LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition.
LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition.
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DOI：
10.3389/fimmu.2023.1253568
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发表时间：
2023
影响因子：
7.3
通讯作者：
Heiland, Teri
中科院分区：
文献类型：
--
作者：
Buchta Rosean, Claire;Leyder, Erica C.;Hamilton, Jeneice;Carter, Joseph J.;Galloway, Denise A.;Koelle, David M.;Nghiem, Paul;Heiland, Teri
默克尔细胞癌(MCC)是一种罕见的高度侵袭性神经内分泌皮肤癌，大多数病例与默克尔细胞多瘤病毒(MCPyV)感染有关。MCPyV整合到宿主基因组中，导致癌蛋白在感染细胞中表达，包括截短形式的病毒大T抗原(LT)。这些癌蛋白是治疗性癌症疫苗的诱人靶点。我们设计了一种癌症疫苗，可以促进对MCPyV-LT有效的、抗原特异性的CD4T细胞反应。为了在体内激活抗原特异性的CD4T细胞，我们利用了我们的核酸平台Unite™(通用细胞内靶向表达)，它将肿瘤相关抗原与溶酶体相关膜蛋白1融合在一起。这种溶酶体靶向技术可以增强抗原呈递能力和强大的抗原特异性T细胞反应。LTS220A编码MCPyV-LT的突变形式，使其致癌活性降低，并被引入联合™平台。用LTS220A联合™DNA疫苗(ITI3000)免疫B16F10黑色素瘤细胞可诱导抗原特异性的CD4T细胞反应和强烈的体液反应，足以延缓肿瘤的生长。这一效应依赖于CD4T细胞产生干扰素γ的能力。此外，ITI-3000诱导了良好的肿瘤微环境(TME)，包括Th1型细胞因子，并显著增加了CD4和CD8T细胞以及NK和NKT细胞的数量。此外，ITI-3000与α-PD-1免疫检查点抑制剂协同作用，进一步减缓肿瘤生长并提高存活率。这些发现有力地表明，在临床前研究中，使用联合™平台的ITI-3000 DNA疫苗可以增强CD4T细胞对MCPyV-LT的反应，从而产生显著的抗肿瘤免疫反应。这些数据支持启动一项人类首个(FIH)阶段1开放标签研究，以评估ITI-3000在多瘤病毒阳性MCC(NCT05422781)患者中的安全性、耐受性和免疫原性。
Most cases of Merkel cell carcinoma (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of oncoproteins including a truncated form of the viral large T antigen (LT) in infected cells. These oncoproteins are an attractive target for a therapeutic cancer vaccine. We designed a cancer vaccine that promotes potent, antigen-specific CD4 T cell responses to MCPyV-LT. To activate antigen-specific CD4 T cells in vivo, we utilized our nucleic acid platform, UNITE™ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and potent antigen-specific T cell responses. LTS220A, encoding a mutated form of MCPyV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE™ platform. Vaccination with LTS220A-UNITE™ DNA vaccine (ITI-3000) induced antigen-specific CD4 T cell responses and a strong humoral response that were sufficient to delay tumor growth of a B16F10 melanoma line expressing LTS220A. This effect was dependent on the CD4 T cells’ ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including Th1-type cytokines and significantly enhanced numbers of CD4 and CD8 T cells as well as NK and NKT cells. Additionally, ITI-3000 synergized with an α-PD-1 immune checkpoint inhibitor to further slow tumor growth and enhance survival. These findings strongly suggest that in pre-clinical studies, DNA vaccination with ITI-3000, using the UNITE™ platform, enhances CD4 T cell responses to MCPyV-LT that result in significant anti-tumor immune responses. These data support the initiation of a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC (NCT05422781).
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影响因子：
10.9
作者：
通讯作者：
--
影响因子：
4.7
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.1200061
发表时间：
2013-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Green AM;Difazio R;Flynn JL
通讯作者：
Flynn JL
影响因子：
6.2
作者：
Fields, Ryan C.;Busam, Klaus J.;Coit, Daniel G.
通讯作者：
Coit, Daniel G.
影响因子：
7.5
作者：
Gomez, Bianca P.;Wang, Connie;Hung, Chien-Fu
通讯作者：
Hung, Chien-Fu