Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
J Immunother Cancer. 2019 Jan 31;7(1):25. doi: 10.1186/s40425-019-0500-9.
The capacity of cytomegalovirus (CMV) to elicit long-lasting strong T cell responses, and the ability to engineer the genome of this DNA virus positions CMV-based vaccine vectors highly suitable as a cancer vaccine platform. Defined immune thresholds for tumor protection and the factors affecting such thresholds have not well been investigated in cancer immunotherapy. We here determined using CMV as a vaccine platform whether critical thresholds of vaccine-specific T cell responses can be established that relate to tumor protection, and which factors control such thresholds.
We generated CMV-based vaccine vectors expressing the E7 epitope and tested these in preclinical models of HPV16-induced cancer. Vaccination was applied via different doses and routes (intraperitoneal (IP), subcutaneous (SC) and intranasal (IN)). The magnitude, kinetics and phenotype of the circulating tumor-specific CD8 T cell response were determined. Mice were subsequently challenged with tumor cells, and the tumor protection was monitored.
Immunization with CMV-based vaccines via the IP or SC route eliciting vaccine-induced CD8 T cell responses of > 0.3% of the total circulating CD8 T cell population fully protects mice against lethal tumor challenge. However, low dose inoculations via the IP or SC route or IN vaccination elicited vaccine-induced CD8 T cell responses that did not reach protective thresholds for tumor protection. In addition, whereas weak pre-existing immunity did not alter the protective thresholds of the vaccine-specific T cell response following subsequent immunization with CMV-based vaccine vectors, strong pre-existing immunity inhibited the development of vaccine-induced T cells and their control on tumor progression.
This study highlight the effectiveness of CMV-based vaccine vectors, and shows that demarcated thresholds of vaccine-specific T cells could be defined that correlate to tumor protection. Together, these results may hold importance for cancer vaccine development to achieve high efficacy in vaccine recipients.
巨细胞病毒（CMV）能够引发持久而强烈的 T 细胞反应，并且能够对这种 DNA 病毒进行基因组工程改造，这使得 CMV 为基础的疫苗载体非常适合作为癌症疫苗平台。在癌症免疫治疗中，尚未很好地研究肿瘤保护的定义性免疫阈值以及影响这些阈值的因素。我们在这里使用 CMV 作为疫苗平台，确定是否可以建立与肿瘤保护相关的疫苗特异性 T 细胞反应的临界阈值，以及哪些因素控制这些阈值。
我们生成了表达 E7 表位的 CMV 为基础的疫苗载体，并在 HPV16 诱导的癌症的临床前模型中测试了这些载体。通过不同剂量和途径（腹腔内（IP）、皮下（SC）和鼻内（IN））进行疫苗接种。测定循环肿瘤特异性 CD8 T 细胞反应的幅度、动力学和表型。随后，用肿瘤细胞对小鼠进行攻击，并监测肿瘤保护情况。
通过 IP 或 SC 途径接种 CMV 为基础的疫苗，引起循环 CD8 T 细胞群体中超过 0.3%的疫苗诱导 CD8 T 细胞反应，可完全保护小鼠免受致命的肿瘤攻击。然而，通过 IP 或 SC 途径进行低剂量接种或 IN 接种，引发的疫苗诱导 CD8 T 细胞反应未达到肿瘤保护的保护阈值。此外，尽管弱的预先存在的免疫不会改变随后用 CMV 为基础的疫苗载体进行免疫接种后疫苗特异性 T 细胞反应的保护阈值，但强烈的预先存在的免疫抑制了疫苗诱导的 T 细胞的发育及其对肿瘤进展的控制。
本研究强调了 CMV 为基础的疫苗载体的有效性，并表明可以定义与肿瘤保护相关的疫苗特异性 T 细胞的明确阈值。这些结果对于癌症疫苗的开发具有重要意义，以实现疫苗接种者的高疗效。
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