Development and Characterization of an HCMV Multi-Antigen Therapeutic Vaccine for Glioblastoma Using the UNITE Platform.
Development and Characterization of an HCMV Multi-Antigen Therapeutic Vaccine for Glioblastoma Using the UNITE Platform.
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DOI：
10.3389/fonc.2022.850546
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发表时间：
2022
影响因子：
4.7
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中科院分区：
文献类型：
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多形性胶质母细胞瘤（GBM）是一种侵袭性形式的脑癌，中位生存期为15个月，尽管标准治疗取得了进展，但仍保持不变。GBM细胞表达人巨细胞病毒（HCMV）蛋白，为靶向治疗提供了独特的机会。我们利用我们的UNITE（UNiplant Intracellular Targeted Expression）平台开发了一种编码HCMV蛋白pp 65、gB和IE-1的多抗原DNA疫苗（ITI-1001）。UNITE平台涉及溶酶体靶向技术，将溶酶体相关膜蛋白1（LAMP 1）与靶抗原融合。我们证明了MHC-I和MHC-II的抗原呈递增加的证据，除了强烈的体液应答外，还提供了强大的抗原特异性CD 4和CD 8 T细胞应答。使用同基因原位GBM小鼠模型，用ITI-1001疫苗进行治疗性处理导致荷瘤小鼠的约56%存活。肿瘤微环境的调查显示显着的CD 4浸润以及增强的Th 1和细胞毒性CD 8 T细胞活化。ITI-1001疫苗接种后调节性T细胞也上调。此外，肿瘤负荷与活化的干扰素（IFN）γ+ CD 4 T细胞呈负相关，重申了CD 4活化在ITI-1001疗效和鉴别治疗应答者和无应答者中的重要性。对这两组的进一步表征显示，与无应答者相比，应答者中CD 3+、CD 4+和CD 8 + T细胞的浸润较高。因此，我们表明，使用ITI-1001-UNITE平台接种HCMV抗原可产生强烈的细胞和体液免疫应答，引发显著的抗肿瘤活性，从而提高GBM小鼠模型的存活率。
Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with a median survival of 15 months that has remained unchanged despite advances in the standard of care. GBM cells express human cytomegalovirus (HCMV) proteins, providing a unique opportunity for targeted therapy. We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins pp65, gB, and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated membrane protein 1 (LAMP1) with target ntigens. We demonstrate evidence of increased antigen presentation by both MHC-I and -II, delivering a robust antigen-specific CD4 and CD8 T-cell response in addition to a strong humoral response. Using a syngeneic orthotopic GBM mouse model, therapeutic treatment with the ITI-1001 vaccine resulted in ~56% survival of tumor-bearing mice. Investigation of the tumor microenvironment showed significant CD4 infiltration as well as enhanced Th1 and cytotoxic CD8 T activation. Regulatory T cells were also upregulated after ITI-1001 vaccination. In addition, tumor burden negatively correlated with activated interferon (IFN)γ+ CD4 T cells, reiterating the importance of CD4 activation in ITI-1001 efficacy and in identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+, and CD8+ T cells in responders compared to non-responders. Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant antitumor activity, leading to enhanced survival in a mouse model of GBM.
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158.5
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Stupp, R;Mason, WP;Ryan, G
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Ryan, G
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Mitchell DA;Batich KA;Gunn MD;Huang MN;Sanchez-Perez L;Nair SK;Congdon KL;Reap EA;Archer GE;Desjardins A;Friedman AH;Friedman HS;Herndon JE 2nd;Coan A;McLendon RE;Reardon DA;Vredenburgh JJ;Bigner DD;Sampson JH
通讯作者：
Sampson JH