Treatment with targeted vesicular stomatitis virus generates therapeutic multifunctional anti-tumor memory CD4 T cells.

A generally applicable, easy-to-use method of focusing a patient's immune system to eradicate or prevent cancer has been elusive. We are attempting to develop a targeted virus to accomplish these aims. We previously created a recombinant replicating Vesicular Stomatitis Virus that preferentially infected Her2/neu expressing breast cancer cells and showed therapeutic efficacy in an implanted Balb/c mouse tumor model. The current work shows that this therapy generated therapeutic anti-tumor CD4 T-cells against multiple tumor antigens. CD4 T-cells transferred directly from cured donor mice could eradicate established tumors in host mice. T-cells were transferred directly from donor mice and were not stimulated ex vivo. Both tumors that expressed Her2/neu and those that did not were cured by transferred T-cells. Analysis of cytokines secreted by anti-tumor memory CD4 T-cells displayed a multifunctional pattern with high levels of IFNγ, IL-4 and IL-17. Anti-tumor memory CD4 T-cells traveled to the mesenteric lymph nodes and were activated there. Treatment with targeted rrVSV is a potent immune adjuvant that generates therapeutic, multifunctional anti-tumor memory CD4 T-cells that recognize multiple tumor antigens. Immunity elicited by viral therapy is independent of host major histocompatibility complex (MHC) or knowledge of tumor antigens. Virus-induced tumor immunity could have great benefit in the prevention and treatment of tumor metastases.

一种普遍适用且易于使用的、能使患者免疫系统聚焦于根除或预防癌症的方法一直难以找到。我们正试图开发一种靶向病毒来实现这些目标。我们先前创造了一种重组复制型水疱性口炎病毒，它优先感染表达Her2/neu的乳腺癌细胞，并在植入的Balb/c小鼠肿瘤模型中显示出治疗效果。目前的研究表明，这种疗法产生了针对多种肿瘤抗原的治疗性抗肿瘤CD4 T细胞。直接从治愈的供体小鼠转移的CD4 T细胞能够根除宿主小鼠体内已形成的肿瘤。T细胞是直接从供体小鼠转移的，没有在体外进行刺激。表达Her2/neu的肿瘤和不表达的肿瘤都能被转移的T细胞治愈。对抗肿瘤记忆CD4 T细胞分泌的细胞因子的分析显示出一种多功能模式，具有高水平的干扰素γ、白细胞介素 - 4和白细胞介素 - 17。抗肿瘤记忆CD4 T细胞迁移到肠系膜淋巴结并在那里被激活。靶向重组水疱性口炎病毒（rrVSV）治疗是一种有效的免疫佐剂，它能产生具有治疗作用的、多功能的抗肿瘤记忆CD4 T细胞，这些细胞能识别多种肿瘤抗原。病毒疗法引发的免疫不依赖于宿主主要组织相容性复合体（MHC）或对肿瘤抗原的了解。病毒诱导的肿瘤免疫在肿瘤转移的预防和治疗中可能具有很大益处。