02 vaccination as a treatment of ATL patients. All ATL subtypes will be considered since THV02 vaccine can be combined with conventional ATL treatments. In addition, as the THV02 antigen contains peptides derived from Tax but also HBZ, p12I and p30II viral proteins, all ATL patients can be treated whatever the status of Tax expression. As secondary objectives, both humoral immune response and clinical effect will be assessed. HTLV-1 RNA expression and clonality of HTLV-1 infected cells will be studied as exploratory objectives. Finally, up to 16 patients will be enrolled in France, UK, French Guiana, Martinique and Guadeloupe before doing a phase of extension cohort in US. Disclosures No relevant conflicts of interest to declare.